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Sample records for purinergic signalling cascade

  1. Purinergic Signalling: Therapeutic Developments

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    Geoffrey Burnstock

    2017-09-01

    Full Text Available Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

  2. Purinergic signalling and diabetes

    DEFF Research Database (Denmark)

    Burnstock, Geoffrey; Novak, Ivana

    2013-01-01

    , and common and divergent roles of receptors for nucleotides and nucleosides in different organ systems will be given. This integrated picture will aid our understanding of the challenges of the potential and currently used drugs targeted to specific organ/cells or disorders associated with diabetes.......The pancreas is an organ with a central role in nutrient breakdown, nutrient sensing and release of hormones regulating whole body nutrient homeostasis. In diabetes mellitus, the balance is broken-cells can be starving in the midst of plenty. There are indications that the incidence of diabetes...... type 1 and 2, and possibly pancreatogenic diabetes, is rising globally. Events leading to insulin secretion and action are complex, but there is emerging evidence that intracellular nucleotides and nucleotides are not only important as intracellular energy molecules but also as extracellular signalling...

  3. Purinergic signalling in epithelial ion transport

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    Novak, Ivana

    2011-01-01

    , including ion transport. In this review, I will first introduce the main components of the extracellular ATP signalling, which have become known as the purinergic signalling system. With more than 50 components or processes, just at cell membranes, it ranks as one of the most versatile signalling systems......-regulators of secretion. On an organ level, both receptor types can exert physiological functions and together with other partners in the purinergic signalling, integrated models for epithelial secretion and absorption are emerging....

  4. Purinergic signalling in the musculoskeletal system.

    Science.gov (United States)

    Burnstock, Geoffrey; Arnett, Timothy R; Orriss, Isabel R

    2013-12-01

    It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone-destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors.

  5. Purinergic signaling during Porphyromonas gingivalis infection

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    Cássio Luiz Coutinho Almeida-da-Silva

    2016-08-01

    Full Text Available Despite recent advances unraveling mechanisms of host–pathogen interactions in innate immunity, the participation of purinergic signaling in infection-driven inflammation remains an emerging research field with many unanswered questions. As one of the most-studied oral pathogens, Porphyromonas gingivalis is considered as a keystone pathogen with a central role in development of periodontal disease. This pathogen needs to evade immune-mediated defense mechanisms and tolerate inflammation in order to survive in the host. In this review, we summarize evidence showing that purinergic signaling modulates P. gingivalis survival and cellular immune responses, and discuss the role played by inflammasome activation and cell death during P. gingivalis infection. Keywords: Purinergic receptors, Innate immunity, Porphyromonas gingivalis, P2X7 receptor, Oral microbes, Inflammasome

  6. Purinergic Signalling in Inflammatory Renal Disease

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    Nishkantha eArulkumaran

    2013-07-01

    Full Text Available Extracellular purines have a role in renal physiology and adaption to inflammation. However, inflammatory renal disease may be mediated by extracellular purines, resulting in renal injury. The role of purinergic signalling is dependent on the concentrations of extracellular purines. Low basal levels of purines are important in normal homeostasis and growth. Concentrations of extracellular purines are significantly elevated during inflammation and mediate either an adaptive role or propagate local inflammation. Adenosine signalling mediates alterations in regional renal blood flow by regulation of the renal microcirculation, tubulo-glomerular feedback, and tubular transport of sodium and water. Increased extracellular ATP and renal P2 receptor-mediated inflammation are associated with various renal diseases, including hypertension, diabetic nephropathy, and glomerulonephritis. Experimental data suggests P2 receptor deficiency or receptor antagonism is associated with amelioration of antibody-mediated nephritis, suggesting a pathogenic (rather than adaptive role of purinergic signalling. We discuss the role of extracellular nucleotides in adaptation to ischaemic renal injury and in the pathogenesis of inflammatory renal disease.

  7. Purinergic signaling pathways in endocrine system.

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    Bjelobaba, Ivana; Janjic, Marija M; Stojilkovic, Stanko S

    2015-09-01

    Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. Published by Elsevier B.V.

  8. Purinergic Signaling Pathways in Endocrine System

    Science.gov (United States)

    Bjelobaba, Ivana; Janjic, Marija M.; Stojilkovic, Stanko S.

    2015-01-01

    Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5′-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5′-triphosphate hydrolysis to adenosine-5′-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. PMID:25960051

  9. Purinergic signalling: from discovery to current developments.

    Science.gov (United States)

    Burnstock, Geoffrey

    2014-01-01

    This lecture is about the history of the purinergic signalling concept. It begins with reference to the paper by Paton & Vane published in 1963, which identified non-cholinergic relaxation in response to vagal nerve stimulation in several species, although they suggested that it might be due to sympathetic adrenergic nerves in the vagal nerve trunk. Using the sucrose gap technique for simultaneous mechanical and electrical recordings in smooth muscle (developed while in Feldberg's department in the National Institute for Medical Research) of the guinea-pig taenia coli preparation (learned when working in Edith Bülbring's smooth muscle laboratory in Oxford Pharmacology), we showed that the hyperpolarizations recorded in the presence of antagonists to the classical autonomic neurotransmitters, acetylcholine and noradrenaline, were inhibitory junction potentials in response to non-adrenergic, non-cholinergic neurotransmission, mediated by intrinsic enteric nerves controlled by vagal and sacral parasympathetic nerves. We then showed that ATP satisfied the criteria needed to identify a neurotransmitter released by these nerves. Subsequently, it was shown that ATP is a cotransmitter in all nerves in the peripheral and central nervous systems. The receptors for purines and pyrimidines were cloned and characterized in the early 1990 s, and immunostaining showed that most non-neuronal cells as well as nerve cells expressed these receptors. The physiology and pathophysiology of purinergic signalling is discussed.

  10. The role of purinergic signalling in exocrine pancreas

    DEFF Research Database (Denmark)

    Haanes, Kristian Agmund

    ATP is a fundamentally important molecule in intracellular processes, especially recognised as the molecular source of energy. ATP is however also released as a signal from most cell types, and extracellular signalling by ATP goes under the common name purinergic signalling and it includes releas...

  11. Purinergic signalling in the pancreas in health and disease

    DEFF Research Database (Denmark)

    Burnstock, G; Novak, I

    2012-01-01

    Pancreatic cells contain specialised stores for ATP. Purinergic receptors (P2 and P1) and ecto-nucleotidases are expressed in both endocrine and exocrine calls, as well as in stromal cells. The pancreas, especially the endocrine cells, were an early target for the actions of ATP. After the histor......Pancreatic cells contain specialised stores for ATP. Purinergic receptors (P2 and P1) and ecto-nucleotidases are expressed in both endocrine and exocrine calls, as well as in stromal cells. The pancreas, especially the endocrine cells, were an early target for the actions of ATP. After...... the historical perspective of purinergic signalling in the pancreas, the focus of this review will be the physiological functions of purinergic signalling in the regulation of both endocrine and exocrine pancreas. Next, we will consider possible interaction between purinergic signalling and other regulatory...... systems and their relation to nutrient homeostasis and cell survival. The pancreas is an organ exhibiting several serious diseases - cystic fibrosis, pancreatitis, pancreatic cancer and diabetes - and some are associated with changes in life-style and are increasing in incidence. There is upcoming...

  12. Trichomoniasis immunity and the involvement of the purinergic signaling

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    Camila Braz Menezes

    2016-08-01

    Full Text Available Innate and adaptive immunity play a significant role in trichomoniasis, the most common non-viral sexually transmitted disease worldwide. In the urogenital tract, innate immunity is accomplished by a defense physical barrier constituted by epithelial cells, mucus, and acidic pH. During infection, immune cells, antimicrobial peptides, cytokines, chemokines, and adaptive immunity evolve in the reproductive tract, and a proinflammatory response is generated to eliminate the invading extracellular pathogen Trichomonas vaginalis. However, the parasite has developed complex evolutionary mechanisms to evade the host immune response through cysteine proteases, phenotypic variation, and molecular mimicry. The purinergic system constitutes a signaling cellular net where nucleotides and nucleosides, enzymes, purinoceptors and transporters are involved in almost all cells and tissues signaling pathways, especially in central and autonomic nervous systems, endocrine, respiratory, cardiac, reproductive, and immune systems, during physiological as well as pathological processes. The involvement of the purinergic system in T. vaginalis biology and infection has been demonstrated and this review highlights the participation of this signaling pathway in the parasite immune evasion strategies. Keywords: Trichomoniasis, Innate immune response, Adaptive immune response, Evasion mechanisms, Purinergic signaling

  13. Involvement of purinergic signaling on nitric oxide production by neutrophils stimulated with Trichomonas vaginalis.

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    Frasson, Amanda Piccoli; De Carli, Geraldo Attilio; Bonan, Carla Denise; Tasca, Tiana

    2012-03-01

    Trichomonas vaginalis is a parasite from the human urogenital tract that causes trichomonosis, the most prevalent non-viral sexually transmitted disease. The neutrophil infiltration has been considered to be primarily responsible for cytological changes observed at infection site, and the chemoattractants can play an important role in this leukocytic recruitment. Nitric oxide (NO) is one of the most widespread mediator compounds, and it is implicated in modulation of immunological mechanisms. Extracellular nucleotides and nucleosides are signaling molecules involved in several processes, including immune responses and control of leukocyte trafficking. Ectonucleoside triphosphate diphosphohydrolase members, ecto-5'-nucleotidase, and adenosine deaminase (ectoADA) have been characterized in T. vaginalis. Herein, we investigated the effects of purinergic system on NO production by neutrophils stimulated with T. vaginalis. The trophozoites were able to induce a high NO synthesis by neutrophils through iNOS pathway. The extracellular nucleotides ATP, ADP, and ATPγS (a non-hydrolyzable ATP analog) showed no significant change in NO secretion. In contrast, adenosine and its degradation product, inosine, promoted a low production of the compound. The immunosuppressive effect of adenosine upon NO release by neutrophils occurred due to adenosine A(2A) receptor activation. The ecto-5'-nucleotidase activity displayed by T. vaginalis was shown to be important in adenosine generation, indicating the efficiency of purinergic cascade. Our data suggest the influence of purinergic signaling, specifically adenosinergic system, on NO production by neutrophils in T. vaginalis infection, contributing to the immunological aspects of disease.

  14. Intrarenal purinergic signaling in the control of renal tubular transport

    DEFF Research Database (Denmark)

    Prætorius, Helle; Leipziger, Jens Georg

    2010-01-01

    Renal tubular epithelial cells receive hormonal input that regulates volume and electrolyte homeostasis. In addition, numerous intrarenal, local signaling agonists have appeared on the stage of renal physiology. One such system is that of intrarenal purinergic signaling. This system involves all......-reaching advances indicate that ATP is often used as a local transmitter for classical sensory transduction. This transmission apparently also applies to sensory functions in the kidney. Locally released ATP is involved in sensing of renal tubular flow or in detecting the distal tubular load of NaCl at the macula...

  15. Purinergic Signaling in Mast Cell Degranulation and Asthma

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    Zhan-Guo Gao

    2017-12-01

    Full Text Available Mast cells are responsible for the majority of allergic conditions. It was originally thought that almost all allergic events were mediated directly only via the high-affinity immunoglobulin E receptors. However, recent evidence showed that many other receptors, such as G protein-coupled receptors and ligand-gated ion channels, are also directly involved in mast cell degranulation, the release of inflammatory mediators such as histamine, serine proteases, leukotrienes, heparin, and serotonin. These mediators are responsible for the symptoms in allergic conditions such as allergic asthma. In recent years, it has been realized that purinergic signaling, induced via the activation of G protein-coupled adenosine receptors and P2Y nucleotide receptors, as well as by ATP-gated P2X receptors, plays a significant role in mast cell degranulation. Both adenosine and ATP can induce degranulation and bronchoconstriction on their own and synergistically with allergens. All three classes of receptors, adenosine, P2X and P2Y are involved in tracheal mucus secretion. This review will summarize the currently available knowledge on the role of purinergic signaling in mast cell degranulation and its most relevant disease, asthma.

  16. Purinergic signaling to terminate TLR responses in macrophages

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    Kajal eHamidzadeh

    2016-03-01

    Full Text Available Macrophages undergo profound physiological alterations when they encounter pathogen associated molecular patterns (PAMPs. These alterations can result in the elaboration of cytokines and mediators that promote immune responses and contribute to the clearance of pathogens. These innate immune responses by myeloid cells are transient. The termination of these secretory responses is not due to the dilution of stimuli, but rather to the active down-regulation of innate responses induced by the very PAMPs that initiated them. Here we describe a purinergic autoregulatory program whereby TLR-stimulated macrophages control their activation state. In this program, TLR stimulated macrophages undergo metabolic alterations that result in the production of ATP and its release through membrane pannexin channels. This purine nucleotide is rapidly hydrolyzed to adenosine by ectoenzymes on the macrophage surface, CD39 and CD73. Adenosine then signals through the P1 class of seven transmembrane receptors to induce a regulatory state that is characterized by the down-regulation of inflammatory cytokines and the production of anti-inflammatory cytokines and growth factors. This purinergic autoregulatory system mitigates the collateral damage that would be caused by the prolonged activation of macrophages, and rather allows the macrophage to maintain homeostasis. The transient activation of macrophages can be prolonged by treating macrophages with IFN-γ. IFN-γ treated macrophages become less sensitive to the regulatory effects of adenosine, allowing them to sustain macrophage activation for the duration of an adaptive immune response.

  17. Regulation of adult neural progenitor cell functions by purinergic signaling.

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    Tang, Yong; Illes, Peter

    2017-02-01

    Extracellular purines are signaling molecules in the neurogenic niches of the brain and spinal cord, where they activate cell surface purinoceptors at embryonic neural stem cells (NSCs) and adult neural progenitor cells (NPCs). Although mRNA and protein are expressed at NSCs/NPCs for almost all subtypes of the nucleotide-sensitive P2X/P2Y, and the nucleoside-sensitive adenosine receptors, only a few of those have acquired functional significance. ATP is sequentially degraded by ecto-nucleotidases to ADP, AMP, and adenosine with agonistic properties for distinct receptor-classes. Nucleotides/nucleosides facilitate or inhibit NSC/NPC proliferation, migration and differentiation. The most ubiquitous effect of all agonists (especially of ATP and ADP) appears to be the facilitation of cell proliferation, usually through P2Y1Rs and sometimes through P2X7Rs. However, usually P2X7R activation causes necrosis/apoptosis of NPCs. Differentiation can be initiated by P2Y2R-activation or P2X7R-blockade. A key element in the transduction mechanism of either receptor is the increase of the intracellular free Ca 2+ concentration, which may arise due to its release from intracellular storage sites (G protein-coupling; P2Y) or due to its passage through the receptor-channel itself from the extracellular space (ATP-gated ion channel; P2X). Further research is needed to clarify how purinergic signaling controls NSC/NPC fate and how the balance between the quiescent and activated states is established with fine and dynamic regulation. GLIA 2017;65:213-230. © 2016 Wiley Periodicals, Inc.

  18. Purinergic signaling modulates the cerebral inflammatory response in experimentally infected fish with Streptococcus agalactiae: an attempt to improve the immune response.

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    Souza, Carine F; Baldissera, Matheus D; Bottari, Nathiele B; Moreira, Karen L S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; Santos, Roberto C V; Baldisserotto, Bernardo

    2018-06-01

    Appropriate control of the immune response is a critical determinant of fish health, and the purinergic cascade has an important role in the immune and inflammatory responses. This cascade regulates the levels of adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate and adenosine (Ado), molecules involved in physiological or pathological events as inflammatory and anti-inflammatory mediators. Thus, the aim of this study was to evaluate whether purinergic signaling, through the activities of nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase, and adenosine deaminase (ADA), is capable of modulating the cerebral immune and inflammatory responses in silver catfish that is experimentally infected with Streptococcus agalactiae. Cerebral NTPDase (with ATP as substrate) and 5'-nucleotidase activities increased, while ADA activity decreased in silver catfish that is experimentally infected with S. agalactiae, compared to the control group. Moreover, the cerebral levels of ATP and Ado increased in infected animals compared to the uninfected control group. Brain histopathology in infected animals revealed inflammatory demyelination (the presence of occasional bubbly collections), increased cellular density in the area near to pia-mater and intercellular edema. Based on this evidence, the modulation of the purinergic cascade by the enzymes NTPDase, 5'-nucleotidase, and ADA exerts an anti-inflammatory profile due to the regulation of ATP and Ado levels. This suggests involvement of purinergic enzymes on streptococcosis pathogenesis, through regulating cerebral ATP and Ado levels, molecules known to participate in physiological or pathological events as inflammatory and anti-inflammatory mediators, respectively. In summary, the modulation of the cerebral purinergic cascade exerts an anti-inflammatory profile in an attempt to reduce inflammatory damage.

  19. Señales purinérgicas Purinergic signals

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    Eduardo R Lazarowski

    2009-04-01

    Full Text Available En la última década se ha aportado clara evidencia de que tanto nucleósidos como nucleótidos de adenina y uridina pueden funcionar como factores de señalización extracelular. Su acción es mediada por dos tipos principales de receptores de superficie denominados purinérgicos. Los receptores P1 se activan por adenosina, y son todos metabotrópicos, mientras que los receptores de nucleótidos (ATP, ADP, UTP y UDP y nucleótidos-azúcares (UDP-glucosa y UDP-galactosa pueden ser metabotrópicos (P2Y o ionotrópicos (P2X. La importancia y complejidad de este sistema de señalización se evidencia por la diversidad de mecanismos de liberación de nucleótidos al medio extracelular y por la distribución ubicua de varios grupos de ectonucleotidasas capaces de catalizar la degradación y conversión de nucleótidos. Hasta el momento se han descrito y clonado una veintena de estos receptores que modulan una variedad de respuestas, como el impulso nervioso, la respuesta inflamatoria, la secreción de insulina, la regulación del tono vascular y la percepción del dolor. En la presente revisión se describen las características estructurales y farmacológicas de los receptores purinérgicos y se analiza la interacción dinámica entre estos receptores, los nucleósidos y nucleótidos, y las ectonucleotidasas, con especial atención a la dinámica de la agregación plaquetaria, la respuesta inmune y la hidratación de las mucosas respiratorias.In the last decade evidence accumulated that nucleosides and nucleotides of both uridine and adenine can act as extracellular signaling factors. Their action is mediated by two main types of surface receptors commonly known as purinergic. P1 receptors are metabotropic and activated by adenosine, whereas receptors for nucleotides (ATP, ADP, UTP and UDP and nucleotide-sugars (UDP-glucose and UDP-galactose can be either metabotropic (P2Y or ionotropic (P2X. The importance and complexity of this signaling system

  20. Signaling by purinergic receptors and channels in the pituitary gland

    Czech Academy of Sciences Publication Activity Database

    Stojilkovic, S. S.; He, M. L.; Koshimizu, T.; Balík, A.; Zemková, Hana

    2010-01-01

    Roč. 314, č. 2 (2010), s. 184-191 ISSN 0303-7207 R&D Projects: GA ČR(CZ) GA305/07/0681 Institutional research plan: CEZ:AV0Z50110509 Keywords : purinergic receptors * ATP * anterior pituitary Subject RIV: ED - Physiology Impact factor: 4.119, year: 2010

  1. Effects of ionizing radiation on purinergic signaling modulation in rat brain nerve cells

    International Nuclear Information System (INIS)

    Stanojevic, I.; Milosevic, M.; Drakulic, D.; Horvat, A.; Stanojevic, I.)

    2007-01-01

    Purinergic signaling is composed of three modulatory components: a) source of extracellular nucleotides, b) specific receptor expression for these transmitter molecules and c) ectonucleotidase selection that dictate cell response gradually degradation extracellular nucleotides to nucleosides. ATP acts as a fast excitatory transmitter in the CNS. Postsynaptic actions of ATP are mediated by an extended family of purinergic, P2X receptors, widely expressed throughout the CNS. NTPDases hydrolyse extracellular ATP and ADP to AMP and are responsive for purinergfic termination. To investigate if ionizing irradiation could modulate CNS purinergic signalization we monitored activity of NTPDases and abundance of P2X7 receptor in synaptic plasma membranes after whole-body acute irradiation using low (0,5Gy) or therapeutic (2Gy) doses, 1h i 72h after irradiating juvenile (15-day old) and adult (90-day old) rats. Acute irradiation modulate purinergic system components investigated at the different ways in the rat development brain SPM and in the adult brain dependent of dose and time after irradiation [sr

  2. Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration.

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    Glaser, Talita; Cappellari, Angélica Regina; Pillat, Micheli Mainardi; Iser, Isabele Cristiana; Wink, Márcia Rosângela; Battastini, Ana Maria Oliveira; Ulrich, Henning

    2012-09-01

    Replacement of lost or dysfunctional tissues by stem cells has recently raised many investigations on therapeutic applications. Purinergic signaling has been shown to regulate proliferation, differentiation, cell death, and successful engraftment of stem cells originated from diverse origins. Adenosine triphosphate release occurs in a controlled way by exocytosis, transporters, and lysosomes or in large amounts from damaged cells, which is then subsequently degraded into adenosine. Paracrine and autocrine mechanisms induced by immune responses present critical factors for the success of stem cell therapy. While P1 receptors generally exert beneficial effects including anti-inflammatory activity, P2 receptor-mediated actions depend on the subtype of stimulated receptors and localization of tissue repair. Pro-inflammatory actions and excitatory tissue damages mainly result from P2X7 receptor activation, while other purinergic receptor subtypes participate in proliferation and differentiation, thereby providing adequate niches for stem cell engraftment and novel mechanisms for cell therapy and endogenous tissue repair. Therapeutic applications based on regulation of purinergic signaling are foreseen for kidney and heart muscle regeneration, Clara-like cell replacement for pulmonary and bronchial epithelial cells as well as for induction of neurogenesis in case of neurodegenerative diseases.

  3. Purinergic signalling - a possible mechanism for KCNQ1 channel response to cell volume challenges

    DEFF Research Database (Denmark)

    Bomholtz, Sofia Hammami; Willumsen, Niels J.; Meinild, A.-K.

    2013-01-01

    AIM: A number of K(+) channels are regulated by small, fast changes in cell volume. The mechanisms underlying cell volume sensitivity are not known, but one possible mechanism could be purinergic signalling. Volume activated ATP release could trigger signalling pathways that subsequently lead...... stimuli. Basal ATP release was approx. three times higher in the KCNQ1 + AQP1 and KCNQ1 injected oocytes compared to the non-injected ones. Exogenously added ATP (0.1 mm) did not have any substantial effect on volume-induced KCNQ1 currents. Nevertheless, apyrase decreased all currents by about 50...

  4. Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage.

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    Pappas, Anthony C; Koide, Masayo; Wellman, George C

    2016-11-01

    Neurovascular coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca 2+ signals (eHACSs) caused a pathologic shift in neurovascular coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca 2+ oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca 2+ signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory neurovascular coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting G q -coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca 2+ events resembling eHACSs and disrupted neurovascular coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling. © The Author(s) 2016.

  5. Purinergic receptors have different effects in rat exocrine pancreas. Calcium signals monitored by fura-2 using confocal microscopy

    DEFF Research Database (Denmark)

    Novak, Ivana; Nitschke, Roland; Amstrup, Jan

    2002-01-01

    Pancreatic ducts have several types of purinergic P2 receptors, however, nothing is known about P2 receptors in acini. The aim was to establish whether acini express functional P2 receptors coupled to intracellular Ca2+ signals and to measure the signals ratiometrically in a confocal laser scanning...

  6. Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.

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    Belcik, J Todd; Davidson, Brian P; Xie, Aris; Wu, Melinda D; Yadava, Mrinal; Qi, Yue; Liang, Sherry; Chon, Chae Ryung; Ammi, Azzdine Y; Field, Joshua; Harmann, Leanne; Chilian, William M; Linden, Joel; Lindner, Jonathan R

    2017-03-28

    Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for 10 minutes after intravenous injection of 2×10 8 lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signaling pathways were assessed by studying interventions that (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or K ATP channels; or (3) inhibited downstream signaling pathways involving endothelial nitric oxide synthase or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease. Therapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with sickle cell disease. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced an ≈40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of

  7. Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity

    Directory of Open Access Journals (Sweden)

    Stephan Menzel

    2018-03-01

    Full Text Available Adenosine triphosphate (ATP and nicotinamide adenine dinucleotide (NAD+ are released as danger signals from cells during infection and sterile inflammation. In the extracellular compartment ATP is converted by CD39, CD73, and other ecto-enzymes into metabolites that modulate the activity of T cells and macrophages. While ATP mediates pro-inflammatory signals via P2X7 and other P2 receptors, adenosine triggers anti-inflammatory signaling via the adenosine 2a receptor (Adora2a and other P1 receptors. The latter also plays a role in maintaining an immunosuppressive tumor microenvironment. NAD+ is converted by CD38, CD203 and other ecto-enzymes to the Ca2+ mobilizing messengers cyclic ADP-ribose and ADP-ribose, and to adenosine. Recent findings on the roles of CD38, CD39, CD73, CD203, P2X7, and Adora2a in inflammation and immunity underscore the potential of these proteins as drug targets. However, available small molecule inhibitors often lack specificity and mediate unwanted off-target toxicity. Nanobodies – single domain antibodies derived from heavy chain antibodies that naturally occur in camelids – display a propensity to bind functional epitopes not accessible to conventional antibodies. Like conventional antibodies, nanobodies and nanobody-based biologics are highly specific and have well-understood, tunable in vivo pharmacodynamics with little if any toxicity. Nanobodies thus represent attractive alternatives to small molecule inhibitors for modulating purinergic signaling in inflammation and immunity. Here we review recent progress made in developing nanobodies against key targets of purinergic signaling.

  8. Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity.

    Science.gov (United States)

    Menzel, Stephan; Schwarz, Nicole; Haag, Friedrich; Koch-Nolte, Friedrich

    2018-01-01

    Adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD + ) are released as danger signals from cells during infection and sterile inflammation. In the extracellular compartment ATP is converted by CD39, CD73, and other ecto-enzymes into metabolites that modulate the activity of T cells and macrophages. While ATP mediates pro-inflammatory signals via P2X7 and other P2 receptors, adenosine triggers anti-inflammatory signaling via the adenosine 2a receptor (Adora2a) and other P1 receptors. The latter also plays a role in maintaining an immunosuppressive tumor microenvironment. NAD + is converted by CD38, CD203 and other ecto-enzymes to the Ca 2+ mobilizing messengers cyclic ADP-ribose and ADP-ribose, and to adenosine. Recent findings on the roles of CD38, CD39, CD73, CD203, P2X7, and Adora2a in inflammation and immunity underscore the potential of these proteins as drug targets. However, available small molecule inhibitors often lack specificity and mediate unwanted off-target toxicity. Nanobodies - single domain antibodies derived from heavy chain antibodies that naturally occur in camelids - display a propensity to bind functional epitopes not accessible to conventional antibodies. Like conventional antibodies, nanobodies and nanobody-based biologics are highly specific and have well-understood, tunable in vivo pharmacodynamics with little if any toxicity. Nanobodies thus represent attractive alternatives to small molecule inhibitors for modulating purinergic signaling in inflammation and immunity. Here we review recent progress made in developing nanobodies against key targets of purinergic signaling.

  9. Purinergic signaling during macrophage differentiation results in M2 alternative activated macrophages.

    Science.gov (United States)

    Barberà-Cremades, Maria; Baroja-Mazo, Alberto; Pelegrín, Pablo

    2016-02-01

    Macrophages represent a highly heterogenic cell population of the innate immune system, with important roles in the initiation and resolution of the inflammatory response. Purinergic signaling regulates both M1 and M2 macrophage function at different levels by controlling the secretion of cytokines, phagocytosis, and the production of reactive oxygen species. We found that extracellular nucleotides arrest macrophage differentiation from bone marrow precursors via adenosine and P2 receptors. This results in a mature macrophage with increased expression of M2, but not M1, genes. Similar to adenosine and ATP, macrophage growth arrested with LPS treatment resulted in an increase of the M2-related marker Ym1. Recombinant Ym1 was able to affect macrophage proliferation and could, potentially, be involved in the arrest of macrophage growth during hematopoiesis. © Society for Leukocyte Biology.

  10. Paracrine effect of carbon monoxide - astrocytes promote neuroprotection through purinergic signaling in mice.

    Science.gov (United States)

    Queiroga, Cláudia S F; Alves, Raquel M A; Conde, Sílvia V; Alves, Paula M; Vieira, Helena L A

    2016-08-15

    The neuroprotective role of carbon monoxide (CO) has been studied in a cell-autonomous mode. Herein, a new concept is disclosed - CO affects astrocyte-neuron communication in a paracrine manner to promote neuroprotection. Neuronal survival was assessed when co-cultured with astrocytes that had been pre-treated or not with CO. The CO-pre-treated astrocytes reduced neuronal cell death, and the cellular mechanisms were investigated, focusing on purinergic signaling. CO modulates astrocytic metabolism and extracellular ATP content in the co-culture medium. Moreover, several antagonists of P1 adenosine and P2 ATP receptors partially reverted CO-induced neuroprotection through astrocytes. Likewise, knocking down expression of the neuronal P1 adenosine receptor A2A-R (encoded by Adora2a) reverted the neuroprotective effects of CO-exposed astrocytes. The neuroprotection of CO-treated astrocytes also decreased following prevention of ATP or adenosine release from astrocytic cells and inhibition of extracellular ATP metabolism into adenosine. Finally, the neuronal downstream event involves TrkB (also known as NTRK2) receptors and BDNF. Pharmacological and genetic inhibition of TrkB receptors reverts neuroprotection triggered by CO-treated astrocytes. Furthermore, the neuronal ratio of BDNF to pro-BDNF increased in the presence of CO-treated astrocytes and decreased whenever A2A-R expression was silenced. In summary, CO prevents neuronal cell death in a paracrine manner by targeting astrocytic metabolism through purinergic signaling. © 2016. Published by The Company of Biologists Ltd.

  11. Purinergic transmission and transglial signaling between neuron somata in the dorsal root ganglion.

    Science.gov (United States)

    Rozanski, Gabriela M; Li, Qi; Kim, Hyunhee; Stanley, Elise F

    2013-02-01

    Most dorsal root ganglion neuronal somata (NS) are isolated from their neighbours by a satellite glial cell (SGC) sheath. However, some NS are associated in pairs, separated solely by the membrane septum of a common SGC to form a neuron-glial cell-neuron (NGlN) trimer. We reported that stimulation of one NS evokes a delayed, noisy and long-duration inward current in both itself and its passive partner that was blocked by suramin, a general purinergic antagonist. Here we test the hypothesis that NGlN transmission involves purinergic activation of the SGC. Stimulation of the NS triggered a sustained current noise in the SGC. Block of transmission through the NGlN by reactive blue 2 or thapsigargin, a Ca(2+) store-depletion agent, implicated a Ca(2+) store discharge-linked P2Y receptor. P2Y2 was identified by simulation of the NGlN-like transmission by puffing UTP onto the SGC and by immunocytochemical localization to the SGC membrane septum. Block of the UTP effect by BAPTA, an intracellular Ca(2+) scavenger, supported the involvement of SGC Ca(2+) stores in the signaling pathway. We infer that transmission through the NGlN trimer involves secretion of ATP from the NS and triggering of SGC Ca(2+) store discharge via P2Y2 receptors. Presumably, cytoplasmic Ca(2+) elevation leads to the release of an as-yet unidentified second transmitter from the glial cell to complete transmission. Thus, the two NS of the NGlN trimer communicate via a 'sandwich synapse' transglial pathway, a novel signaling mechanism that may contribute to information transfer in other regions of the nervous system. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  12. Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions.

    Science.gov (United States)

    Yegutkin, Gennady G; Guerrero-Toro, Cindy; Kilinc, Erkan; Koroleva, Kseniya; Ishchenko, Yevheniia; Abushik, Polina; Giniatullina, Raisa; Fayuk, Dmitriy; Giniatullin, Rashid

    2016-09-01

    Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca(2+) transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

  13. MAPK cascades in guard cell signal transduction

    Directory of Open Access Journals (Sweden)

    Yuree eLee

    2016-02-01

    Full Text Available Guard cells form stomata on the epidermis and continuously respond to endogenous and environmental stimuli to fine-tune the gas exchange and transpirational water loss, processes which involve mitogen-activated protein kinase (MAPK cascades. MAPKs form three-tiered kinase cascades with MAPK kinases and MAPK kinase kinases, by which signals are transduced to the target proteins. MAPK cascade genes are highly conserved in all eukaryotes, and they play crucial roles in myriad developmental and physiological processes. MAPK cascades function during biotic and abiotic stress responses by linking extracellular signals received by receptors to cytosolic events and gene expression. In this review, we highlight recent findings and insights into MAPK-mediated guard cell signaling, including the specificity of MAPK cascades and the remaining questions.

  14. P2X receptor-mediated ATP purinergic signaling in health and disease

    Directory of Open Access Journals (Sweden)

    Jiang LH

    2012-09-01

    Full Text Available Lin-Hua JiangSchool of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United KingdomAbstract: Purinergic P2X receptors are plasma membrane proteins present in a wide range of mammalian cells where they act as a cellular sensor, enabling cells to detect and respond to extracellular adenosine triphosphate (ATP, an important signaling molecule. P2X receptors function as ligand-gated Ca2+-permeable cationic channels that open upon ATP binding to elevate intracellular Ca2+ concentrations and cause membrane depolarization. In response to sustained activation, P2X receptors induce formation of a pore permeable to large molecules. P2X receptors also interact with distinct functional proteins and membrane lipids to form specialized signaling complexes. Studies have provided compelling evidence to show that such P2X receptor-mediated ATP-signaling mechanisms determine and regulate a growing number and diversity of important physiological processes, including neurotransmission, muscle contraction, and cytokine release. There is accumulating evidence to support strong causative relationships of altered receptor expression and function with chronic pain, inflammatory diseases, cancers, and other pathologies or diseases. Numerous high throughput screening drug discovery programs and preclinical studies have thus far demonstrated the proof of concepts that the P2X receptors are druggable targets and selective receptor antagonism is a promising therapeutics approach. This review will discuss the recent progress in understanding the mammalian P2X receptors with respect to the ATP-signaling mechanisms, physiological and pathophysiological roles, and development and preclinical studies of receptor antagonists.Keywords: extracellular ATP, ion channel, large pore, signaling complex, chronic pain, inflammatory diseases

  15. Bile acid effects are mediated by ATP release and purinergic signalling in exocrine pancreatic cells

    DEFF Research Database (Denmark)

    Kowal, Justyna Magdalena; Haanes, Kristian Agmund; Christensen, Nynne

    2015-01-01

    BACKGROUND: In many cells, bile acids (BAs) have a multitude of effects, some of which may be mediated by specific receptors such the TGR5 or FXR receptors. In pancreas systemic BAs, as well as intra-ductal BAs from bile reflux, can affect pancreatic secretion. Extracellular ATP and purinergic...

  16. Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling.

    Science.gov (United States)

    Moriyama, Yoshinori; Hiasa, Miki; Sakamoto, Shohei; Omote, Hiroshi; Nomura, Masatoshi

    2017-09-01

    Vesicular storage of ATP is one of the processes initiating purinergic chemical transmission. Although an active transport mechanism was postulated to be involved in the processes, a transporter(s) responsible for the vesicular storage of ATP remained unidentified for some time. In 2008, SLC17A9, the last identified member of the solute carrier 17 type I inorganic phosphate transporter family, was found to encode the vesicular nucleotide transporter (VNUT) that is responsible for the vesicular storage of ATP. VNUT transports various nucleotides in a membrane potential-dependent fashion and is expressed in the various ATP-secreting cells. Mice with knockout of the VNUT gene lose vesicular storage and release of ATP from neurons and neuroendocrine cells, resulting in blockage of the initiation of purinergic chemical transmission. Thus, VNUT plays an essential role in the vesicular storage and release of ATP. The VNUT knockout mice exhibit resistance for neuropathic pain and a therapeutic effect against diabetes by way of increased insulin sensitivity. Thus, VNUT inhibitors and suppression of VNUT gene expression may be used for therapeutic purposes through suppression of purinergic chemical transmission. This review summarizes the studies to date on VNUT and discusses what we have learned about the relevance of vesicular ATP release as a potential drug target.

  17. Extracellular gentamicin reduces the activity of connexin hemichannels and interferes with purinergic Ca2+ signaling in HeLa cells

    Science.gov (United States)

    Figueroa, Vania A.; Retamal, Mauricio A.; Cea, Luis A.; Salas, José D.; Vargas, Aníbal A.; Verdugo, Christian A.; Jara, Oscar; Martínez, Agustín D.; Sáez, Juan C.

    2014-01-01

    Gap junction channels (GJCs) and hemichannels (HCs) are composed of protein subunits termed connexins (Cxs) and are permeable to ions and small molecules. In most organs, GJCs communicate the cytoplasm of adjacent cells, while HCs communicate the intra and extracellular compartments. In this way, both channel types coordinate physiological responses of cell communities. Cx mutations explain several genetic diseases, including about 50% of autosomal recessive non-syndromic hearing loss. However, the possible involvement of Cxs in the etiology of acquired hearing loss remains virtually unknown. Factors that induce post-lingual hearing loss are diverse, exposure to gentamicin an aminoglycoside antibiotic, being the most common. Gentamicin has been proposed to block GJCs, but its effect on HCs remains unknown. In this work, the effect of gentamicin on the functional state of HCs was studied and its effect on GJCs was reevaluated in HeLa cells stably transfected with Cxs. We focused on Cx26 because it is the main Cx expressed in the cochlea of mammals where it participates in purinergic signaling pathways. We found that gentamicin applied extracellularly reduces the activity of HCs, while dye transfer across GJCs was not affected. HCs were also blocked by streptomycin, another aminoglycoside antibiotic. Gentamicin also reduced the adenosine triphosphate release and the HC-dependent oscillations of cytosolic free-Ca2+ signal. Moreover, gentamicin drastically reduced the Cx26 HC-mediated membrane currents in Xenopus laevis oocytes. Therefore, the extracellular gentamicin-induced inhibition of Cx HCs may adversely affect autocrine and paracrine signaling, including the purinergic one, which might partially explain its ototoxic effects. PMID:25237294

  18. Plant MAPK cascades: Just rapid signaling modules?

    KAUST Repository

    Boudsocq, Marie

    2015-08-27

    © 2015 Taylor & Francis Group, LLC. Abscisic acid (ABA) is a major phytohormone mediating important stress-related processes. We recently unveiled an ABA-activated MAPK signaling module constituted of MAP3K17/18-MKK3-MPK1/2/7/14. Unlike classical rapid MAPK activation, we showed that the activation of the new MAPK module is delayed and relies on the MAP3K protein synthesis. In this addendum, we discuss the role of this original and unexpected activation mechanism of MAPK cascades which suggests that MAPKs can regulate both early and longterm plant stress responses.

  19. Tunable signal processing in synthetic MAP kinase cascades.

    Science.gov (United States)

    O'Shaughnessy, Ellen C; Palani, Santhosh; Collins, James J; Sarkar, Casim A

    2011-01-07

    The flexibility of MAPK cascade responses enables regulation of a vast array of cell fate decisions, but elucidating the mechanisms underlying this plasticity is difficult in endogenous signaling networks. We constructed insulated mammalian MAPK cascades in yeast to explore how intrinsic and extrinsic perturbations affect the flexibility of these synthetic signaling modules. Contrary to biphasic dependence on scaffold concentration, we observe monotonic decreases in signal strength as scaffold concentration increases. We find that augmenting the concentration of sequential kinases can enhance ultrasensitivity and lower the activation threshold. Further, integrating negative regulation and concentration variation can decouple ultrasensitivity and threshold from the strength of the response. Computational analyses show that cascading can generate ultrasensitivity and that natural cascades with different kinase concentrations are innately biased toward their distinct activation profiles. This work demonstrates that tunable signal processing is inherent to minimal MAPK modules and elucidates principles for rational design of synthetic signaling systems. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Signaling Cascades: Consequences of Varying Substrate and Phosphatase Levels

    DEFF Research Database (Denmark)

    Feliu, Elisenda; Knudsen, Michael; Wiuf, Carsten Henrik

    2012-01-01

    We study signaling cascades with an arbitrary number of layers of one-site phosphorylation cycles. Such cascades are abundant in nature and integrated parts of many pathways. Based on the Michaelis-Menten model of enzyme kinetics and the law of mass-action, we derive explicit analytic expressions...

  1. Positional information generated by spatially distributed signaling cascades.

    Directory of Open Access Journals (Sweden)

    Javier Muñoz-García

    2009-03-01

    Full Text Available The temporal and stationary behavior of protein modification cascades has been extensively studied, yet little is known about the spatial aspects of signal propagation. We have previously shown that the spatial separation of opposing enzymes, such as a kinase and a phosphatase, creates signaling activity gradients. Here we show under what conditions signals stall in the space or robustly propagate through spatially distributed signaling cascades. Robust signal propagation results in activity gradients with long plateaus, which abruptly decay at successive spatial locations. We derive an approximate analytical solution that relates the maximal amplitude and propagation length of each activation profile with the cascade level, protein diffusivity, and the ratio of the opposing enzyme activities. The control of the spatial signal propagation appears to be very different from the control of transient temporal responses for spatially homogenous cascades. For spatially distributed cascades where activating and deactivating enzymes operate far from saturation, the ratio of the opposing enzyme activities is shown to be a key parameter controlling signal propagation. The signaling gradients characteristic for robust signal propagation exemplify a pattern formation mechanism that generates precise spatial guidance for multiple cellular processes and conveys information about the cell size to the nucleus.

  2. Plant MAPK cascades: Just rapid signaling modules?

    KAUST Repository

    Boudsocq, Marie; Danquah, Agyemang; Zé licourt, Axel de; Hirt, Heribert; Colcombet, Jean

    2015-01-01

    rapid MAPK activation, we showed that the activation of the new MAPK module is delayed and relies on the MAP3K protein synthesis. In this addendum, we discuss the role of this original and unexpected activation mechanism of MAPK cascades which suggests

  3. Purinergic receptors and calcium signalling in human pancreatic duct cell lines

    DEFF Research Database (Denmark)

    Hansen, Mette R; Krabbe, Simon; Novak, Ivana

    2008-01-01

    pancreatic duct cell lines PANC-1 and CFPAC-1. Expression of P2 receptors was examined using RT-PCR and immunocytochemistry. Both cell lines, and also Capan-1 cells, express RNA transcripts for the following receptors: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11-14 and P2X1, P2X2, P2X4, P2X5, P2X6 and P2X7. Using Fura-2...... and single-cell imaging we tested effects of various nucleotide analogues on intracellular Ca(2+) signals in PANC-1 and CFPAC-1 cells. The cell lines responded to all nucleotides with the following efficiency: UTP >or= ATP = ATPgammaS > BzATP. ATP, UTP and ATPgammaS elicited oscillatory responses. Bz...

  4. Lifelong physical activity preserves functional sympatholysis and purinergic signalling in the ageing human leg

    DEFF Research Database (Denmark)

    Mortensen, S P; Nyberg, Michael; Winding, K

    2012-01-01

    Ageing is associated with an impaired ability to modulate sympathetic vasoconstrictor activity (functional sympatholysis) and a reduced exercise hyperaemia. The purpose of this study was to investigate whether a physically active lifestyle can offset the impaired functional sympatholysis and exer......Ageing is associated with an impaired ability to modulate sympathetic vasoconstrictor activity (functional sympatholysis) and a reduced exercise hyperaemia. The purpose of this study was to investigate whether a physically active lifestyle can offset the impaired functional sympatholysis...... and exercise hyperaemia in the leg and whether ATP signalling is altered by ageing and physical activity. Leg haemodynamics, interstitial [ATP] and P2Y(2) receptor content was determined in eight young (23 ± 1 years), eight lifelong sedentary elderly (66 ± 2 years) and eight lifelong active elderly (62 ± 2...

  5. Sign epistasis caused by hierarchy within signalling cascades.

    Science.gov (United States)

    Nghe, Philippe; Kogenaru, Manjunatha; Tans, Sander J

    2018-04-13

    Sign epistasis is a central evolutionary constraint, but its causal factors remain difficult to predict. Here we use the notion of parameterised optima to explain epistasis within a signalling cascade, and test these predictions in Escherichia coli. We show that sign epistasis arises from the benefit of tuning phenotypic parameters of cascade genes with respect to each other, rather than from their complex and incompletely known genetic bases. Specifically, sign epistasis requires only that the optimal phenotypic parameters of one gene depend on the phenotypic parameters of another, independent of other details, such as activating or repressing nature, position within the cascade, intra-genic pleiotropy or genotype. Mutational effects change sign more readily in downstream genes, indicating that optimising downstream genes is more constrained. The findings show that sign epistasis results from the inherent upstream-downstream hierarchy between signalling cascade genes, and can be addressed without exhaustive genotypic mapping.

  6. L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade

    KAUST Repository

    Jourdain, P.

    2016-02-19

    Converging experimental data indicate a neuroprotective action of L-Lactate. Using Digital Holographic Microscopy, we observe that transient application of glutamate (100 μM; 2 min) elicits a NMDA-dependent death in 65% of mouse cortical neurons in culture. In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%. UK5099, a blocker of the Mitochondrial Pyruvate Carrier, fully prevents L-Lactate-mediated neuroprotection. In addition, L-Lactate-induced neuroprotection is not only inhibited by probenicid and carbenoxolone, two blockers of ATP channel pannexins, but also abolished by apyrase, an enzyme degrading ATP, suggesting that ATP produced by the Lactate/Pyruvate pathway is released to act on purinergic receptors in an autocrine/paracrine manner. Finally, pharmacological approaches support the involvement of the P2Y receptors associated to the PI3-kinase pathway, leading to activation of KATP channels. This set of results indicates that L-Lactate acts as a signalling molecule for neuroprotection against excitotoxicity through coordinated cellular pathways involving ATP production, release and activation of a P2Y/KATP cascade.

  7. L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade

    KAUST Repository

    Jourdain, P.; Allaman, I.; Rothenfusser, K.; Fiumelli, Hubert; Marquet, P.; Magistretti, Pierre J.

    2016-01-01

    Converging experimental data indicate a neuroprotective action of L-Lactate. Using Digital Holographic Microscopy, we observe that transient application of glutamate (100 μM; 2 min) elicits a NMDA-dependent death in 65% of mouse cortical neurons in culture. In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%. UK5099, a blocker of the Mitochondrial Pyruvate Carrier, fully prevents L-Lactate-mediated neuroprotection. In addition, L-Lactate-induced neuroprotection is not only inhibited by probenicid and carbenoxolone, two blockers of ATP channel pannexins, but also abolished by apyrase, an enzyme degrading ATP, suggesting that ATP produced by the Lactate/Pyruvate pathway is released to act on purinergic receptors in an autocrine/paracrine manner. Finally, pharmacological approaches support the involvement of the P2Y receptors associated to the PI3-kinase pathway, leading to activation of KATP channels. This set of results indicates that L-Lactate acts as a signalling molecule for neuroprotection against excitotoxicity through coordinated cellular pathways involving ATP production, release and activation of a P2Y/KATP cascade.

  8. Purinergic receptors expressed in human skeletal muscle fibres

    DEFF Research Database (Denmark)

    Bornø, A; Ploug, Thorkil; Bune, L T

    2012-01-01

    distribution of purinergic receptors in skeletal muscle fibres. We speculate that the intracellular localization of purinergic receptors may reflect a role in regulation of muscle metabolism; further studies are nevertheless needed to determine the function of the purinergic system in skeletal muscle cells.......Purinergic receptors are present in most tissues and thought to be involved in various signalling pathways, including neural signalling, cell metabolism and local regulation of the microcirculation in skeletal muscles. The present study aims to determine the distribution and intracellular content...... of purinergic receptors in skeletal muscle fibres in patients with type 2 diabetes and age-matched controls. Muscle biopsies from vastus lateralis were obtained from six type 2 diabetic patients and seven age-matched controls. Purinergic receptors were analysed using light and confocal microscopy...

  9. Sign epistasis caused by hierarchy within signalling cascades

    NARCIS (Netherlands)

    Nghe, Philippe; Kogenaru, Manjunatha; Tans, S.J.

    2018-01-01

    Sign epistasis is a central evolutionary constraint, but its causal factors remain difficult to predict. Here we use the notion of parameterised optima to explain epistasis within a signalling cascade, and test these predictions in Escherichia coli. We show that sign epistasis arises from the

  10. An algebraic approach to signaling cascades with N layers

    DEFF Research Database (Denmark)

    Feliu, Elisenda; Knudsen, Michael; Andersen, Lars Nørvang

    2012-01-01

    Posttranslational modification of proteins is key in transmission of signals in cells. Many signaling pathways contain several layers of modification cycles that mediate and change the signal through the pathway. Here, we study a simple signaling cascade consisting of n layers of modification cyc...... state for any given total amounts of substrates and enzymes.We demonstrate that many steady-state concentrations are related through rational functions that can be found recursively. For example, stimulus-response curves arise as inverse functions to explicit rational functions. We show...

  11. Prion protein induced signaling cascades in monocytes

    International Nuclear Information System (INIS)

    Krebs, Bjarne; Dorner-Ciossek, Cornelia; Schmalzbauer, Ruediger; Vassallo, Neville; Herms, Jochen; Kretzschmar, Hans A.

    2006-01-01

    Prion proteins play a central role in transmission and pathogenesis of transmissible spongiform encephalopathies. The cellular prion protein (PrP C ), whose physiological function remains elusive, is anchored to the surface of a variety of cell types including neurons and cells of the lymphoreticular system. In this study, we investigated the response of a mouse monocyte/macrophage cell line to exposure with PrP C fusion proteins synthesized with a human Fc-tag. PrP C fusion proteins showed an attachment to the surface of monocyte/macrophages in nanomolar concentrations. This was accompanied by an increase of cellular tyrosine phosphorylation as a result of activated signaling pathways. Detailed investigations exhibited activation of downstream pathways through a stimulation with PrP fusion proteins, which include phosphorylation of ERK 1,2 and Akt kinase. Macrophages opsonize and present antigenic structures, contact lymphocytes, and deliver cytokines. The findings reported here may become the basis of understanding the molecular function of PrP C in monocytes and macrophages

  12. The biochemical properties of the Arabidopsis ecto-nucleoside triphosphate diphosphohydrolase AtAPY1 contradict a direct role in purinergic signaling.

    Directory of Open Access Journals (Sweden)

    Carolin Massalski

    Full Text Available The Arabidopsis E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase AtAPY1 was previously shown to be involved in growth and development, pollen germination and stress responses. It was proposed to perform these functions through regulation of extracellular ATP signals. However, a GFP-tagged version was localized exclusively in the Golgi and did not hydrolyze ATP. In this study, AtAPY1 without the bulky GFP-tag was biochemically characterized with regard to its suggested role in purinergic signaling. Both the full-length protein and a soluble form without the transmembrane domain near the N-terminus were produced in HEK293 cells. Of the twelve nucleotide substrates tested, only three--GDP, IDP and UDP--were hydrolyzed, confirming that ATP was not a substrate of AtAPY1. In addition, the effects of pH, divalent metal ions, known E-NTPDase inhibitors and calmodulin on AtAPY1 activity were analyzed. AtAPY1-GFP extracted from transgenic Arabidopsis seedlings was included in the analyses. All three AtAPY1 versions exhibited very similar biochemical properties. Activity was detectable in a broad pH range, and Ca(2+, Mg(2+ and Mn(2+ were the three most efficient cofactors. Of the inhibitors tested, vanadate was the most potent one. Surprisingly, sulfonamide-based inhibitors shown to inhibit other E-NTPDases and presumed to inhibit AtAPY1 as well were not effective. Calmodulin stimulated the activity of the GFP-tagless membranous and soluble AtAPY1 forms about five-fold, but did not alter their substrate specificities. The apparent Km values obtained with AtAPY1-GFP indicate that AtAPY1 is primarily a GDPase. A putative three-dimensional structural model of the ecto-domain is presented, explaining the potent inhibitory potential of vanadate and predicting the binding mode of GDP. The found substrate specificity classifies AtAPY1 as a nucleoside diphosphatase typical of N-terminally anchored Golgi E-NTPDases and negates a direct function in

  13. dq-Frame Cascaded Delayed Signal Cancellation-Based PLL

    DEFF Research Database (Denmark)

    Golestan, Saeed; Ramezani, Malek; Guerrero, Josep M.

    2015-01-01

    on their position in the PLL structure. Inspired from the concept of delayed signal cancellation (DSC), the idea of cascaded DSC (CDSC) has recently been introduced as an effective solution to improve the performance of the PLL under adverse grid conditions. However, the focus has been on the application of CDSC...... operator as the pre-filtering stage of PLL, and little work has been conducted on its application as the in-loop filtering stage of PLL. This paper provides a detailed analysis and design of dqCDSC-PLL (PLL with in-loop dq-frame CDSC operator). The study is started with an overview of this PLL...

  14. Artifact removal from EEG signals using adaptive filters in cascade

    Science.gov (United States)

    Garcés Correa, A.; Laciar, E.; Patiño, H. D.; Valentinuzzi, M. E.

    2007-11-01

    Artifacts in EEG (electroencephalogram) records are caused by various factors, like line interference, EOG (electro-oculogram) and ECG (electrocardiogram). These noise sources increase the difficulty in analyzing the EEG and to obtaining clinical information. For this reason, it is necessary to design specific filters to decrease such artifacts in EEG records. In this paper, a cascade of three adaptive filters based on a least mean squares (LMS) algorithm is proposed. The first one eliminates line interference, the second adaptive filter removes the ECG artifacts and the last one cancels EOG spikes. Each stage uses a finite impulse response (FIR) filter, which adjusts its coefficients to produce an output similar to the artifacts present in the EEG. The proposed cascade adaptive filter was tested in five real EEG records acquired in polysomnographic studies. In all cases, line-frequency, ECG and EOG artifacts were attenuated. It is concluded that the proposed filter reduces the common artifacts present in EEG signals without removing significant information embedded in these records.

  15. Artifact removal from EEG signals using adaptive filters in cascade

    International Nuclear Information System (INIS)

    Garces Correa, A; Laciar, E; Patino, H D; Valentinuzzi, M E

    2007-01-01

    Artifacts in EEG (electroencephalogram) records are caused by various factors, like line interference, EOG (electro-oculogram) and ECG (electrocardiogram). These noise sources increase the difficulty in analyzing the EEG and to obtaining clinical information. For this reason, it is necessary to design specific filters to decrease such artifacts in EEG records. In this paper, a cascade of three adaptive filters based on a least mean squares (LMS) algorithm is proposed. The first one eliminates line interference, the second adaptive filter removes the ECG artifacts and the last one cancels EOG spikes. Each stage uses a finite impulse response (FIR) filter, which adjusts its coefficients to produce an output similar to the artifacts present in the EEG. The proposed cascade adaptive filter was tested in five real EEG records acquired in polysomnographic studies. In all cases, line-frequency, ECG and EOG artifacts were attenuated. It is concluded that the proposed filter reduces the common artifacts present in EEG signals without removing significant information embedded in these records

  16. Artifact removal from EEG signals using adaptive filters in cascade

    Energy Technology Data Exchange (ETDEWEB)

    Garces Correa, A [Gabinete de TecnologIa Medica, Facultad de Ingenieria, Universidad Nacional de San Juan (Argentina); Laciar, E [Gabinete de TecnologIa Medica, Facultad de Ingenieria, Universidad Nacional de San Juan (Argentina); Patino, H D [Instituto de Automatica, Facultad de Ingenieria, Universidad Nacional de San Juan (Argentina); Valentinuzzi, M E [Instituto Superior de Investigaciones Biologicas (INSIBIO), UNT-CONICET, Tucuman (Argentina)

    2007-11-15

    Artifacts in EEG (electroencephalogram) records are caused by various factors, like line interference, EOG (electro-oculogram) and ECG (electrocardiogram). These noise sources increase the difficulty in analyzing the EEG and to obtaining clinical information. For this reason, it is necessary to design specific filters to decrease such artifacts in EEG records. In this paper, a cascade of three adaptive filters based on a least mean squares (LMS) algorithm is proposed. The first one eliminates line interference, the second adaptive filter removes the ECG artifacts and the last one cancels EOG spikes. Each stage uses a finite impulse response (FIR) filter, which adjusts its coefficients to produce an output similar to the artifacts present in the EEG. The proposed cascade adaptive filter was tested in five real EEG records acquired in polysomnographic studies. In all cases, line-frequency, ECG and EOG artifacts were attenuated. It is concluded that the proposed filter reduces the common artifacts present in EEG signals without removing significant information embedded in these records.

  17. Network features and pathway analyses of a signal transduction cascade

    Directory of Open Access Journals (Sweden)

    Ryoji Yanashima

    2009-05-01

    Full Text Available The scale-free and small-world network models reflect the functional units of networks. However, when we investigated the network properties of a signaling pathway using these models, no significant differences were found between the original undirected graphs and the graphs in which inactive proteins were eliminated from the gene expression data. We analyzed signaling networks by focusing on those pathways that best reflected cellular function. Therefore, our analysis of pathways started from the ligands and progressed to transcription factors and cytoskeletal proteins. We employed the Python module to assess the target network. This involved comparing the original and restricted signaling cascades as a directed graph using microarray gene expression profiles of late onset Alzheimer's disease. The most commonly used method of shortest-path analysis neglects to consider the influences of alternative pathways that can affect the activation of transcription factors or cytoskeletal proteins. We therefore introduced included k-shortest paths and k-cycles in our network analysis using the Python modules, which allowed us to attain a reasonable computational time and identify k-shortest paths. This technique reflected results found in vivo and identified pathways not found when shortest path or degree analysis was applied. Our module enabled us to comprehensively analyse the characteristics of biomolecular networks and also enabled analysis of the effects of diseases considering the feedback loop and feedforward loop control structures as an alternative path.

  18. Interaction of LRRK2 with kinase and GTPase signaling cascades

    Directory of Open Access Journals (Sweden)

    Joon Y Boon

    2014-07-01

    Full Text Available LRRK2 is a protein that interacts with a plethora of signaling molecules, but the complexity of LRRK2 function presents a challenge for understanding the role of LRRK2 in the pathophysiology of Parkinson’s disease. Studies of LRRK2 using over-expression in transgenic mice have been disappointing, however studies using invertebrate systems have yielded a much clearer picture, with clear effects of LRRK2 expression, knockdown or deletion in C. elegans and Drosophila on modulation of survival of dopaminergic neurons. Recent studies have begun to focus attention on particular signaling cascades that are a target of LRRK2 function. LRRK2 interacts with members of the MAPK pathway and might regulate the pathway action by acting as a scaffold that directs the location of MAPK pathway activity, without strongly affecting the amount of MAPK pathway activity. Binding to GTPases, GAPs and GEFs are another strong theme in LRRK2 biology, with LRRK2 binding to Rac1, cdc42, rab5, rab7L1, endoA, RGS2, ArfGAP1 and ArhGEF7. All of these molecules appear to feed into a function output for LRRK2 that modulates cytoskeletal outgrowth and vesicular dynamics, including autophagy. These functions likely impact modulation of α-synuclein aggregation and associated toxicity eliciting the disease processes that we term Parkinson’s disease.

  19. Cascadability of Silicon Microring Resonators for40-Gbit/s OOK and DPSK Optical Signals

    DEFF Research Database (Denmark)

    Ozolins, Oskars; An, Yi; Lali-Dastjerdi, Zohreh

    2012-01-01

    The cascadability of a single silicon micro-ring resonator for CSRZ-OOK and CSRZ-DPSK signals is experimentally demonstrated at 40 Gbit/s for the first time. Error-free performance is obtained for both modulation formats after 5 cascaded resonators.......The cascadability of a single silicon micro-ring resonator for CSRZ-OOK and CSRZ-DPSK signals is experimentally demonstrated at 40 Gbit/s for the first time. Error-free performance is obtained for both modulation formats after 5 cascaded resonators....

  20. Purinergic signaling is required for fluid shear stress-induced NF-{kappa}B translocation in osteoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Genetos, Damian C., E-mail: dgenetos@ucdavis.edu [Department of Anatomy, Cell Biology, and Physiology, School of Veterinary Medicine, University of California, Davis, CA (United States); Karin, Norman J. [Cell Biology and Biochemistry, Pacific Northwest National Laboratory, Richland, WA (United States); Geist, Derik J. [Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN (United States); Donahue, Henry J. [Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Pennsylvania State College of Medicine, Hershey, PA (United States); Duncan, Randall L. [Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN (United States)

    2011-04-01

    Fluid shear stress regulates gene expression in osteoblasts, in part by activation of the transcription factor NF-{kappa}B. We examined whether this process was under the control of purinoceptor activation. MC3T3-E1 osteoblasts under static conditions expressed the NF-{kappa}B inhibitory protein I{kappa}B{alpha} and exhibited cytosolic localization of NF-{kappa}B. Under fluid shear stress, I{kappa}B{alpha} levels decreased, and concomitant nuclear localization of NF-{kappa}B was observed. Cells exposed to fluid shear stress in ATP-depleted medium exhibited no significant reduction in I{kappa}B{alpha}, and NF-{kappa}B remained within the cytosol. Similar results were found using oxidized ATP or Brilliant Blue G, P2X{sub 7} receptor antagonists, indicating that the P2X{sub 7} receptor is responsible for fluid shear-stress-induced I{kappa}B{alpha} degradation and nuclear accumulation of NF-{kappa}B. Pharmacologic blockage of the P2Y6 receptor also prevented shear-induced I{kappa}B{alpha} degradation. These phenomena involved neither ERK1/2 signaling nor autocrine activation by P2X{sub 7}-generated lysophosphatidic acid. Our results suggest that fluid shear stress regulates NF-{kappa}B activity through the P2Y{sub 6} and P2X{sub 7} receptor.

  1. A Discrete Dynamical System Approach to Pathway Activation Profiles of Signaling Cascades.

    Science.gov (United States)

    Catozzi, S; Sepulchre, J-A

    2017-08-01

    In living organisms, cascades of covalent modification cycles are one of the major intracellular signaling mechanisms, allowing to transduce physical or chemical stimuli of the external world into variations of activated biochemical species within the cell. In this paper, we develop a novel method to study the stimulus-response of signaling cascades and overall the concept of pathway activation profile which is, for a given stimulus, the sequence of activated proteins at each tier of the cascade. Our approach is based on a correspondence that we establish between the stationary states of a cascade and pieces of orbits of a 2D discrete dynamical system. The study of its possible phase portraits in function of the biochemical parameters, and in particular of the contraction/expansion properties around the fixed points of this discrete map, as well as their bifurcations, yields a classification of the cascade tiers into three main types, whose biological impact within a signaling network is examined. In particular, our approach enables to discuss quantitatively the notion of cascade amplification/attenuation from this new perspective. The method allows also to study the interplay between forward and "retroactive" signaling, i.e., the upstream influence of an inhibiting drug bound to the last tier of the cascade.

  2. Ultrasensitivity in signaling cascades revisited: Linking local and global ultrasensitivity estimations.

    Directory of Open Access Journals (Sweden)

    Edgar Altszyler

    Full Text Available Ultrasensitive response motifs, capable of converting graded stimuli into binary responses, are well-conserved in signal transduction networks. Although it has been shown that a cascade arrangement of multiple ultrasensitive modules can enhance the system's ultrasensitivity, how a given combination of layers affects a cascade's ultrasensitivity remains an open question for the general case. Here, we introduce a methodology that allows us to determine the presence of sequestration effects and to quantify the relative contribution of each module to the overall cascade's ultrasensitivity. The proposed analysis framework provides a natural link between global and local ultrasensitivity descriptors and it is particularly well-suited to characterize and understand mathematical models used to study real biological systems. As a case study, we have considered three mathematical models introduced by O'Shaughnessy et al. to study a tunable synthetic MAPK cascade, and we show how our methodology can help modelers better understand alternative models.

  3. Compartmentalization of NO signaling cascade in skeletal muscles

    International Nuclear Information System (INIS)

    Buchwalow, Igor B.; Minin, Evgeny A.; Samoilova, Vera E.; Boecker, Werner; Wellner, Maren; Schmitz, Wilhelm; Neumann, Joachim; Punkt, Karla

    2005-01-01

    Skeletal muscle functions regulated by NO are now firmly established. However, the literature on the compartmentalization of NO signaling in myocytes is highly controversial. To address this issue, we examined localization of enzymes engaged in L-arginine-NO-cGMP signaling in the rat quadriceps muscle. Employing immunocytochemical labeling complemented with tyramide signal amplification and electron microscopy, we found NO synthase expressed not only in the sarcolemma, but also along contractile fibers, in the sarcoplasmic reticulum and mitochondria. The expression pattern of NO synthase in myocytes showed striking parallels with the enzymes engaged in L-arginine-NO-cGMP signaling (arginase, phosphodiesterase, and soluble guanylyl cyclase). Our findings are indicative of an autocrine fashion of NO signaling in skeletal muscles at both cellular and subcellular levels, and challenge the notion that the NO generation is restricted to the sarcolemma

  4. Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury.

    Science.gov (United States)

    Hasan, Djo; Blankman, Paul; Nieman, Gary F

    2017-09-01

    Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.

  5. Wnt Signaling Cascades and the Roles of Syndecan Proteoglycans

    DEFF Research Database (Denmark)

    Pataki, Csilla A; Couchman, John R; Brábek, Jan

    2015-01-01

    /planar cell polarity and Wnt/calcium signaling. Syndecans are type I transmembrane proteoglycans with a long evolutionary history, being expressed in all Bilateria and in almost all cell types. Both Wnt pathways have been extensively studied over the past 30 years and shown to have roles during development...... and in a multitude of diseases. Although the first evidence for interactions between syndecans and Wnts dates back to 1997, the number of studies connecting these pathways is low, and many open questions remained unanswered. In this review, syndecan's involvement in Wnt signaling pathways as well as some...

  6. Purinergic Receptors in Neurological Diseases With Motor Symptoms: Targets for Therapy

    Directory of Open Access Journals (Sweden)

    Ágatha Oliveira-Giacomelli

    2018-04-01

    Full Text Available Since proving adenosine triphosphate (ATP functions as a neurotransmitter in neuron/glia interactions, the purinergic system has been more intensely studied within the scope of the central nervous system. In neurological disorders with associated motor symptoms, including Parkinson's disease (PD, motor neuron diseases (MND, multiple sclerosis (MS, amyotrophic lateral sclerosis (ALS, Huntington's Disease (HD, restless leg syndrome (RLS, and ataxias, alterations in purinergic receptor expression and activity have been noted, indicating a potential role for this system in disease etiology and progression. In neurodegenerative conditions, neural cell death provokes extensive ATP release and alters calcium signaling through purinergic receptor modulation. Consequently, neuroinflammatory responses, excitotoxicity and apoptosis are directly or indirectly induced. This review analyzes currently available data, which suggests involvement of the purinergic system in neuro-associated motor dysfunctions and underlying mechanisms. Possible targets for pharmacological interventions are also discussed.

  7. The role of purinergic receptors in stem cell differentiation

    Directory of Open Access Journals (Sweden)

    Constanze Kaebisch

    2015-01-01

    Full Text Available A major challenge modern society has to face is the increasing need for tissue regeneration due to degenerative diseases or tumors, but also accidents or warlike conflicts. There is great hope that stem cell-based therapies might improve current treatments of cardiovascular diseases, osteochondral defects or nerve injury due to the unique properties of stem cells such as their self-renewal and differentiation potential. Since embryonic stem cells raise severe ethical concerns and are prone to teratoma formation, adult stem cells are still in the focus of research. Emphasis is placed on cellular signaling within these cells and in between them for a better understanding of the complex processes regulating stem cell fate. One of the oldest signaling systems is based on nucleotides as ligands for purinergic receptors playing an important role in a huge variety of cellular processes such as proliferation, migration and differentiation. Besides their natural ligands, several artificial agonists and antagonists have been identified for P1 and P2 receptors and are already used as drugs. This review outlines purinergic receptor expression and signaling in stem cells metabolism. We will briefly describe current findings in embryonic and induced pluripotent stem cells as well as in cancer-, hematopoietic-, and neural crest-derived stem cells. The major focus will be placed on recent findings of purinergic signaling in mesenchymal stem cells addressed in in vitro and in vivo studies, since stem cell fate might be manipulated by this system guiding differentiation towards the desired lineage in the future.

  8. Modeling DNA?damage-induced pneumopathy in mice: insight from danger signaling cascades

    OpenAIRE

    Wirsd?rfer, Florian; Jendrossek, Verena

    2017-01-01

    Radiation-induced pneumonitis and fibrosis represent severe and dose-limiting side effects in the radiotherapy of thorax-associated neoplasms leading to decreased quality of life or - as a consequence of treatment with suboptimal radiation doses - to fatal outcomes by local recurrence or metastatic disease. It is assumed that the initial radiation-induced damage to the resident cells triggers a multifaceted damage-signalling cascade in irradiated normal tissues including a multifactorial secr...

  9. Cascaded analysis of signal and noise propagation through a heterogeneous breast model

    International Nuclear Information System (INIS)

    Mainprize, James G.; Yaffe, Martin J.

    2010-01-01

    Purpose: The detectability of lesions in radiographic images can be impaired by patterns caused by the surrounding anatomic structures. The presence of such patterns is often referred to as anatomic noise. Others have previously extended signal and noise propagation theory to include variable background structure as an additional noise term and used in simulations for analysis by human and ideal observers. Here, the analytic forms of the signal and noise transfer are derived to obtain an exact expression for any input random distribution and the ''power law'' filter used to generate the texture of the tissue distribution. Methods: A cascaded analysis of propagation through a heterogeneous model is derived for x-ray projection through simulated heterogeneous backgrounds. This is achieved by considering transmission through the breast as a correlated amplification point process. The analytic forms of the cascaded analysis were compared to monoenergetic Monte Carlo simulations of x-ray propagation through power law structured backgrounds. Results: As expected, it was found that although the quantum noise power component scales linearly with the x-ray signal, the anatomic noise will scale with the square of the x-ray signal. There was a good agreement between results obtained using analytic expressions for the noise power and those from Monte Carlo simulations for different background textures, random input functions, and x-ray fluence. Conclusions: Analytic equations for the signal and noise properties of heterogeneous backgrounds were derived. These may be used in direct analysis or as a tool to validate simulations in evaluating detectability.

  10. Hedgehog signaling acts with the temporal cascade to promote neuroblast cell cycle exit.

    Directory of Open Access Journals (Sweden)

    Phing Chian Chai

    Full Text Available In Drosophila postembryonic neuroblasts, transition in gene expression programs of a cascade of transcription factors (also known as the temporal series acts together with the asymmetric division machinery to generate diverse neurons with distinct identities and regulate the end of neuroblast proliferation. However, the underlying mechanism of how this "temporal series" acts during development remains unclear. Here, we show that Hh signaling in the postembryonic brain is temporally regulated; excess (earlier onset of Hh signaling causes premature neuroblast cell cycle exit and under-proliferation, whereas loss of Hh signaling causes delayed cell cycle exit and excess proliferation. Moreover, the Hh pathway functions downstream of Castor but upstream of Grainyhead, two components of the temporal series, to schedule neuroblast cell cycle exit. Interestingly, hh is likely a target of Castor. Hence, Hh signaling provides a link between the temporal series and the asymmetric division machinery in scheduling the end of neurogenesis.

  11. Purinergic Receptors in Ocular Inflammation

    Directory of Open Access Journals (Sweden)

    Ana Guzman-Aranguez

    2014-01-01

    Full Text Available Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly “tuned,” can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P1,P4-diadenosine tetraphosphate (Ap4A, and P1,P5-diadenosine pentaphosphate (Ap5A are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particular A2A adenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3 receptor, selective agonists like N6-(3-iodobenzyl-5′-N-methylcarboxamidoadenosine (CF101 have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation.

  12. Dioscin inhibits osteoclast differentiation and bone resorption though down-regulating the Akt signaling cascades

    Energy Technology Data Exchange (ETDEWEB)

    Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang; Li, Haowei [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Ouyang, Zhengxiao [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Department of Orthopaedics, Hunan Provincial Tumor Hospital and Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha (China); Wu, Chuanlong [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Liu, Guangwang [Department of Orthopaedic Surgery, The Central Hospital of Xuzhou, Affiliated Hospital of Medical Collage of Southeast University, Xuzhou (China); Fan, Qiming; Tang, Tingting [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Qin, An, E-mail: dr.qinan@gmail.com [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Dai, Kerong, E-mail: krdai@163.com [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China)

    2014-01-10

    Highlights: •A natural-derived compound, dioscin, suppresses osteoclast formation and bone resorption. •Dioscin inhibits osteolytic bone loss in vivo. •Dioscin impairs the Akt signaling cascades pathways during osteoclastogenesis. •Dioscin have therapeutic value in treating osteoclast-related diseases. -- Abstract: Bone resorption is the unique function of osteoclasts (OCs) and is critical for both bone homeostasis and pathologic bone diseases including osteoporosis, rheumatoid arthritis and tumor bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. In this study, we for the first time demonstrated that dioscin suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro in a dose-dependent manner. The suppressive effect of dioscin is supported by the reduced expression of osteoclast-specific markers. Further molecular analysis revealed that dioscin abrogated AKT phosphorylation, which subsequently impaired RANKL-induced nuclear factor-kappaB (NF-κB) signaling pathway and inhibited NFATc1 transcriptional activity. Moreover, in vivo studies further verified the bone protection activity of dioscin in osteolytic animal model. Together our data demonstrate that dioscin suppressed RANKL-induced osteoclast formation and function through Akt signaling cascades. Therefore, dioscin is a potential natural agent for the treatment of osteoclast-related diseases.

  13. Dioscin inhibits osteoclast differentiation and bone resorption though down-regulating the Akt signaling cascades

    International Nuclear Information System (INIS)

    Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang; Li, Haowei; Ouyang, Zhengxiao; Wu, Chuanlong; Liu, Guangwang; Fan, Qiming; Tang, Tingting; Qin, An; Dai, Kerong

    2014-01-01

    Highlights: •A natural-derived compound, dioscin, suppresses osteoclast formation and bone resorption. •Dioscin inhibits osteolytic bone loss in vivo. •Dioscin impairs the Akt signaling cascades pathways during osteoclastogenesis. •Dioscin have therapeutic value in treating osteoclast-related diseases. -- Abstract: Bone resorption is the unique function of osteoclasts (OCs) and is critical for both bone homeostasis and pathologic bone diseases including osteoporosis, rheumatoid arthritis and tumor bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. In this study, we for the first time demonstrated that dioscin suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro in a dose-dependent manner. The suppressive effect of dioscin is supported by the reduced expression of osteoclast-specific markers. Further molecular analysis revealed that dioscin abrogated AKT phosphorylation, which subsequently impaired RANKL-induced nuclear factor-kappaB (NF-κB) signaling pathway and inhibited NFATc1 transcriptional activity. Moreover, in vivo studies further verified the bone protection activity of dioscin in osteolytic animal model. Together our data demonstrate that dioscin suppressed RANKL-induced osteoclast formation and function through Akt signaling cascades. Therefore, dioscin is a potential natural agent for the treatment of osteoclast-related diseases

  14. A cascade of morphogenic signaling initiated by the meninges controls corpus callosum formation.

    Science.gov (United States)

    Choe, Youngshik; Siegenthaler, Julie A; Pleasure, Samuel J

    2012-02-23

    The corpus callosum is the most prominent commissural connection between the cortical hemispheres, and numerous neurodevelopmental disorders are associated with callosal agenesis. By using mice either with meningeal overgrowth or selective loss of meninges, we have identified a cascade of morphogenic signals initiated by the meninges that regulates corpus callosum development. The meninges produce BMP7, an inhibitor of callosal axon outgrowth. This activity is overcome by the induction of expression of Wnt3 by the callosal pathfinding neurons, which antagonize the inhibitory effects of BMP7. Wnt3 expression in the cingulate callosal pathfinding axons is developmentally regulated by another BMP family member, GDF5, which is produced by the adjacent Cajal-Retzius neurons and turns on before outgrowth of the callosal axons. The effects of GDF5 are in turn under the control of a soluble GDF5 inhibitor, Dan, made by the meninges. Thus, the meninges and medial neocortex use a cascade of signals to regulate corpus callosum development. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Microscopic insight into thermodynamics of conformational changes of SAP-SLAM complex in signal transduction cascade

    Science.gov (United States)

    Samanta, Sudipta; Mukherjee, Sanchita

    2017-04-01

    The signalling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, associate with SLAM-associated protein (SAP)-related molecules, composed of single SH2 domain architecture. SAP activates Src-family kinase Fyn after SLAM ligation, resulting in a SLAM-SAP-Fyn complex, where, SAP binds the Fyn SH3 domain that does not involve canonical SH3 or SH2 interactions. This demands insight into this SAP mediated signalling cascade. Thermodynamics of the conformational changes are extracted from the histograms of dihedral angles obtained from the all-atom molecular dynamics simulations of this structurally well characterized SAP-SLAM complex. The results incorporate the binding induced thermodynamic changes of individual amino acid as well as the secondary structural elements of the protein and the solvent. Stabilization of the peptide partially comes through a strong hydrogen bonding network with the protein, while hydrophobic interactions also play a significant role where the peptide inserts itself into a hydrophobic cavity of the protein. SLAM binding widens SAP's second binding site for Fyn, which is the next step in the signal transduction cascade. The higher stabilization and less fluctuation of specific residues of SAP in the Fyn binding site, induced by SAP-SLAM complexation, emerge as the key structural elements to trigger the recognition of SAP by the SH3 domain of Fyn. The thermodynamic quantification of the protein due to complexation not only throws deeper understanding in the established mode of SAP-SLAM interaction but also assists in the recognition of the relevant residues of the protein responsible for alterations in its activity.

  16. A growth factor signaling cascade confined to circular ruffles in macrophages

    Directory of Open Access Journals (Sweden)

    Timothy P. Welliver

    2012-06-01

    The formation of macropinosomes requires large-scale movements of membranes and the actin cytoskeleton. Over several minutes, actin-rich surface ruffles transform into 1–5 µm diameter circular ruffles, which close at their distal margins, creating endocytic vesicles. Previous studies using fluorescent reporters of phosphoinositides and Rho-family GTPases showed that signals generated by macrophages in response to the growth factor Macrophage Colony-Stimulating Factor (M-CSF appeared transiently in domains of plasma membrane circumscribed by circular ruffles. To address the question of how signaling molecules are coordinated in such large domains of plasma membrane, this study analyzed the relative timing of growth factor-dependent signals as ruffles transformed into macropinosomes. Fluorescent protein chimeras expressed in macrophages were imaged by microscopy and quantified relative to circular ruffle formation and cup closure. The large size of macropinocytic cups allowed temporal resolution of the transitions in phosphoinositides and associated enzyme activities that organize cup closure. Circular ruffles contained transient and sequential spikes of phosphatidylinositol (4,5-bisphosphate (PI(4,5P2, phosphatidylinositol (3,4,5-trisphosphate (PIP3, diacylglycerol, PI(3,4P2, PI(3P and the activities of protein kinase C-α, Rac1, Ras and Rab5. The confinement of this signal cascade to circular ruffles indicated that diffusion barriers present in these transient structures focus feedback activation and deactivation of essential enzyme activities into restricted domains of plasma membrane.

  17. Therapeutic peptides for cancer therapy. Part I - peptide inhibitors of signal transduction cascades.

    Science.gov (United States)

    Bidwell, Gene L; Raucher, Drazen

    2009-10-01

    Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration. The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that inhibit signal transduction cascades are discussed. The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery. Given our current knowledge of protein sequences, structures and interaction interfaces, therapeutic peptides that inhibit interactions of interest are easily designed. These peptides are advantageous because they are highly specific for the interaction of interest, and they are much more easily developed than small molecule inhibitors of the same interactions. The main hurdle to application of peptides for cancer therapy is their poor pharmacokinetic and biodistribution parameters. Therefore, successful development of peptide delivery vectors could potentially make possible the use of this new and very promising class of anticancer agents.

  18. A Gibberellin-Mediated DELLA-NAC Signaling Cascade Regulates Cellulose Synthesis in Rice[OPEN

    Science.gov (United States)

    Huang, Debao; Wang, Shaogan; Zhang, Baocai; Shang-Guan, Keke; Shi, Yanyun; Zhang, Dongmei; Liu, Xiangling; Wu, Kun; Xu, Zuopeng; Fu, Xiangdong; Zhou, Yihua

    2015-01-01

    Cellulose, which can be converted into numerous industrial products, has important impacts on the global economy. It has long been known that cellulose synthesis in plants is tightly regulated by various phytohormones. However, the underlying mechanism of cellulose synthesis regulation remains elusive. Here, we show that in rice (Oryza sativa), gibberellin (GA) signals promote cellulose synthesis by relieving the interaction between SLENDER RICE1 (SLR1), a DELLA repressor of GA signaling, and NACs, the top-layer transcription factors for secondary wall formation. Mutations in GA-related genes and physiological treatments altered the transcription of CELLULOSE SYNTHASE genes (CESAs) and the cellulose level. Multiple experiments demonstrated that transcription factors NAC29/31 and MYB61 are CESA regulators in rice; NAC29/31 directly regulates MYB61, which in turn activates CESA expression. This hierarchical regulation pathway is blocked by SLR1-NAC29/31 interactions. Based on the results of anatomical analysis and GA content examination in developing rice internodes, this signaling cascade was found to be modulated by varied endogenous GA levels and to be required for internode development. Genetic and gene expression analyses were further performed in Arabidopsis thaliana GA-related mutants. Altogether, our findings reveal a conserved mechanism by which GA regulates secondary wall cellulose synthesis in land plants and provide a strategy for manipulating cellulose production and plant growth. PMID:26002868

  19. A Gibberellin-Mediated DELLA-NAC Signaling Cascade Regulates Cellulose Synthesis in Rice.

    Science.gov (United States)

    Huang, Debao; Wang, Shaogan; Zhang, Baocai; Shang-Guan, Keke; Shi, Yanyun; Zhang, Dongmei; Liu, Xiangling; Wu, Kun; Xu, Zuopeng; Fu, Xiangdong; Zhou, Yihua

    2015-06-01

    Cellulose, which can be converted into numerous industrial products, has important impacts on the global economy. It has long been known that cellulose synthesis in plants is tightly regulated by various phytohormones. However, the underlying mechanism of cellulose synthesis regulation remains elusive. Here, we show that in rice (Oryza sativa), gibberellin (GA) signals promote cellulose synthesis by relieving the interaction between SLENDER RICE1 (SLR1), a DELLA repressor of GA signaling, and NACs, the top-layer transcription factors for secondary wall formation. Mutations in GA-related genes and physiological treatments altered the transcription of CELLULOSE SYNTHASE genes (CESAs) and the cellulose level. Multiple experiments demonstrated that transcription factors NAC29/31 and MYB61 are CESA regulators in rice; NAC29/31 directly regulates MYB61, which in turn activates CESA expression. This hierarchical regulation pathway is blocked by SLR1-NAC29/31 interactions. Based on the results of anatomical analysis and GA content examination in developing rice internodes, this signaling cascade was found to be modulated by varied endogenous GA levels and to be required for internode development. Genetic and gene expression analyses were further performed in Arabidopsis thaliana GA-related mutants. Altogether, our findings reveal a conserved mechanism by which GA regulates secondary wall cellulose synthesis in land plants and provide a strategy for manipulating cellulose production and plant growth. © 2015 American Society of Plant Biologists. All rights reserved.

  20. The Signaling Cascades of Ginkgolide B-Induced Apoptosis in MCF-7 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Wen-Hsiung Chan

    2007-11-01

    Full Text Available Ginkgolide B, the major active component of Ginkgo biloba extracts, can bothstimulate and inhibit apoptotic signaling. Here, we demonstrate that ginkgolide B caninduce the production of reactive oxygen species in MCF-7 breast cancer cells, leading toan increase in the intracellular concentrations of cytoplasmic free Ca2+ and nitric oxide(NO, loss of mitochondrial membrane potential (MMP, activation of caspase-9 and -3,and increase the mRNA expression levels of p53 and p21, which are known to be involvedin apoptotic signaling. In addition, prevention of ROS generation by pretreatment withN-acetyl cysteine (NAC could effectively block intracellular Ca2+ concentrationsincreases and apoptosis in ginkgolide B-treated MCF-7 cells. Moreover, pretreatment withnitric oxide (NO scavengers could inhibit ginkgolide B-induced MMP change andsequent apoptotic processes. Overall, our results signify that both ROS and NO playedimportant roles in ginkgolide B-induced apoptosis of MCF-7 cells. Based on these studyresults, we propose a model for ginkgolide B-induced cell apoptosis signaling cascades inMCF-7 cells.

  1. Evolutionary origins of the purinergic signalling system

    Czech Academy of Sciences Publication Activity Database

    Burnstock, G.; Verkhratsky, Alexei

    2009-01-01

    Roč. 195, č. 4 (2009), s. 415-447 ISSN 1748-1708 R&D Projects: GA ČR GA305/08/1384 Institutional research plan: CEZ:AV0Z50390512 Keywords : adenosine * ATP * invertebrate Subject RIV: FH - Neurology Impact factor: 2.810, year: 2009

  2. The Purinergic System and Glial Cells: Emerging Costars in Nociception

    Directory of Open Access Journals (Sweden)

    Giulia Magni

    2014-01-01

    Full Text Available It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel “druggable” glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states.

  3. Evolutionary origins of taste buds: phylogenetic analysis of purinergic neurotransmission in epithelial chemosensors

    Science.gov (United States)

    Kirino, Masato; Parnes, Jason; Hansen, Anne; Kiyohara, Sadao; Finger, Thomas E.

    2013-01-01

    Taste buds are gustatory endorgans which use an uncommon purinergic signalling system to transmit information to afferent gustatory nerve fibres. In mammals, ATP is a crucial neurotransmitter released by the taste cells to activate the afferent nerve fibres. Taste buds in mammals display a characteristic, highly specific ecto-ATPase (NTPDase2) activity, suggesting a role in inactivation of the neurotransmitter. The purpose of this study was to test whether the presence of markers of purinergic signalling characterize taste buds in anamniote vertebrates and to test whether similar purinergic systems are employed by other exteroceptive chemosensory systems. The species examined include several teleosts, elasmobranchs, lampreys and hagfish, the last of which lacks vertebrate-type taste buds. For comparison, Schreiner organs of hagfish and solitary chemosensory cells (SCCs) of teleosts, both of which are epidermal chemosensory end organs, were also examined because they might be evolutionarily related to taste buds. Ecto-ATPase activity was evident in elongate cells in all fish taste buds, including teleosts, elasmobranchs and lampreys. Neither SCCs nor Schreiner organs show specific ecto-ATPase activity, suggesting that purinergic signalling is not crucial in those systems as it is for taste buds. These findings suggest that the taste system did not originate from SCCs but arose independently in early vertebrates. PMID:23466675

  4. Evolutionary origins of taste buds: phylogenetic analysis of purinergic neurotransmission in epithelial chemosensors.

    Science.gov (United States)

    Kirino, Masato; Parnes, Jason; Hansen, Anne; Kiyohara, Sadao; Finger, Thomas E

    2013-03-06

    Taste buds are gustatory endorgans which use an uncommon purinergic signalling system to transmit information to afferent gustatory nerve fibres. In mammals, ATP is a crucial neurotransmitter released by the taste cells to activate the afferent nerve fibres. Taste buds in mammals display a characteristic, highly specific ecto-ATPase (NTPDase2) activity, suggesting a role in inactivation of the neurotransmitter. The purpose of this study was to test whether the presence of markers of purinergic signalling characterize taste buds in anamniote vertebrates and to test whether similar purinergic systems are employed by other exteroceptive chemosensory systems. The species examined include several teleosts, elasmobranchs, lampreys and hagfish, the last of which lacks vertebrate-type taste buds. For comparison, Schreiner organs of hagfish and solitary chemosensory cells (SCCs) of teleosts, both of which are epidermal chemosensory end organs, were also examined because they might be evolutionarily related to taste buds. Ecto-ATPase activity was evident in elongate cells in all fish taste buds, including teleosts, elasmobranchs and lampreys. Neither SCCs nor Schreiner organs show specific ecto-ATPase activity, suggesting that purinergic signalling is not crucial in those systems as it is for taste buds. These findings suggest that the taste system did not originate from SCCs but arose independently in early vertebrates.

  5. Orphan receptor GPR179 forms macromolecular complexes with components of metabotropic signaling cascade in retina ON-bipolar neurons.

    Science.gov (United States)

    Orlandi, Cesare; Cao, Yan; Martemyanov, Kirill A

    2013-10-29

    In the mammalian retina, synaptic transmission between light-excited rod photoreceptors and downstream ON-bipolar neurons is indispensable for dim vision, and disruption of this process leads to congenital stationary night blindness in human patients. The ON-bipolar neurons use the metabotropic signaling cascade, initiated by the mGluR6 receptor, to generate depolarizing responses to light-induced changes in neurotransmitter glutamate release from the photoreceptor axonal terminals. Evidence for the identity of the components involved in transducing these signals is growing rapidly. Recently, the orphan receptor, GPR179, a member of the G protein-coupled receptor (GPCR) superfamily, has been shown to be indispensable for the synaptic responses of ON-bipolar cells. In our study, we investigated the interaction of GPR179 with principle components of the signal transduction cascade. We used immunoprecipitation and proximity ligation assays in transfected cells and native retinas to characterize the protein-protein interactions involving GPR179. The influence of cascade components on GPR179 localization was examined through immunohistochemical staining of the retinas from genetic mouse models. We demonstrated that, in mouse retinas, GPR179 forms physical complexes with the main components of the metabotropic cascade, recruiting mGluR6, TRPM1, and the RGS proteins. Elimination of mGluR6 or RGS proteins, but not TRPM1, detrimentally affects postsynaptic targeting or GPR179 expression. These observations suggest that the mGluR6 signaling cascade is scaffolded as a macromolecular complex in which the interactions between the components ensure the optimal spatiotemporal characteristics of signal transduction.

  6. Purinergic receptors in the endocrine and exocrine pancreas.

    Science.gov (United States)

    Novak, I

    2008-09-01

    The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly, these processes have been viewed separately. In beta cells, stimulation of P2Y(1) receptors amplifies secretion of insulin in the presence of glucose. Nucleotides released from secretory granules could also contribute to autocrine/paracrine regulation in pancreatic islets. In addition to P2Y(1) receptors, there is also evidence for other P2 and adenosine receptors in beta cells (P2Y(2), P2Y(4), P2Y(6), P2X subtypes and A(1) receptors) and in glucagon-secreting alpha cells (P2X(7), A(2) receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors are prominent in pancreatic ducts, and several studies indicate that P2Y(2), P2Y(4), P2Y(11), P2X(4) and P2X(7) receptors could regulate secretion, primarily by affecting Cl(-) and K(+) channels and intracellular Ca(2+) signalling. In order to understand the physiology of the whole organ, it is necessary to consider the full complement of purinergic receptors on different cells as well as the structural and functional relation between various cells within the whole organ. In addition to the possible physiological function of purinergic receptors, this review analyses whether the receptors could be potential therapeutic targets for drug design aimed at treatment of pancreatic diseases.

  7. Electrochemical immunoassay for thyroxine detection using cascade catalysis as signal amplified enhancer and multi-functionalized magnetic graphene sphere as signal tag

    Energy Technology Data Exchange (ETDEWEB)

    Han, Jing; Zhuo, Ying, E-mail: yingzhuo@swu.edu.cn; Chai, Yaqin; Yu, Yanqing; Liao, Ni; Yuan, Ruo, E-mail: yuanruo@swu.edu.cn

    2013-08-06

    Graphical abstract: -- Highlights: •A reusable electrochemical immunosensor is developed for thyroxine detection. •Cascade catalysis as signal amplified enhancer. •Multi-functionalized magnetic graphene sphere as signal tag. •The novel strategy has the advantages of high sensitivity, good selectivity and reproducibility. -- Abstract: This paper constructed a reusable electrochemical immunosensor for the detection of thyroxine at an ultralow concentration using cascade catalysis of cytochrome c (Cyt c) and glucose oxidase (GOx) as signal amplified enhancer. It is worth pointing out that numerous Cyt c and GOx were firstly carried onto the double-stranded DNA polymers based on hybridization chain reaction (HCR), and then the amplified responses could be achieved by cascade catalysis of Cyt c and GOx recycling with the help of glucose. Moreover, multi-functionalized magnetic graphene sphere was synthesized and used as signal tag, which not only exhibited good mechanical properties, large surface area and an excellent electron transfer rate of graphene, but also possessed excellent redox activity and desirable magnetic property. With a sandwich-type immunoreaction, the proposed cascade catalysis amplification strategy could greatly enhance the sensitivity for the detection of thyroxine. Under the optimal conditions, the immunosensor showed a wide linear ranged from 0.05 pg mL{sup −1} to 5 ng mL{sup −1} and a low detection limit down to 15 fg mL{sup −1}. Importantly, the proposed method offers promise for reproducible and cost-effective analysis of biological samples.

  8. Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade

    Directory of Open Access Journals (Sweden)

    Alexandre Dumoulin

    2018-04-01

    Full Text Available Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP, the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα. In the absence of any one of these components, neurons in dorsal root ganglia (DRG and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

  9. Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade.

    Science.gov (United States)

    Dumoulin, Alexandre; Ter-Avetisyan, Gohar; Schmidt, Hannes; Rathjen, Fritz G

    2018-04-24

    Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP)-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, neurons in dorsal root ganglia (DRG) and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

  10. Fast subcellular localization by cascaded fusion of signal-based and homology-based methods

    Directory of Open Access Journals (Sweden)

    Wang Wei

    2011-10-01

    Full Text Available Abstract Background The functions of proteins are closely related to their subcellular locations. In the post-genomics era, the amount of gene and protein data grows exponentially, which necessitates the prediction of subcellular localization by computational means. Results This paper proposes mitigating the computation burden of alignment-based approaches to subcellular localization prediction by a cascaded fusion of cleavage site prediction and profile alignment. Specifically, the informative segments of protein sequences are identified by a cleavage site predictor using the information in their N-terminal shorting signals. Then, the sequences are truncated at the cleavage site positions, and the shortened sequences are passed to PSI-BLAST for computing their profiles. Subcellular localization are subsequently predicted by a profile-to-profile alignment support-vector-machine (SVM classifier. To further reduce the training and recognition time of the classifier, the SVM classifier is replaced by a new kernel method based on the perturbational discriminant analysis (PDA. Conclusions Experimental results on a new dataset based on Swiss-Prot Release 57.5 show that the method can make use of the best property of signal- and homology-based approaches and can attain an accuracy comparable to that achieved by using full-length sequences. Analysis of profile-alignment score matrices suggest that both profile creation time and profile alignment time can be reduced without significant reduction in subcellular localization accuracy. It was found that PDA enjoys a short training time as compared to the conventional SVM. We advocate that the method will be important for biologists to conduct large-scale protein annotation or for bioinformaticians to perform preliminary investigations on new algorithms that involve pairwise alignments.

  11. Activation of Signaling Cascades by Weak Extremely Low Frequency Electromagnetic Fields

    Directory of Open Access Journals (Sweden)

    Einat Kapri-Pardes

    2017-10-01

    Full Text Available Background/Aims: Results from recent studies suggest that extremely low frequency magnetic fields (ELF-MF interfere with intracellular signaling pathways related to proliferative control. The mitogen-activated protein kinases (MAPKs, central signaling components that regulate essentially all stimulated cellular processes, include the extracellular signal-regulated kinases 1/2 (ERK1/2 that are extremely sensitive to extracellular cues. Anti-phospho-ERK antibodies serve as a readout for ERK1/2 activation and are able to detect minute changes in ERK stimulation. The objective of this study was to explore whether activation of ERK1/2 and other signaling cascades can be used as a readout for responses of a variety of cell types, both transformed and non-transformed, to ELF-MF. Methods: We applied ELF-MF at various field strengths and time periods to eight different cell types with an exposure system housed in a tissue culture incubator and followed the phosphorylation of MAPKs and Akt by western blotting. Results: We found that the phosphorylation of ERK1/2 is increased in response to ELF-MF. However, the phosphorylation of ERK1/2 is likely too low to induce ELF-MF-dependent proliferation or oncogenic transformation. The p38 MAPK was very slightly phosphorylated, but JNK or Akt were not. The effect on ERK1/2 was detected for exposures to ELF-MF strengths as low as 0.15 µT and was maximal at ∼10 µT. We also show that ERK1/2 phosphorylation is blocked by the flavoprotein inhibitor diphenyleneiodonium, indicating that the response to ELF-MF may be exerted via NADP oxidase similar to the phosphorylation of ERK1/2 in response to microwave radiation. Conclusions: Our results further indicate that cells are responsive to ELF-MF at field strengths much lower than previously suspected and that the effect may be mediated by NADP oxidase. However, the small increase in ERK1/2 phosphorylation is probably insufficient to affect proliferation and oncogenic

  12. Evolutionary origins of taste buds: phylogenetic analysis of purinergic neurotransmission in epithelial chemosensors

    OpenAIRE

    Kirino, Masato; Parnes, Jason; Hansen, Anne; Kiyohara, Sadao; Finger, Thomas E.

    2013-01-01

    Taste buds are gustatory endorgans which use an uncommon purinergic signalling system to transmit information to afferent gustatory nerve fibres. In mammals, ATP is a crucial neurotransmitter released by the taste cells to activate the afferent nerve fibres. Taste buds in mammals display a characteristic, highly specific ecto-ATPase (NTPDase2) activity, suggesting a role in inactivation of the neurotransmitter. The purpose of this study was to test whether the presence of markers of purinergi...

  13. ERK5 signaling gets XIAPed: a role for ubiquitin in the disassembly of a MAPK cascade

    Science.gov (United States)

    Klein, Aileen M; Cobb, Melanie H

    2014-01-01

    Mitogen-activated protein kinase (MAPK) cascades are tightly controlled through a series of well-characterized phospho-regulatory events. In this issue, Takeda et al (2014) identify the inhibitor of apoptosis protein, XIAP, as a key regulator of ERK5 activation via uncoupling of upstream kinase activity by non-degradative ubiquitination. PMID:25012518

  14. Zinc promotes proliferation and activation of myogenic cells via the PI3K/Akt and ERK signaling cascade

    Energy Technology Data Exchange (ETDEWEB)

    Ohashi, Kazuya, E-mail: asuno10k@yahoo.co.jp [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo (Japan); Nagata, Yosuke, E-mail: cynagata@mail.ecc.u-tokyo.ac.jp [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo (Japan); Wada, Eiji, E-mail: gacchu1@yahoo.co.jp [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo (Japan); Zammit, Peter S., E-mail: peter.zammit@kcl.ac.uk [Randall Division of Cell and Molecular Biophysics, King' s College London, London SE1 1UL (United Kingdom); Shiozuka, Masataka, E-mail: cmuscle@mail.ecc.u-tokyo.ac.jp [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo (Japan); Matsuda, Ryoichi, E-mail: cmatsuda@mail.ecc.u-tokyo.ac.jp [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo (Japan)

    2015-05-01

    Skeletal muscle stem cells named muscle satellite cells are normally quiescent but are activated in response to various stimuli, such as injury and overload. Activated satellite cells enter the cell cycle and proliferate to produce a large number of myogenic progenitor cells, and these cells then differentiate and fuse to form myofibers. Zinc is one of the essential elements in the human body, and has multiple roles, including cell growth and DNA synthesis. However, the role of zinc in myogenic cells is not well understood, and is the focus of this study. We first examined the effects of zinc on differentiation of murine C2C12 myoblasts and found that zinc promoted proliferation, with an increased number of cells incorporating EdU, but inhibited differentiation with reduced myogenin expression and myotube formation. Furthermore, we used the C2C12 reserve cell model of myogenic quiescence to investigate the role of zinc on activation of myogenic cells. The number of reserve cells incorporating BrdU was increased by zinc in a dose dependent manner, with the number dramatically further increased using a combination of zinc and insulin. Akt and extracellular signal-regulated kinase (ERK) are downstream of insulin signaling, and both were phosphorylated after zinc treatment. The zinc/insulin combination-induced activation involved the phosphoinositide 3-kinase (PI3K)/Akt and ERK cascade. We conclude that zinc promotes activation and proliferation of myogenic cells, and this activation requires phosphorylation of PI3K/Akt and ERK as part of the signaling cascade. - Highlights: • Zinc has roles for promoting proliferation and inhibition differentiation of C2C12. • Zinc promotes activation of reserve cells. • Insulin and zinc synergize activation of reserve cells. • PI3K/Akt and ERK cascade affect zinc/insulin-mediated activation of reserve cells.

  15. Signal-Pressure Curves of Cascaded Four-Wave Mixing in Gas-Filled Capillary by fs Pulses

    International Nuclear Information System (INIS)

    Chen Baozhen; Huang Zuqia

    2005-01-01

    The theoretical framework for the cascaded four waves mixing (CFWM) in gas-filled capillary by fs pulses is constructed. Based on the theoretical framework, the signal-pressure curves (SPC) of the CFWM in gas-filled capillary by fs pulses are calculated. With a comparison between the theoretical and experimental SPC we have discussed the influence of the walk-off and phase modulation on the SPC. At the same time, we have discussed the possible origin of the first three peaks of the SPC.

  16. Purinergic responses of chondrogenic stem cells to dynamic loading

    Directory of Open Access Journals (Sweden)

    Gađanski Ivana

    2013-01-01

    Full Text Available In habitually loaded tissues, dynamic loading can trigger ATP (adenosine 5’- triphosphate release to extracellular environment, and result in calcium signaling via ATP binding to purine P2 receptors1. In the current study we have compared purinergic responses (ATP release of two types of cells: bovine chondrocytes (bCHs and human mesenchymal stem cells (hMSC that were encapsulated in agarose and subjected to dynamic loading. Both cell types were cultured under chondrogenic conditions, and their responses to loading were evaluated by ATP release assay in combination with connexin (Cx-sensitive fluorescent dye (Lucifer Yellow - LY and a Cx-hemichannel blocker (Flufenamic acid - FFA. In response to dynamic loading, chondrogenic hMSCs released significantly higher amounts of ATP (5-fold in comparison to the bCHs early in culture (day 2. Triggering of LY uptake in the bCHs and hMSCs by dynamic loading implies opening of the Cx-hemichannels. However, the number of LY-positive cells in hMSC-constructs was 2.5-fold lower compared to the loaded bCH-constructs, suggesting utilization of additional mechanisms of ATP release. Cx-reactive sites were detected in both bCHs and hMSCs-constructs. FFA application led to reduced ATP release both in bCHs and hMSCs, which confirms the involvement of connexin hemichannels, with more prominent effects in bCHs than in hMSCs, further implying the existence of additional mechanism of ATP release in chondrogenic hMSCs. Taken together, these results indicate stronger purinergic response to dynamic loading of chondrogenic hMSCs than primary chondrocytes, by activation of connexin hemichannels and additional mechanisms of ATP release. [Projekat Ministrastva nauke Republike Srbije, ON174028 i br. III41007

  17. Spectroscopic approaches to resolving ambiguities of hyper-polarized NMR signals from different reaction cascades

    DEFF Research Database (Denmark)

    Jensen, Pernille Rose; Meier, Sebastian

    2016-01-01

    The influx of exogenous substrates into cellular reaction cascades on the seconds time scale is directly observable by NMR spectroscopy when using nuclear spin polarization enhancement. Conventional NMR assignment spectra for the identification of reaction intermediates are not applicable...... in these experiments due to the non-equilibrium nature of the nuclear spin polarization enhancement. We show that ambiguities in the intracellular identification of transient reaction intermediates can be resolved by experimental schemes using site-specific isotope labelling, optimised referencing and response...

  18. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2012-02-01

    BACKGROUND: Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. RESULTS: Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. CONCLUSION: Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.

  19. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2011-08-22

    Abstract Background Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. Results Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. Conclusion Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.

  20. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium

    Directory of Open Access Journals (Sweden)

    Hatt Hanns

    2011-08-01

    Full Text Available Abstract Background Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. Results Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. Conclusion Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.

  1. Search for QGP signals at AGS with a TPC spectrometer, and comparison of our event generator predictions for plasma model and cascade interactions

    International Nuclear Information System (INIS)

    Lindenbaum, S.J.; Foley, K.J.; Eiseman, S.E.

    1988-01-01

    We have developed and successfully tested a TPC Magnetic Spectrometer to search for QGP signals produced by ion beams at AGS. We also developed a cascade and plasma event generator the predictions of which are used to illustrate how our technique can detect possible plasma signals. 4 refs., 6 figs., 1 tab

  2. A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development.

    Science.gov (United States)

    Xiao, Ying; Thoresen, Daniel T; Miao, Lingling; Williams, Jonathan S; Wang, Chaochen; Atit, Radhika P; Wong, Sunny Y; Brownell, Isaac

    2016-07-01

    The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.

  3. A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development.

    Directory of Open Access Journals (Sweden)

    Ying Xiao

    2016-07-01

    Full Text Available The Sonic hedgehog (Shh signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.

  4. Reactive oxygen species and hormone signaling cascades in endophytic bacterium induced essential oil accumulation in Atractylodes lancea.

    Science.gov (United States)

    Zhou, Jia-Yu; Li, Xia; Zhao, Dan; Deng-Wang, Meng-Yao; Dai, Chuan-Chao

    2016-09-01

    Pseudomonas fluorescens induces gibberellin and ethylene signaling via hydrogen peroxide in planta . Ethylene activates abscisic acid signaling. Hormones increase sesquiterpenoid biosynthesis gene expression and enzyme activity, inducing essential oil accumulation. Atractylodes lancea is a famous Chinese medicinal plant, whose main active components are essential oils. Wild A. lancea has become endangered due to habitat destruction and over-exploitation. Although cultivation can ensure production of the medicinal material, the essential oil content in cultivated A. lancea is significantly lower than that in the wild herb. The application of microbes as elicitors has become an effective strategy to increase essential oil accumulation in cultivated A. lancea. Our previous study identified an endophytic bacterium, Pseudomonas fluorescens ALEB7B, which can increase essential oil accumulation in A. lancea more efficiently than other endophytes; however, the underlying mechanisms remain unknown (Physiol Plantarum 153:30-42, 2015; Appl Environ Microb 82:1577-1585, 2016). This study demonstrates that P. fluorescens ALEB7B firstly induces hydrogen peroxide (H2O2) signaling in A. lancea, which then simultaneously activates gibberellin (GA) and ethylene (ET) signaling. Subsequently, ET activates abscisic acid (ABA) signaling. GA and ABA signaling increase expression of HMGR and DXR, which encode key enzymes involved in sesquiterpenoid biosynthesis, leading to increased levels of the corresponding enzymes and then an accumulation of essential oils. Specific reactive oxygen species and hormone signaling cascades induced by P. fluorescens ALEB7B may contribute to high-efficiency essential oil accumulation in A. lancea. Illustrating the regulation mechanisms underlying P. fluorescens ALEB7B-induced essential oil accumulation not only provides the theoretical basis for the inducible synthesis of terpenoids in many medicinal plants, but also further reveals the complex and diverse

  5. Molecular dissection of purinergic P2X receptor channels

    Czech Academy of Sciences Publication Activity Database

    Stojilkovic, S. S.; Tomič, M.; He, M. L.; Yan, Z.; Koshimizu, T.; Zemková, Hana

    2005-01-01

    Roč. 1048, - (2005), s. 116-130 ISSN 0077-8923 Institutional research plan: CEZ:AV0Z50110509 Keywords : ATP * purinergic receptors * deactivation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.971, year: 2005

  6. Laminar shear flow increases hydrogen sulfide and activates a nitric oxide producing signaling cascade in endothelial cells.

    Science.gov (United States)

    Huang, Bin; Chen, Chang-Ting; Chen, Chi-Shia; Wang, Yun-Ming; Hsieh, Hsyue-Jen; Wang, Danny Ling

    2015-09-04

    Laminar shear flow triggers a signaling cascade that maintains the integrity of endothelial cells (ECs). Hydrogen sulfide (H2S), a new gasotransmitter is regarded as an upstream regulator of nitric oxide (NO). Whether the H2S-generating enzymes are correlated to the enzymes involved in NO production under shear flow conditions remains unclear as yet. In the present study, the cultured ECs were subjected to a constant shear flow (12 dyn/cm(2)) in a parallel flow chamber system. We investigated the expression of three key enzymes for H2S biosynthesis, cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercapto-sulfurtransferase (3-MST). Shear flow markedly increased the level of 3-MST. Shear flow enhanced the production of H2S was determined by NBD-SCN reagent that can bind to cysteine/homocystein. Exogenous treatment of NaHS that can release gaseous H2S, ECs showed an increase of phosphorylation in Akt(S473), ERK(T202/Y204) and eNOS(S1177). This indicated that H2S can trigger the NO-production signaling cascade. Silencing of CSE, CBS and 3-MST genes by siRNA separately attenuated the phosphorylation levels of Akt(S473) and eNOS(S1177) under shear flow conditions. The particular mode of shear flow increased H2S production. The interplay between H2S and NO-generating enzymes were discussed in the present study. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Hormonal Signaling Cascade during an Early-Adult Critical Period Required for Courtship Memory Retention in Drosophila.

    Science.gov (United States)

    Lee, Sang Soo; Ding, Yike; Karapetians, Natalie; Rivera-Perez, Crisalejandra; Noriega, Fernando Gabriel; Adams, Michael E

    2017-09-25

    Formation and expression of memories are critical for context-dependent decision making. In Drosophila, a courting male rejected by a mated female subsequently courts less avidly when paired with a virgin female, a behavioral modification attributed to "courtship memory." Here we show the critical role of hormonal state for maintenance of courtship memory. Ecdysis-triggering hormone (ETH) is essential for courtship memory through regulation of juvenile hormone (JH) levels in adult males. Reduction of JH levels via silencing of ETH signaling genes impairs short-term courtship memory, a phenotype rescuable by the JH analog methoprene. JH-deficit-induced memory impairment involves rapid decay rather than failure of memory acquisition. A critical period governs memory performance during the first 3 days of adulthood. Using sex-peptide-expressing "pseudo-mated" trainers, we find that robust courtship memory elicited in the absence of aversive chemical mating cues also is dependent on ETH-JH signaling. Finally, we find that JH acts through dopaminergic neurons and conclude that an ETH-JH-dopamine signaling cascade is required during a critical period for promotion of social-context-dependent memory. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Involvement of AMPK signaling cascade in capsaicin-induced apoptosis of HT-29 colon cancer cells.

    Science.gov (United States)

    Kim, Young Min; Hwang, Jin-Taek; Kwak, Dong Wook; Lee, Yun Kyung; Park, Ock Jin

    2007-01-01

    Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is activated during ATP-depleting metabolic states, such as hypoxia, heat shock, oxidative stress, and exercise. As a highly conserved heterotrimeric kinase that functions as a major metabolic switch to maintain energy homeostasis, AMPK has been shown to exert as an intrinsic regulator of mammalian cell cycle. Moreover, AMPK cascade has emerged as an important pathway implicated in cancer control. In this article, we have investigated the effects of capsaicin on apoptosis in relation to AMPK activation in colon cancer cell. Capsaicin-induced apoptosis was revealed by the presence of nucleobodies in the capsaicin-treated HT-29 colon cancer cells. Concomitantly, the activation of AMPK and the increased expression of the inactive form of acetyl-CoA carboxylase (ACC) were detected in capsaicin-treated colon cancer cells. We showed that both capsaicin and 5'-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR), an AMPK activator possess the AMPK-activating capacity as well as apoptosis-inducing properties. Evidence of the association between AMPK activation and the increased apoptosis in HT-29 colon cancer cells by capsaicin treatment, and further findings of the correlation of the activated AMPK and the elevated apoptosis by cotreatment of AICAR and capsaicin support AMPK as an important component of apoptosis, as well as a possible target of cancer control.

  9. Hepatocyte growth factor triggers signaling cascades mediating vascular smooth muscle cell migration

    NARCIS (Netherlands)

    Taher, Taher E. I.; Derksen, Patrick W. B.; de Boer, Onno J.; Spaargaren, Marcel; Teeling, Peter; van der Wal, Allard C.; Pals, Steven T.

    2002-01-01

    A key event in neointima formation and atherogenesis is the migration of vascular smooth muscle cells (VSMCs) into the intima. This is controlled by cytokines and extracellular matix (ECM) components within the microenvironment of the diseased vessel wall. At present, these signals have only been

  10. Analysis of Cell Signal Transduction Based on Kullback–Leibler Divergence: Channel Capacity and Conservation of Its Production Rate during Cascade

    Directory of Open Access Journals (Sweden)

    Tatsuaki Tsuruyama

    2018-06-01

    Full Text Available Kullback–Leibler divergence (KLD is a type of extended mutual entropy, which is used as a measure of information gain when transferring from a prior distribution to a posterior distribution. In this study, KLD is applied to the thermodynamic analysis of cell signal transduction cascade and serves an alternative to mutual entropy. When KLD is minimized, the divergence is given by the ratio of the prior selection probability of the signaling molecule to the posterior selection probability. Moreover, the information gain during the entire channel is shown to be adequately described by average KLD production rate. Thus, this approach provides a framework for the quantitative analysis of signal transduction. Moreover, the proposed approach can identify an effective cascade for a signaling network.

  11. The roles of DNA damage-dependent signals and MAPK cascades in tributyltin-induced germline apoptosis in Caenorhabditis elegans.

    Science.gov (United States)

    Wang, Yun; Wang, Shunchang; Luo, Xun; Yang, Yanan; Jian, Fenglei; Wang, Xuemin; Xie, Lucheng

    2014-08-01

    The induction of apoptosis is recognized to be a major mechanism of tributyltin (TBT) toxicity. However, the underlying signaling pathways for TBT-induced apoptosis remain unclear. In this study, using the nematode Caenorhabditis elegans, we examined whether DNA damage response (DDR) pathway and mitogen-activated protein kinase (MAPK) signaling cascades are involved in TBT-induced germline apoptosis and cell cycle arrest. Our results demonstrated that exposing worms to TBT at the dose of 10nM for 6h significantly increased germline apoptosis in N2 strain. Germline apoptosis was absent in strains that carried ced-3 or ced-4 loss-of-function alleles, indicating that both caspase protein CED-3 and Apaf-1 protein CED-4 were required for TBT-induced apoptosis. TBT-induced apoptosis was blocked in the Bcl-2 gain-of-function strain ced-9(n1950), whereas TBT induced a minor increase in the BH3-only protein EGL-1 mutated strain egl-1(n1084n3082). Checkpoint proteins HUS-1 and CLK-2 exerted proapoptotic effects, and the null mutation of cep-1, the homologue of tumor suppressor gene p53, significantly inhibited TBT-induced apoptosis. Apoptosis in the loss-of-function strains of ERK, JNK and p38 MAPK signaling pathways were completely or mildly suppressed under TBT stress. These results were supported by the results of mRNA expression levels of corresponding genes. The present study indicated that TBT-induced apoptosis required the core apoptotic machinery, and that DDR genes and MAPK pathways played essential roles in signaling the processes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Peroxisome Proliferator-Activated Receptor-γ Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer

    Directory of Open Access Journals (Sweden)

    Costas Giaginis

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-γ ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis. In this aspect, accumulating in vitro and in vivo studies have provided extensive evidence that PPAR-γ ligands can function as modulators of the angiogenic signaling cascade. In the current review, the crucial role of PPAR-γ ligands and the underlying mechanisms participating in tumor angiogenesis are summarized. Targeting PPAR-γ may prove to be a potential therapeutic strategy in combined treatments with conventional chemotherapy; however, special attention should be taken as there is also substantial evidence to support that PPAR-γ ligands can enhance angiogenic phenotype in tumoral cells.

  13. Nitric oxide/cGMP/PKG signaling pathway activated by M1-type muscarinic acetylcholine receptor cascade inhibits Na+-activated K+ currents in Kenyon cells

    Science.gov (United States)

    Hasebe, Masaharu

    2016-01-01

    The interneurons of the mushroom body, known as Kenyon cells, are essential for the long-term memory of olfactory associative learning in some insects. Some studies have reported that nitric oxide (NO) is strongly related to this long-term memory in Kenyon cells. However, the target molecules and upstream and downstream NO signaling cascades are not completely understood. Here we analyzed the effect of the NO signaling cascade on Na+-activated K+ (KNa) channel activity in Kenyon cells of crickets (Gryllus bimaculatus). We found that two different NO donors, S-nitrosoglutathione (GSNO) and S-nitroso-N-acetyl-dl-penicillamine (SNAP), strongly suppressed KNa channel currents. Additionally, this inhibitory effect of GSNO on KNa channel activity was diminished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), and KT5823, an inhibitor of protein kinase G (PKG). Next, we analyzed the role of ACh in the NO signaling cascade. ACh strongly suppressed KNa channel currents, similar to NO donors. Furthermore, this inhibitory effect of ACh was blocked by pirenzepine, an M1 muscarinic ACh receptor antagonist, but not by 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) and mecamylamine, an M3 muscarinic ACh receptor antagonist and a nicotinic ACh receptor antagonist, respectively. The ACh-induced inhibition of KNa channel currents was also diminished by the PLC inhibitor U73122 and the calmodulin antagonist W-7. Finally, we found that ACh inhibition was blocked by the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME). These results suggested that the ACh signaling cascade promotes NO production by activating NOS and NO inhibits KNa channel currents via the sGC/cGMP/PKG signaling cascade in Kenyon cells. PMID:26984419

  14. Perturbation of cellular signaling cascades modulated by ionizing radiation and environmental stress

    International Nuclear Information System (INIS)

    Ugolini, M.

    2014-01-01

    Cellular signaling plays a central role in the regulation of several cell functions, which can be perturbed by different external stimuli, including environmental stress and ionizing radiation. The dysregulation of intra- and extracellular mechanisms may alter the correct behaviour of cells. The aim of this work was to investigate the activation of strongly interlaced intracellular signaling pathways, following the exposure to low- and medium-doses of X-rays, with a focus on the mechanisms involved in the inflammatory- and apoptotic-related responses. In particular, the temporal dynamics of the ERK1/2 and PKB/AKT pathways and their possible dose dependences were investigated. The presented results indicate a clear dose dependence of such pathways only at early time points, suggesting a fast response of the system to X-rays and the need for further studies at shorter times after exposures.

  15. Melanopsin-expressing amphioxus photoreceptors transduce light via a phospholipase C signaling cascade.

    Directory of Open Access Journals (Sweden)

    Juan Manuel Angueyra

    Full Text Available Melanopsin, the receptor molecule that underlies light sensitivity in mammalian 'circadian' receptors, is homologous to invertebrate rhodopsins and has been proposed to operate via a similar signaling pathway. Its downstream effectors, however, remain elusive. Melanopsin also expresses in two distinct light-sensitive cell types in the neural tube of amphioxus. This organism is the most basal extant chordate and can help outline the evolutionary history of different photoreceptor lineages and their transduction mechanisms; moreover, isolated amphioxus photoreceptors offer unique advantages, because they are unambiguously identifiable and amenable to single-cell physiological assays. In the present study whole-cell patch clamp recording, pharmacological manipulations, and immunodetection were utilized to investigate light transduction in amphioxus photoreceptors. A G(q was identified and selectively localized to the photosensitive microvillar membrane, while the pivotal role of phospholipase C was established pharmacologically. The photocurrent was profoundly depressed by IP₃ receptor antagonists, highlighting the importance of IP₃ receptors in light signaling. By contrast, surrogates of diacylglycerol (DAG, as well as poly-unsaturated fatty acids failed to activate a membrane conductance or to alter the light response. The results strengthen the notion that calcium released from the ER via IP₃-sensitive channels may fulfill a key role in conveying--directly or indirectly--the melanopsin-initiated light signal to the photoconductance; moreover, they challenge the dogma that microvillar photoreceptors and phoshoinositide-based light transduction are a prerogative of invertebrate eyes.

  16. Effects of Hypoxia on Erythrocyte Membrane Properties—Implications for Intravascular Hemolysis and Purinergic Control of Blood Flow

    Directory of Open Access Journals (Sweden)

    Ryszard Grygorczyk

    2017-12-01

    Full Text Available Intravascular hemolysis occurs in hereditary, acquired, and iatrogenic hemolytic conditions but it could be also a normal physiological process contributing to intercellular signaling. New evidence suggests that intravascular hemolysis and the associated release of adenosine triphosphate (ATP may be an important mechanism for in vivo local purinergic signaling and blood flow regulation during exercise and hypoxia. However, the mechanisms that modulate hypoxia-induced RBC membrane fragility remain unclear. Here, we provide an overview of the role of RBC ATP release in the regulation of vascular tone and prevailing assumptions on the putative release mechanisms. We show importance of intravascular hemolysis as a source of ATP for local purinergic regulation of blood flow and discuss processes that regulate membrane propensity to rupture under stress and hypoxia.

  17. 17β-estradiol regulates the differentiation of cementoblasts via Notch signaling cascade

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Jing; Zhou, Zeyuan; Huang, Li; Li, Yuyu [Department of Orthodontics, The State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province (China); Li, Jingtao [Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province (China); Zou, Shujuan, E-mail: drzsj@scu.edu.cn [Department of Orthodontics, The State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province (China)

    2016-08-12

    Estrogen has been well recognized as a key factor in the homeostasis of bone and periodontal tissue, but the way it regulates the activities of cementoblasts, the cell population maintaining cementum has not been fully understood. In this study, we examined the expression of estrogen receptor in OCCM-30 cells and the effect of 17β-estradiol (E2) on the proliferation and differentiation of OCCM-30 cells. We found that both estrogen receptor α and β were expressed in OCCM-30 cells. E2 exerted no significant influence on the proliferation of OCCM-30 cells, but inhibited the transcription and translation of BSP and Runx2 in the early phase of osteogenic induction except the BSP mRNA. Afterwards in the late phase of osteogenic induction, E2 enhanced the transcription and translation of BSP and Runx2 and promoted the calcium deposition. In addition, the expression level of Notch1, NICD and Hey1 mRNAs responded to exogenous E2 in a pattern similar to that of the osteoblastic markers. DAPT could attenuate the effect of E2 on the expression of osteoblastic markers. These findings indicated that E2 might regulate the differentiation of cementoblasts via Notch signaling. - Highlights: • 17β-estradiol showed no significant effect on the proliferation of cementoblasts. • 17β-estradiol promoted the osteoblastic differentiation of cementoblasts despite of an early transient inhibition. • Notch signaling was regulated by 17β-estradiol and was responsible for mediating the effect of E2 on cementoblasts. • Hey1 might display an opposite expression pattern to Notch signaling in certain circumstances.

  18. Sonic hedgehog signaling regulates actin cytoskeleton via Tiam1-Rac1 cascade during spine formation.

    Science.gov (United States)

    Sasaki, Nobunari; Kurisu, Junko; Kengaku, Mineko

    2010-12-01

    The sonic hedgehog (Shh) pathway has essential roles in several processes during development of the vertebrate central nervous system (CNS). Here, we report that Shh regulates dendritic spine formation in hippocampal pyramidal neurons via a novel pathway that directly regulates the actin cytoskeleton. Shh signaling molecules Patched (Ptc) and Smoothened (Smo) are expressed in several types of postmitotic neurons, including cerebellar Purkinje cells and hippocampal pyramidal neurons. Knockdown of Smo induces dendritic spine formation in cultured hippocampal neurons independently of Gli-mediated transcriptional activity. Smo interacts with Tiam1, a guanine nucleotide exchange factor for Rac1, via its cytoplasmic C-terminal region. Inhibition of Tiam1 or Rac1 activity suppresses spine induction by Smo knockdown. Shh induces remodeling of the actin cytoskeleton independently of transcriptional activation in mouse embryonic fibroblasts. These findings demonstrate a novel Shh pathway that regulates the actin cytoskeleton via Tiam1-Rac1 activation. Copyright © 2010 Elsevier Inc. All rights reserved.

  19. Distinct Signaling Cascades Elicited by Different Formyl Peptide Receptor 2 (FPR2 Agonists

    Directory of Open Access Journals (Sweden)

    Fabio Cattaneo

    2013-04-01

    Full Text Available The formyl peptide receptor 2 (FPR2 is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR family. FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a ligand-specific fashion. In addition to the anti-inflammatory lipid, lipoxin A4, several other endogenous agonists also bind FPR2, including serum amyloid A, glucocorticoid-induced annexin 1, urokinase and its receptor, suggesting that the activation of FPR2 may result in potent pro- or anti-inflammatory responses. Other endogenous ligands, also present in biological samples, include resolvins, amyloidogenic proteins, such as beta amyloid (Aβ-42 and prion protein (Prp106–126, the neuroprotective peptide, humanin, antibacterial peptides, annexin 1-derived peptides, chemokine variants, the neuropeptides, vasoactive intestinal peptide (VIP and pituitary adenylate cyclase activating polypeptide (PACAP-27, and mitochondrial peptides. Upon activation, intracellular domains of FPR2 mediate signaling to G-proteins, which trigger several agonist-dependent signal transduction pathways, including activation of phospholipase C (PLC, protein kinase C (PKC isoforms, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt pathway, the mitogen-activated protein kinase (MAPK pathway, p38MAPK, as well as the phosphorylation of cytosolic tyrosine kinases, tyrosine kinase receptor transactivation, phosphorylation and nuclear translocation of regulatory transcriptional factors, release of calcium and production of oxidants. FPR2 is an attractive therapeutic target, because of its involvement in a range of normal physiological processes and pathological diseases. Here, we review and discuss the most significant findings on the intracellular pathways and on the cross-communication between FPR2 and tyrosine kinase receptors triggered by different FPR2

  20. Ouabain rescues rat nephrogenesis during intrauterine growth restriction by regulating the complement and coagulation cascades and calcium signaling pathway.

    Science.gov (United States)

    Chen, L; Yue, J; Han, X; Li, J; Hu, Y

    2016-02-01

    Intrauterine growth restriction (IUGR) is associated with a reduction in the numbers of nephrons in neonates, which increases the risk of hypertension. Our previous study showed that ouabain protects the development of the embryonic kidney during IUGR. To explore this molecular mechanism, IUGR rats were induced by protein and calorie restriction throughout pregnancy, and ouabain was delivered using a mini osmotic pump. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) of the embryonic kidneys. DEGs were submitted to the Database for Annotation and Visualization and Integrated Discovery, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Maternal malnutrition significantly reduced fetal weight, but ouabain treatment had no significant effect on body weight. A total of 322 (177 upregulated and 145 downregulated) DEGs were detected between control and the IUGR group. Meanwhile, 318 DEGs were found to be differentially expressed (180 increased and 138 decreased) between the IUGR group and the ouabain-treated group. KEGG pathway analysis indicated that maternal undernutrition mainly disrupts the complement and coagulation cascades and the calcium signaling pathway, which could be protected by ouabain treatment. Taken together, these two biological pathways may play an important role in nephrogenesis, indicating potential novel therapeutic targets against the unfavorable effects of IUGR.

  1. Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells.

    Science.gov (United States)

    Vilches, Silvia; Vergara, Cristina; Nicolás, Oriol; Mata, Ágata; Del Río, José A; Gavín, Rosalina

    2016-09-01

    The biological functions of the cellular prion protein remain poorly understood. In fact, numerous studies have aimed to determine specific functions for the different protein domains. Studies of cellular prion protein (PrP(C)) domains through in vivo expression of molecules carrying internal deletions in a mouse Prnp null background have provided helpful data on the implication of the protein in signalling cascades in affected neurons. Nevertheless, understanding of the mechanisms underlying the neurotoxicity induced by these PrP(C) deleted forms is far from complete. To better define the neurotoxic or neuroprotective potential of PrP(C) N-terminal domains, and to overcome the heterogeneity of results due to the lack of a standardized model, we used neuroblastoma cells to analyse the effects of overexpressing PrP(C) deleted forms. Results indicate that PrP(C) N-terminal deleted forms were properly processed through the secretory pathway. However, PrPΔF35 and PrPΔCD mutants led to death by different mechanisms sharing loss of alpha-cleavage and activation of caspase-3. Our data suggest that both gain-of-function and loss-of-function pathogenic mechanisms may be associated with N-terminal domains and may therefore contribute to neurotoxicity in prion disease. Dissecting the molecular response induced by PrPΔF35 may be the key to unravelling the physiological and pathological functions of the prion protein.

  2. A novel Drosophila injury model reveals severed axons are cleared through a Draper/MMP-1 signaling cascade

    Science.gov (United States)

    Purice, Maria D; Ray, Arpita; Münzel, Eva Jolanda; Pope, Bernard J; Park, Daniel J; Speese, Sean D; Logan, Mary A

    2017-01-01

    Neural injury triggers swift responses from glia, including glial migration and phagocytic clearance of damaged neurons. The transcriptional programs governing these complex innate glial immune responses are still unclear. Here, we describe a novel injury assay in adult Drosophila that elicits widespread glial responses in the ventral nerve cord (VNC). We profiled injury-induced changes in VNC gene expression by RNA sequencing (RNA-seq) and found that responsive genes fall into diverse signaling classes. One factor, matrix metalloproteinase-1 (MMP-1), is induced in Drosophila ensheathing glia responding to severed axons. Interestingly, glial induction of MMP-1 requires the highly conserved engulfment receptor Draper, as well as AP-1 and STAT92E. In MMP-1 depleted flies, glia do not properly infiltrate neuropil regions after axotomy and, as a consequence, fail to clear degenerating axonal debris. This work identifies Draper-dependent activation of MMP-1 as a novel cascade required for proper glial clearance of severed axons. DOI: http://dx.doi.org/10.7554/eLife.23611.001 PMID:28825401

  3. Probing safety of nanoparticles by outlining sea urchin sensing and signaling cascades.

    Science.gov (United States)

    Alijagic, Andi; Pinsino, Annalisa

    2017-10-01

    Among currently identified issues presenting risks and benefits to human and ocean health, engineered nanoparticles (ENP) represent a priority. Predictions of their economic and social impact appear extraordinary, but their release in the environment at an uncontrollable rate is in striking contrast with the extremely limited number of studies on environmental impact, especially on the marine environment. The sea urchin has a remarkable sensing environmental system whose function and diversity came into focus during the recent years, after sea urchin genome sequencing. The complex immune system may be the basis wherefore sea urchins can adapt to a dynamic environment and survive even in hazardous conditions both in the adult and in the embryonic life. This review is aimed at discussing the literature in nanotoxicological/ecotoxicological studies with a focus on stress and innate immune signaling in sea urchins. In addition, here we introduce our current development of in vitro-driven probes that could be used to dissect ENP aftermaths, suggesting their future use in immune-nanotoxicology. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Short- and long-term memory: differential involvement of neurotransmitter systems and signal transduction cascades

    Directory of Open Access Journals (Sweden)

    MÔNICA R.M. VIANNA

    2000-09-01

    Full Text Available Since William James (1890 first distinguished primary from secondary memory, equivalent to short- and long-term memory, respectively, it has been assumed that short-term memory processes are in charge of cognition while long-term memory is being consolidated. From those days a major question has been whether short-term memory is merely a initial phase of long-term memory, or a separate phenomena. Recent experiments have shown that many treatments with specific molecular actions given into the hippocampus and related brain areas after one-trial avoidance learning can effectively cancel short-term memory without affecting long-term memory formation. This shows that short-term memory and long-term memory involve separate mechanisms and are independently processed. Other treatments, however, influence both memory types similarly, suggesting links between both at the receptor and at the post-receptor level, which should not be surprising as they both deal with nearly the same sensorimotor representations. This review examines recent advances in short- and long-term memory mechanisms based on the effect of intra-hippocampal infusion of drugs acting upon neurotransmitter and signal transduction systems on both memory types.

  5. Regulatory cross-talks and cascades in rice hormone biosynthesis pathways contribute to stress signaling

    Directory of Open Access Journals (Sweden)

    Arindam Deb

    2016-08-01

    Full Text Available Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each other’s production directly. Thus multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones.

  6. Fluvoxamine moderates reduced voluntary activity following chronic dexamethasone infusion in mice via recovery of BDNF signal cascades.

    Science.gov (United States)

    Terada, Kazuki; Izumo, Nobuo; Suzuki, Biora; Karube, Yoshiharu; Morikawa, Tomomi; Ishibashi, Yukiko; Kameyama, Toshiki; Chiba, Koji; Sasaki, Noriko; Iwata, Keiko; Matsuzaki, Hideo; Manabe, Takayuki

    2014-04-01

    Major depression is a complex disorder characterized by genetic and environmental interactions. Selective serotonin reuptake inhibitors (SSRIs) effectively treat depression. Neurogenesis following chronic antidepressant treatment activates brain derived neurotrophic factor (BDNF) signaling. In this study, we analyzed the effects of the SSRI fluvoxamine (Flu) on locomotor activity and forced-swim behavior using chronic dexamethasone (cDEX) infusions in mice, which engenders depression-like behavior. Infusion of cDEX decreased body weight and produced a trend towards lower locomotor activity during darkness. In the forced-swim test, cDEX-mice exhibited increased immobility times compared with mice administered saline. Flu treatment reversed decreased locomotor activity and mitigated forced-swim test immobility. Real-time polymerase chain reactions using brain RNA samples yielded significantly lower BDNF mRNA levels in cDEX-mice compared with the saline group. Endoplasmic reticulum stress-associated X-box binding protein-1 (XBP1) gene expression was lower in cDEX-mice compared with the saline group. However, marked expression of the XBP1 gene was observed in cDEX-mice treated with Flu compared with mice given saline and untreated cDEX-mice. Expression of 5-HT2A and Sigma-1 receptors decreased after cDEX infusion compared with the saline group, and these decreases normalized to control levels upon Flu treatment. Our results indicate that the Flu moderates reductions in voluntary activity following chronic dexamethasone infusions in mice via recovery of BDNF signal cascades. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. The ATM signaling cascade promotes recombination-dependent pachytene arrest in mouse spermatocytes.

    Directory of Open Access Journals (Sweden)

    Sarai Pacheco

    2015-03-01

    Full Text Available Most mutations that compromise meiotic recombination or synapsis in mouse spermatocytes result in arrest and apoptosis at the pachytene stage of the first meiotic prophase. Two main mechanisms are thought to trigger arrest: one independent of the double-strand breaks (DSBs that initiate meiotic recombination, and another activated by persistent recombination intermediates. Mechanisms underlying the recombination-dependent arrest response are not well understood, so we sought to identify factors involved by examining mutants deficient for TRIP13, a conserved AAA+ ATPase required for the completion of meiotic DSB repair. We find that spermatocytes with a hypomorphic Trip13 mutation (Trip13mod/mod arrest with features characteristic of early pachynema in wild type, namely, fully synapsed chromosomes without incorporation of the histone variant H1t into chromatin. These cells then undergo apoptosis, possibly in response to the arrest or in response to a defect in sex body formation. However, TRIP13-deficient cells that additionally lack the DSB-responsive kinase ATM progress further, reaching an H1t-positive stage (i.e., similar to mid/late pachynema in wild type despite the presence of unrepaired DSBs. TRIP13-deficient spermatocytes also progress to an H1t-positive stage if ATM activity is attenuated by hypomorphic mutations in Mre11 or Nbs1 or by elimination of the ATM-effector kinase CHK2. These mutant backgrounds nonetheless experience an apoptotic block to further spermatogenic progression, most likely caused by failure to form a sex body. DSB numbers are elevated in Mre11 and Nbs1 hypomorphs but not Chk2 mutants, thus delineating genetic requirements for the ATM-dependent negative feedback loop that regulates DSB numbers. The findings demonstrate for the first time that ATM-dependent signaling enforces the normal pachytene response to persistent recombination intermediates. Our work supports the conclusion that recombination defects trigger

  8. Beneficial effects of Ginkgo biloba extract on insulin signaling cascade, dyslipidemia, and body adiposity of diet-induced obese rats

    Directory of Open Access Journals (Sweden)

    R.M. Banin

    2014-09-01

    Full Text Available Ginkgo biloba extract (GbE has been indicated as an efficient medicine for the treatment of diabetes mellitus type 2. It remains unclear if its effects are due to an improvement of the insulin signaling cascade, especially in obese subjects. The aim of the present study was to evaluate the effect of GbE on insulin tolerance, food intake, body adiposity, lipid profile, fasting insulin, and muscle levels of insulin receptor substrate 1 (IRS-1, protein tyrosine phosphatase 1B (PTP-1B, and protein kinase B (Akt, as well as Akt phosphorylation, in diet-induced obese rats. Rats were fed with a high-fat diet (HFD or a normal fat diet (NFD for 8 weeks. After that, the HFD group was divided into two groups: rats gavaged with a saline vehicle (HFD+V, and rats gavaged with 500 mg/kg of GbE diluted in the saline vehicle (HFD+Gb. NFD rats were gavaged with the saline vehicle only. At the end of the treatment, the rats were anesthetized, insulin was injected into the portal vein, and after 90s, the gastrocnemius muscle was removed. The quantification of IRS-1, Akt, and Akt phosphorylation was performed using Western blotting. Serum levels of fasting insulin and glucose, triacylglycerols and total cholesterol, and LDL and HDL fractions were measured. An insulin tolerance test was also performed. Ingestion of a hyperlipidic diet promoted loss of insulin sensitivity and also resulted in a significant increase in body adiposity, plasma triacylglycerol, and glucose levels. In addition, GbE treatment significantly reduced food intake and body adiposity while it protected against hyperglycemia and dyslipidemia in diet-induced obesity rats. It also enhanced insulin sensitivity in comparison to HFD+V rats, while it restored insulin-induced Akt phosphorylation, increased IRS-1, and reduced PTP-1B levels in gastrocnemius muscle. The present findings suggest that G. biloba might be efficient in preventing and treating obesity-induced insulin signaling impairment.

  9. Beneficial effects of Ginkgo biloba extract on insulin signaling cascade, dyslipidemia, and body adiposity of diet-induced obese rats

    International Nuclear Information System (INIS)

    Banin, R.M.; Hirata, B.K.S.; Andrade, I.S.; Zemdegs, J.C.S.; Clemente, A.P.G.; Dornellas, A.P.S.; Boldarine, V.T.; Estadella, D.; Albuquerque, K.T.; Oyama, L.M.; Ribeiro, E.B.; Telles, M.M.

    2014-01-01

    Ginkgo biloba extract (GbE) has been indicated as an efficient medicine for the treatment of diabetes mellitus type 2. It remains unclear if its effects are due to an improvement of the insulin signaling cascade, especially in obese subjects. The aim of the present study was to evaluate the effect of GbE on insulin tolerance, food intake, body adiposity, lipid profile, fasting insulin, and muscle levels of insulin receptor substrate 1 (IRS-1), protein tyrosine phosphatase 1B (PTP-1B), and protein kinase B (Akt), as well as Akt phosphorylation, in diet-induced obese rats. Rats were fed with a high-fat diet (HFD) or a normal fat diet (NFD) for 8 weeks. After that, the HFD group was divided into two groups: rats gavaged with a saline vehicle (HFD+V), and rats gavaged with 500 mg/kg of GbE diluted in the saline vehicle (HFD+Gb). NFD rats were gavaged with the saline vehicle only. At the end of the treatment, the rats were anesthetized, insulin was injected into the portal vein, and after 90s, the gastrocnemius muscle was removed. The quantification of IRS-1, Akt, and Akt phosphorylation was performed using Western blotting. Serum levels of fasting insulin and glucose, triacylglycerols and total cholesterol, and LDL and HDL fractions were measured. An insulin tolerance test was also performed. Ingestion of a hyperlipidic diet promoted loss of insulin sensitivity and also resulted in a significant increase in body adiposity, plasma triacylglycerol, and glucose levels. In addition, GbE treatment significantly reduced food intake and body adiposity while it protected against hyperglycemia and dyslipidemia in diet-induced obesity rats. It also enhanced insulin sensitivity in comparison to HFD+V rats, while it restored insulin-induced Akt phosphorylation, increased IRS-1, and reduced PTP-1B levels in gastrocnemius muscle. The present findings suggest that G. biloba might be efficient in preventing and treating obesity-induced insulin signaling impairment

  10. Beneficial effects of Ginkgo biloba extract on insulin signaling cascade, dyslipidemia, and body adiposity of diet-induced obese rats

    Energy Technology Data Exchange (ETDEWEB)

    Banin, R. M.; Hirata, B. K.S. [Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, SP (Brazil); Andrade, I. S.; Zemdegs, J. C.S. [Disciplina de Fisiologia da Nutrição, Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Clemente, A. P.G. [Faculdade de Nutrição, Universidade Federal de Alagoas, Maceió, AL (Brazil); Dornellas, A. P.S.; Boldarine, V. T. [Disciplina de Fisiologia da Nutrição, Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Estadella, D. [Departamento de Biociências, Universidade Federal de São Paulo, Baixada Santista, SP (Brazil); Albuquerque, K. T. [Curso de Nutrição, Universidade Federal do Rio de Janeiro, Macaé, RJ (Brazil); Oyama, L. M.; Ribeiro, E. B. [Disciplina de Fisiologia da Nutrição, Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Telles, M. M. [Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, SP (Brazil)

    2014-07-25

    Ginkgo biloba extract (GbE) has been indicated as an efficient medicine for the treatment of diabetes mellitus type 2. It remains unclear if its effects are due to an improvement of the insulin signaling cascade, especially in obese subjects. The aim of the present study was to evaluate the effect of GbE on insulin tolerance, food intake, body adiposity, lipid profile, fasting insulin, and muscle levels of insulin receptor substrate 1 (IRS-1), protein tyrosine phosphatase 1B (PTP-1B), and protein kinase B (Akt), as well as Akt phosphorylation, in diet-induced obese rats. Rats were fed with a high-fat diet (HFD) or a normal fat diet (NFD) for 8 weeks. After that, the HFD group was divided into two groups: rats gavaged with a saline vehicle (HFD+V), and rats gavaged with 500 mg/kg of GbE diluted in the saline vehicle (HFD+Gb). NFD rats were gavaged with the saline vehicle only. At the end of the treatment, the rats were anesthetized, insulin was injected into the portal vein, and after 90s, the gastrocnemius muscle was removed. The quantification of IRS-1, Akt, and Akt phosphorylation was performed using Western blotting. Serum levels of fasting insulin and glucose, triacylglycerols and total cholesterol, and LDL and HDL fractions were measured. An insulin tolerance test was also performed. Ingestion of a hyperlipidic diet promoted loss of insulin sensitivity and also resulted in a significant increase in body adiposity, plasma triacylglycerol, and glucose levels. In addition, GbE treatment significantly reduced food intake and body adiposity while it protected against hyperglycemia and dyslipidemia in diet-induced obesity rats. It also enhanced insulin sensitivity in comparison to HFD+V rats, while it restored insulin-induced Akt phosphorylation, increased IRS-1, and reduced PTP-1B levels in gastrocnemius muscle. The present findings suggest that G. biloba might be efficient in preventing and treating obesity-induced insulin signaling impairment.

  11. Role of purinergic receptor polymorphisms in human bone

    DEFF Research Database (Denmark)

    Wesselius, Anke; Bours, Martijn J L; Agrawal, Ankita

    2011-01-01

    Osteoporosis is a multifactorial disease with a strong genetic component. Variations in a number of genes have been shown to associate with bone turnover and risk of osteoporosis. P2 purinergic receptors are proteins that have ATP or other nucleotides as their natural ligands. Various P2Y and P2X...

  12. Rapid resensitization of purinergic receptor function in human platelets.

    Science.gov (United States)

    Mundell, S J; Barton, J F; Mayo-Martin, M B; Hardy, A R; Poole, A W

    2008-08-01

    Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors (GPCRs), the P2Y(1) and P2Y(12) purinergic receptors. Recently, we demonstrated that both receptors desensitize and internalize in human platelets by differential kinase-dependent mechanisms. To demonstrate whether responses to P2Y(1) and P2Y(12) purinergic receptors resensitize in human platelets and determine the role of receptor traffic in this process. These studies were undertaken either in human platelets or in cells stably expressing epitope-tagged P2Y(1) and P2Y(12) purinergic receptor constructs. In this study we show for the first time that responses to both of these receptors can rapidly resensitize following agonist-dependent desensitization in human platelets. Further, we show that in human platelets or in 1321N1 cells stably expressing receptor constructs, the disruption of receptor internalization, dephosphorylation or subsequent receptor recycling is sufficient to block resensitization of purinergic receptor responses. We also show that, in platelets, internalization of both these receptors is dependent upon dynamin, and that this process is required for resensitization of responses. This study is therefore the first to show that both P2Y(1) and P2Y(12) receptor activities are rapidly and reversibly modulated in human platelets, and it reveals that the underlying mechanism requires receptor trafficking as an essential part of this process.

  13. Isorhynchophylline, a Potent Plant Alkaloid, Induces Apoptotic and Anti-Metastatic Effects in Human Hepatocellular Carcinoma Cells through the Modulation of Diverse Cell Signaling Cascades.

    Science.gov (United States)

    Lee, Hanwool; Baek, Seung Ho; Lee, Jong Hyun; Kim, Chulwon; Ko, Jeong-Hyeon; Lee, Seok-Geun; Chinnathambi, Arunachalam; Alharbi, Sulaiman Ali; Yang, Woong Mo; Um, Jae-Young; Sethi, Gautam; Ahn, Kwang Seok

    2017-05-19

    Isorhynchophylline (Rhy) is an active pharmacological component of Uncaria rhynchophylla that has been reported previously to exert significant antihypertensive and neuroprotective effects. However, very little is known about its potential anti-cancer activities. This study was carried out to evaluate the anticancer effects of Rhy against various human carcinoma cell lines. We found that Rhy exhibited substantial cytotoxic effect against human hepatocellular carcinoma HepG2 cells when compared with other human carcinoma cell lines including those of lung, pancreas, prostate, head and neck, breast, multiple myeloma, brain and renal cell carcinoma. Rhy induced apoptosis as characterized by accumulation of cells in sub G1 phase; positive Annexin V binding; activation of caspase-8, -9, and -3; and cleavage of PARP (poly-ADP ribose polymerase). This effect of Rhy correlated with the down-regulation of various proteins that mediated cell proliferation, cell survival, metastasis, and angiogenesis. Moreover, cell proliferation, migration, and constitutive CXCR4 (C-X-C chemokine receptor type 4), MMP-9 (Matrix metallopeptidase-9), and MMP-2 expression were inhibited upon Rhy treatment. We further investigated the effect of Rhy on the oncogenic cell signaling cascades through phospho-kinase array profiling assay. Rhy was found to abrogate phospho-p38, ERK, JNK, CREB, c-Jun, Akt, and STAT3 signals, but interestingly enhanced phospho-p53 signal. Overall, our results indicate, for the first time, that Rhy could exert anticancer and anti-metastatic effects through regulation of multiple signaling cascades in hepatocellular carcinoma cells.

  14. Purinergic signalling in the nervous system: an overview

    Czech Academy of Sciences Publication Activity Database

    Abbracchio, M. P.; Burnstock, G.; Verkhratsky, Alexei; Zimmermann, H.

    2009-01-01

    Roč. 32, č. 1 (2009), s. 19-29 ISSN 0166-2236 Institutional research plan: CEZ:AV0Z50390512 Keywords : extracellular hydrolysis * behaviour Subject RIV: FH - Neurology Impact factor: 12.794, year: 2009

  15. Intrarenal purinergic signaling in the control of renal tubular transport

    DEFF Research Database (Denmark)

    Prætorius, Helle; Leipziger, Jens Georg

    2010-01-01

    -reaching advances indicate that ATP is often used as a local transmitter for classical sensory transduction. This transmission apparently also applies to sensory functions in the kidney. Locally released ATP is involved in sensing of renal tubular flow or in detecting the distal tubular load of NaCl at the macula...

  16. The C-terminal tail of CRTH2 is a key molecular determinant that constrains GalphaI- and downstream-signaling cascade activation

    DEFF Research Database (Denmark)

    Schroeder, Ralf; Merten, Nicole; Mathiesen, Jesper Mosolff

    2009-01-01

    Prostaglandin D(2) activation of the seven transmembrane receptor CRTH2 regulates numerous cell functions that are important in inflammatory diseases such as asthma. Despite its disease implication, no studies to date aimed at identifying receptor domains governing signaling and surface expression......2 at the plasma membrane, presence of this domain confers a signaling-compromised conformation onto the receptor. Indeed, a mutant receptor lacking the major portion of its C-terminal tail displays paradoxically enhanced Galphai and ERK1/2 activation in spite of enhanced constitutive and agonist......-mediated internalization. Enhanced activation of Galphai proteins and downstream signaling cascades is likely due to the inability of the tail-truncated receptor to recruit beta-arrestin2 and undergo homologous desensitization. Unexpectedly, CRTH2 is not phosphorylated upon agonist-stimulation, a primary mechanism...

  17. Identification of ASK1, MKK4, JNK, c-Jun, and caspase-3 as a signaling cascade involved in cadmium-induced neuronal cell apoptosis

    International Nuclear Information System (INIS)

    Kim, Sun Don; Moon, Chang Kyu; Eun, Su-Yong; Ryu, Pan Dong; Jo, Sangmee Ahn

    2005-01-01

    Cd induces oxidative stress and apoptosis in various cells by activating mitogen-activated protein kinases (MAPKs), but the precise signaling components of the MAPK cascade and their role in neuronal apoptosis are still unclear. Here, we report that Cd treatment of SH-SY5Y cells caused apoptosis through sequential phosphorylation of the apoptosis signal regulating kinase 1, MAPK kinase 4, c-Jun N-terminal kinase (JNK), and c-Jun as determined by overexpression of dominant negative (DN) constructs of these genes or using a specific JNK inhibitor SP600125. Both Cd-induced JNK and c-Jun phosphorylation and apoptosis were inhibited dramatically by N-acetyl-L-cysteine, a free radical scavenger. In addition, caspase inhibitors, zDEVD and zVAD, reduced apoptosis but not JNK and c-Jun phosphorylation induced by Cd, while overexpression of DN JNK1 inhibited caspase-3 activity. Taken together, our data suggested that the JNK/c-Jun signaling cascade plays a crucial role in Cd-induced neuronal cell apoptosis and provides a molecular linkage between oxidative stress and neuronal apoptosis

  18. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance

    DEFF Research Database (Denmark)

    Houthuijzen, Julia M; Oosterom, Ilse; Hudson, Brian D

    2017-01-01

    Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts....... M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance....

  19. Purinergic Receptors: Key Mediators of HIV-1 infection and inflammation

    Directory of Open Access Journals (Sweden)

    Talia H Swartz

    2015-11-01

    Full Text Available Human immunodeficiency virus (HIV-1 causes a chronic infection that afflicts more than 38 million individuals worldwide. While the infection can be suppressed with potent anti-retroviral therapies, individuals infected with HIV have elevated levels of inflammation as indicated by increased T cell activation, soluble biomarkers, and associated morbidity and mortality. A single mechanism linking HIV pathogenesis to this inflammation has yet to be identified. Purinergic receptors are known to mediate inflammation and have been shown to be required for HIV-1 infection at the level of HIV-1 membrane fusion. Here we review the literature on the role of purinergic receptors in HIV-1 infection and associated inflammation and describe a role for these receptors as potential therapeutic targets.

  20. The p75NTR mediates a bifurcated signal transduction cascade through the NFκB and JNK pathways to inhibit cell survival

    International Nuclear Information System (INIS)

    Allen, Jeffrey; Khwaja, Fatima; Byers, Stephen; Djakiew, Daniel

    2005-01-01

    p75 NTR is most abundantly expressed in the nervous system, but is also widely expressed in many other organs and tissues where it primarily functions as a negative regulator of cell survival. In the prostate, p75 NTR functions as an inhibitory protein capable of slowing proliferation and inducing apoptosis. It has been shown that p75 NTR is expressed in the normal prostate, progressively lost from malignant tumor cells in vivo, and largely absent from prostate cancer cell lines derived from metastases. Although the role of p75 NTR in prostate cancer has been well established, the signal transduction pathway that mediates its inhibitory activity has only been partially elucidated. This study demonstrates that exogenous expression of p75 NTR down-regulates, in a dose-dependent manner, a bifurcated signaling cascade that results in reduced expression of potent transcription effectors. This two-arm signal transduction cascade was directly linked to the upstream receptor by using dominant-negative deletion constructs of p75 NTR that rescued tumor cells from p75 NTR -induced loss of survival and promotion of apoptosis. Furthermore, the dominant negatives rescued alterations in the levels of signal transduction intermediates. Conversely, the use of kinase-inactive intermediates that are downstream of the receptor further reduced expression of involved transcription effectors and reduced survival of the cells. These results provide a definitive link between the proximate p75 NTR and signal transduction intermediates leading to the transcription effectors NFκB and JNK, with associated growth suppression and induction of apoptosis

  1. Activation of AMPA receptor promotes TNF-α release via the ROS-cSrc-NFκB signaling cascade in RAW264.7 macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Xiu-Li [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Ding, Fan [Office of Scientific R& D, Tsinghua University, Beijing (China); Li, Hui; Tan, Xiao-Qiu [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Liu, Xiao [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Cao, Ji-Min, E-mail: caojimin@126.com [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Gao, Xue, E-mail: longlongnose@163.com [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China)

    2015-05-29

    The relationship between glutamate signaling and inflammation has not been well defined. This study aimed to investigate the role of AMPA receptor (AMPAR) in the expression and release of tumor necrosis factor-alpha (TNF-α) from macrophages and the underlying mechanisms. A series of approaches, including confocal microscopy, immunofluorescency, flow cytometry, ELISA and Western blotting, were used to estimate the expression of AMPAR and downstream signaling molecules, TNF-α release and reactive oxygen species (ROS) generation in the macrophage-like RAW264.7 cells. The results demonstrated that AMPAR was expressed in RAW264.7 cells. AMPA significantly enhanced TNF-α release from RAW264.7 cells, and this effect was abolished by CNQX (AMPAR antagonist). AMPA also induced elevation of ROS production, phosphorylation of c-Src and activation of nuclear factor (NF)-κB in RAW264.7 cells. Blocking c-Src by PP2, scavenging ROS by glutathione (GSH) or inhibiting NF-κB activation by pyrrolidine dithiocarbamate (PDTC) decreased TNF-α production from RAW264.7 cells. We concluded that AMPA promotes TNF-α release in RAW264.7 macrophages likely through the following signaling cascade: AMPAR activation → ROS generation → c-Src phosphorylation → NF-κB activation → TNF-α elevation. The study suggests that AMPAR may participate in macrophage activation and inflammation. - Highlights: • AMPAR is expressed in RAW264.7 macrophages and is upregulated by AMPA stimulation. • Activation of AMPAR stimulates TNF-α release in macrophages through the ROS-cSrc-NFκB signaling cascade. • Macrophage AMPAR signaling may play an important role in inflammation.

  2. Isorhynchophylline, a Potent Plant Alkaloid, Induces Apoptotic and Anti-Metastatic Effects in Human Hepatocellular Carcinoma Cells through the Modulation of Diverse Cell Signaling Cascades

    Directory of Open Access Journals (Sweden)

    Hanwool Lee

    2017-05-01

    Full Text Available Isorhynchophylline (Rhy is an active pharmacological component of Uncaria rhynchophylla that has been reported previously to exert significant antihypertensive and neuroprotective effects. However, very little is known about its potential anti-cancer activities. This study was carried out to evaluate the anticancer effects of Rhy against various human carcinoma cell lines. We found that Rhy exhibited substantial cytotoxic effect against human hepatocellular carcinoma HepG2 cells when compared with other human carcinoma cell lines including those of lung, pancreas, prostate, head and neck, breast, multiple myeloma, brain and renal cell carcinoma. Rhy induced apoptosis as characterized by accumulation of cells in sub G1 phase; positive Annexin V binding; activation of caspase-8, -9, and -3; and cleavage of PARP (poly-ADP ribose polymerase. This effect of Rhy correlated with the down-regulation of various proteins that mediated cell proliferation, cell survival, metastasis, and angiogenesis. Moreover, cell proliferation, migration, and constitutive CXCR4 (C-X-C chemokine receptor type 4, MMP-9 (Matrix metallopeptidase-9, and MMP-2 expression were inhibited upon Rhy treatment. We further investigated the effect of Rhy on the oncogenic cell signaling cascades through phospho-kinase array profiling assay. Rhy was found to abrogate phospho-p38, ERK, JNK, CREB, c-Jun, Akt, and STAT3 signals, but interestingly enhanced phospho-p53 signal. Overall, our results indicate, for the first time, that Rhy could exert anticancer and anti-metastatic effects through regulation of multiple signaling cascades in hepatocellular carcinoma cells.

  3. Isorhynchophylline, a Potent Plant Alkaloid, Induces Apoptotic and Anti-Metastatic Effects in Human Hepatocellular Carcinoma Cells through the Modulation of Diverse Cell Signaling Cascades

    Science.gov (United States)

    Lee, Hanwool; Baek, Seung Ho; Lee, Jong Hyun; Kim, Chulwon; Ko, Jeong-Hyeon; Lee, Seok-Geun; Chinnathambi, Arunachalam; Alharbi, Sulaiman Ali; Yang, Woong Mo; Um, Jae-Young; Sethi, Gautam; Ahn, Kwang Seok

    2017-01-01

    Isorhynchophylline (Rhy) is an active pharmacological component of Uncaria rhynchophylla that has been reported previously to exert significant antihypertensive and neuroprotective effects. However, very little is known about its potential anti-cancer activities. This study was carried out to evaluate the anticancer effects of Rhy against various human carcinoma cell lines. We found that Rhy exhibited substantial cytotoxic effect against human hepatocellular carcinoma HepG2 cells when compared with other human carcinoma cell lines including those of lung, pancreas, prostate, head and neck, breast, multiple myeloma, brain and renal cell carcinoma. Rhy induced apoptosis as characterized by accumulation of cells in sub G1 phase; positive Annexin V binding; activation of caspase-8, -9, and -3; and cleavage of PARP (poly-ADP ribose polymerase). This effect of Rhy correlated with the down-regulation of various proteins that mediated cell proliferation, cell survival, metastasis, and angiogenesis. Moreover, cell proliferation, migration, and constitutive CXCR4 (C-X-C chemokine receptor type 4), MMP-9 (Matrix metallopeptidase-9), and MMP-2 expression were inhibited upon Rhy treatment. We further investigated the effect of Rhy on the oncogenic cell signaling cascades through phospho-kinase array profiling assay. Rhy was found to abrogate phospho-p38, ERK, JNK, CREB, c-Jun, Akt, and STAT3 signals, but interestingly enhanced phospho-p53 signal. Overall, our results indicate, for the first time, that Rhy could exert anticancer and anti-metastatic effects through regulation of multiple signaling cascades in hepatocellular carcinoma cells. PMID:28534824

  4. Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling Cascade in Locus Coeruleus Neurons

    Science.gov (United States)

    Borges, Gisela Patrícia; Micó, Juan Antonio; Neto, Fani Lourença

    2015-01-01

    Background: The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the locus coeruleus. Methods: Complete Freund’s adjuvant-induced monoarthritis was used as inflammatory chronic pain model. α-Helical corticotropin-releasing factor receptor antagonist was microinjected into the contralateral locus coeruleus of 4-week-old monoarthritic animals. The nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the paraventricular nucleus and locus coeruleus. Results: Monoarthritic rats manifested anxiety and increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was unaltered. α-Helical corticotropin-releasing factor antagonist administration reversed both the anxiogenic-like behavior and the phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus. Conclusions: Pain-induced anxiety is mediated by corticotropin-releasing factor neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling cascade. PMID:25716783

  5. Porous platinum nanotubes labeled with hemin/G-quadruplex based electrochemical aptasensor for sensitive thrombin analysis via the cascade signal amplification.

    Science.gov (United States)

    Sun, Aili; Qi, Qingan; Wang, Xuannian; Bie, Ping

    2014-07-15

    For the first time, a sensitive electrochemical aptasensor for thrombin (TB) was developed by using porous platinum nanotubes (PtNTs) labeled with hemin/G-quadruplex and glucose dehydrogenase (GDH) as labels. Porous PtNTs with large surface area exhibited the peroxidase-like activity. Coupling with GDH and hemin/G-quadruplex as NADH oxidase and HRP-mimicking DNAzyme, the cascade signal amplification was achieved by the following ways: in the presence of glucose and NAD(+) in the working buffer, GDH electrocatalyzed the oxidation of glucose with the production of NADH. Then, hemin/G-quadruplex as NADH oxidase catalyzed the oxidation of NADH to in situ generate H2O2. Based on the corporate electrocatalysis of PtNTs and hemin/G-quadruplex toward H2O2, the electrochemical signal was significantly amplified, allowing the detection limit of TB down to 0.15 pM level. Moreover, the proposed strategy was simple because the intercalated hemin offered the readout signal, avoiding the adding of additional redox mediator as signal donator. Such an electrochemical aptasensor is highly promising for sensitive detection of other proteins in clinical diagnostics. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. The signaling cascades of Ganoderma lucidum extracts in stimulating non-amyloidogenic protein secretion in human neuroblastoma SH-SY5Y cell lines.

    Science.gov (United States)

    Pinweha, Sirinthorn; Wanikiat, Payong; Sanvarinda, Yupin; Supavilai, Porntip

    2008-12-19

    Ganoderma lucidum (GL) is a medicinal mushroom that possesses various pharmacological properties which are also documented in the ancient reports where GL is praised for its effects on the promotion of health and longevity. In this study, we have investigated the effect of GL mycelia extracts on the non-amyloidogenic protein secretion (sAPPalpha) and the amyloid precursor protein (APP) expression in SH-SY5Y neuroblastoma cells. In order to characterize the signaling pathway which mediates GL-enhanced sAPPalpha secretion, we used inhibitors of nerve growth factor (NGF) signaling pathways, phosphatidylinositol 3 kinase (PI3K), phospholipase Cgamma1 (PLCgamma1), protein kinase C (PKC) and extracellular signal-regulated kinase (ERK1/2), to block GL-mediated sAPPalpha secretion as well as ERK1/2 and PKC activation by using Western blot analysis. Our results provided for the first time evidence that GL mycelia extracts increased APP expression and promoted sAPPalpha secretion. In addition, GL extracts activated ERK1/2 and PKC phosphorylation. The complex signaling cascades of PI3K and ERK may be responsible for GL-mediated sAPPalpha secretion.

  7. Purinergic receptors in the endocrine and exocrine pancreas

    DEFF Research Database (Denmark)

    Novak, I

    2008-01-01

    The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly......, there is also evidence for other P2 and adenosine receptors in beta cells (P2Y(2), P2Y(4), P2Y(6), P2X subtypes and A(1) receptors) and in glucagon-secreting alpha cells (P2X(7), A(2) receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors...

  8. Involvement of purinergic system in inflammation and toxicity induced by copper in zebrafish larvae

    Energy Technology Data Exchange (ETDEWEB)

    Leite, Carlos Eduardo, E-mail: carlos.leite@pucrs.br [Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, CEP 90035-003 (Brazil); Maboni, Lucas de Oliveira [Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Cruz, Fernanda Fernandes [Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Rosemberg, Denis Broock [Programa de Pós-graduação em Ciências Ambientais, Universidade Comunitária da Região de Chapecó, Chapecó, CEP 89809-000 (Brazil); and others

    2013-11-01

    The use of zebrafish (Danio rerio) is increasing as an intermediate preclinical model, to prioritize drug candidates for mammalian testing. As the immune system of the zebrafish is quite similar to that of mammals, models of inflammation are being developed for the screening of new drugs. The characterization of these models is crucial for studies that seek for mechanisms of action and specific pharmacological targets. It is well known that copper is a metal that induces damage and cell migration to hair cells of lateral line of zebrafish. Extracellular nucleotides/nucleosides, as ATP and adenosine (ADO), act as endogenous signaling molecules during tissue damage by exerting effects on inflammatory and immune responses. The present study aimed to characterize the inflammatory status, and to investigate the involvement of the purinergic system in copper-induced inflammation in zebrafish larvae. Fishes of 7 days post-fertilization were exposed to 10 μM of copper for a period of 24 h. The grade of oxidative stress, inflammatory status, copper uptake, the activity and the gene expression of the enzymes responsible for controlling the levels of nucleotides and adenosine were evaluated. Due to the copper accumulation in zebrafish larvae tissues, the damage and oxidative stress were exacerbated over time, resulting in an inflammatory process involving IL-1β, TNF-α, COX-2 and PGE{sub 2}. Within the purinergic system, the mechanisms that control the ADO levels were the most involved, mainly the reactions performed by the isoenzyme ADA 2. In conclusion, our data shed new lights on the mechanisms related to copper-induced inflammation in zebrafish larvae. - Graphical abstract: This scheme provides a chronological proposition for the biochemical events induced by copper in zebrafish larvae. The dashed line shows the absorption of copper over the exposure time. After 1 h of exposure to copper, the release of PGE{sub 2} occurs, followed by an increase of MPO (as a consequence

  9. Involvement of purinergic system in inflammation and toxicity induced by copper in zebrafish larvae

    International Nuclear Information System (INIS)

    Leite, Carlos Eduardo; Maboni, Lucas de Oliveira; Cruz, Fernanda Fernandes; Rosemberg, Denis Broock

    2013-01-01

    The use of zebrafish (Danio rerio) is increasing as an intermediate preclinical model, to prioritize drug candidates for mammalian testing. As the immune system of the zebrafish is quite similar to that of mammals, models of inflammation are being developed for the screening of new drugs. The characterization of these models is crucial for studies that seek for mechanisms of action and specific pharmacological targets. It is well known that copper is a metal that induces damage and cell migration to hair cells of lateral line of zebrafish. Extracellular nucleotides/nucleosides, as ATP and adenosine (ADO), act as endogenous signaling molecules during tissue damage by exerting effects on inflammatory and immune responses. The present study aimed to characterize the inflammatory status, and to investigate the involvement of the purinergic system in copper-induced inflammation in zebrafish larvae. Fishes of 7 days post-fertilization were exposed to 10 μM of copper for a period of 24 h. The grade of oxidative stress, inflammatory status, copper uptake, the activity and the gene expression of the enzymes responsible for controlling the levels of nucleotides and adenosine were evaluated. Due to the copper accumulation in zebrafish larvae tissues, the damage and oxidative stress were exacerbated over time, resulting in an inflammatory process involving IL-1β, TNF-α, COX-2 and PGE 2 . Within the purinergic system, the mechanisms that control the ADO levels were the most involved, mainly the reactions performed by the isoenzyme ADA 2. In conclusion, our data shed new lights on the mechanisms related to copper-induced inflammation in zebrafish larvae. - Graphical abstract: This scheme provides a chronological proposition for the biochemical events induced by copper in zebrafish larvae. The dashed line shows the absorption of copper over the exposure time. After 1 h of exposure to copper, the release of PGE 2 occurs, followed by an increase of MPO (as a consequence of

  10. The EAL domain protein YciR acts as a trigger enzyme in a c-di-GMP signalling cascade in E. coli biofilm control

    Science.gov (United States)

    Lindenberg, Sandra; Klauck, Gisela; Pesavento, Christina; Klauck, Eberhard; Hengge, Regine

    2013-01-01

    C-di-GMP—which is produced by diguanylate cyclases (DGC) and degraded by specific phosphodiesterases (PDEs)—is a ubiquitous second messenger in bacterial biofilm formation. In Escherichia coli, several DGCs (YegE, YdaM) and PDEs (YhjH, YciR) and the MerR-like transcription factor MlrA regulate the transcription of csgD, which encodes a biofilm regulator essential for producing amyloid curli fibres of the biofilm matrix. Here, we demonstrate that this system operates as a signalling cascade, in which c-di-GMP controlled by the DGC/PDE pair YegE/YhjH (module I) regulates the activity of the YdaM/YciR pair (module II). Via multiple direct interactions, the two module II proteins form a signalling complex with MlrA. YciR acts as a connector between modules I and II and functions as a trigger enzyme: its direct inhibition of the DGC YdaM is relieved when it binds and degrades c-di-GMP generated by module I. As a consequence, YdaM then generates c-di-GMP and—by direct and specific interaction—activates MlrA to stimulate csgD transcription. Trigger enzymes may represent a general principle in local c-di-GMP signalling. PMID:23708798

  11. Pharmacodynamic/Pharmacogenomic Modeling of Insulin Resistance Genes in Rat Muscle After Methylprednisolone Treatment: Exploring Regulatory Signaling Cascades

    Directory of Open Access Journals (Sweden)

    Zhenling Yao

    2008-01-01

    Full Text Available Corticosteroids (CS effects on insulin resistance related genes in rat skeletal muscle were studied. In our acute study, adrenalectomized (ADX rats were given single doses of 50 mg/kg methylprednisolone (MPL intravenously. In our chronic study, ADX rats were implanted with Alzet mini-pumps giving zero-order release rates of 0.3 mg/kg/h MPL and sacrificed at various times up to 7 days. Total RNA was extracted from gastrocnemius muscles and hybridized to Affymetrix GeneChips. Data mining and literature searches identified 6 insulin resistance related genes which exhibited complex regulatory pathways. Insulin receptor substrate-1 (IRS-1, uncoupling protein 3 (UCP3, pyruvate dehydrogenase kinase isoenzyme 4 (PDK4, fatty acid translocase (FAT and glycerol-3-phosphate acyltransferase (GPAT dynamic profiles were modeled with mutual effects by calculated nuclear drug-receptor complex (DR(N and transcription factors. The oscillatory feature of endothelin-1 (ET-1 expression was depicted by a negative feedback loop. These integrated models provide test- able quantitative hypotheses for these regulatory cascades.

  12. Andrographolide inhibits nuclear factor-κB activation through JNK-Akt-p65 signaling cascade in tumor necrosis factor-α-stimulated vascular smooth muscle cells.

    Science.gov (United States)

    Chen, Yu-Ying; Hsu, Ming-Jen; Hsieh, Cheng-Ying; Lee, Lin-Wen; Chen, Zhih-Cherng; Sheu, Joen-Rong

    2014-01-01

    Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

  13. Deciphering complex dynamics of water counteraction around secondary structural elements of allosteric protein complex: Case study of SAP-SLAM system in signal transduction cascade.

    Science.gov (United States)

    Samanta, Sudipta; Mukherjee, Sanchita

    2018-01-28

    The first hydration shell of a protein exhibits heterogeneous behavior owing to several attributes, majorly local polarity and structural flexibility as revealed by solvation dynamics of secondary structural elements. We attempt to recognize the change in complex water counteraction generated due to substantial alteration in flexibility during protein complex formation. The investigation is carried out with the signaling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, and interacting with SLAM-associated protein (SAP), composed of one SH2 domain. All atom molecular dynamics simulations are employed to the aqueous solutions of free SAP and SLAM-peptide bound SAP. We observed that water dynamics around different secondary structural elements became highly affected as well as nicely correlated with the SLAM-peptide induced change in structural rigidity obtained by thermodynamic quantification. A few instances of contradictory dynamic features of water to the change in structural flexibility are explained by means of occluded polar residues by the peptide. For βD, EFloop, and BGloop, both structural flexibility and solvent accessibility of the residues confirm the obvious contribution. Most importantly, we have quantified enhanced restriction in water dynamics around the second Fyn-binding site of the SAP due to SAP-SLAM complexation, even prior to the presence of Fyn. This observation leads to a novel argument that SLAM induced more restricted water molecules could offer more water entropic contribution during the subsequent Fyn binding and provide enhanced stability to the SAP-Fyn complex in the signaling cascade. Finally, SLAM induced water counteraction around the second binding site of the SAP sheds light on the allosteric property of the SAP, which becomes an integral part of the underlying signal transduction mechanism.

  14. Deciphering complex dynamics of water counteraction around secondary structural elements of allosteric protein complex: Case study of SAP-SLAM system in signal transduction cascade

    Science.gov (United States)

    Samanta, Sudipta; Mukherjee, Sanchita

    2018-01-01

    The first hydration shell of a protein exhibits heterogeneous behavior owing to several attributes, majorly local polarity and structural flexibility as revealed by solvation dynamics of secondary structural elements. We attempt to recognize the change in complex water counteraction generated due to substantial alteration in flexibility during protein complex formation. The investigation is carried out with the signaling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, and interacting with SLAM-associated protein (SAP), composed of one SH2 domain. All atom molecular dynamics simulations are employed to the aqueous solutions of free SAP and SLAM-peptide bound SAP. We observed that water dynamics around different secondary structural elements became highly affected as well as nicely correlated with the SLAM-peptide induced change in structural rigidity obtained by thermodynamic quantification. A few instances of contradictory dynamic features of water to the change in structural flexibility are explained by means of occluded polar residues by the peptide. For βD, EFloop, and BGloop, both structural flexibility and solvent accessibility of the residues confirm the obvious contribution. Most importantly, we have quantified enhanced restriction in water dynamics around the second Fyn-binding site of the SAP due to SAP-SLAM complexation, even prior to the presence of Fyn. This observation leads to a novel argument that SLAM induced more restricted water molecules could offer more water entropic contribution during the subsequent Fyn binding and provide enhanced stability to the SAP-Fyn complex in the signaling cascade. Finally, SLAM induced water counteraction around the second binding site of the SAP sheds light on the allosteric property of the SAP, which becomes an integral part of the underlying signal transduction mechanism.

  15. Activation of Nrf2 Reduces UVA-Mediated MMP-1 Upregulation via MAPK/AP-1 Signaling Cascades: The Photoprotective Effects of Sulforaphane and Hispidulin

    Science.gov (United States)

    Chaiprasongsuk, Anyamanee; Lohakul, Jinaphat; Soontrapa, Kitipong; Sampattavanich, Somponnat; Akarasereenont, Pravit

    2017-01-01

    UVA irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds that can activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant gene expression, should therefore serve as effective antiphotoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling using human keratinocyte cell line (HaCaT). Antiphotoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38), c-Jun, and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA-induced MMP-1 and AP-1 activities. Moreover, pretreatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA-mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun, and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising antiphotoaging candidates. PMID:28011874

  16. Attenuated purinergic receptor function in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Thaning, Pia; Bune, Laurids T.; Hellsten, Ylva

    2010-01-01

    Objective: Extra cellular nucleotides and nucleosides are involved in regulation of skeletal muscle blood flow. Diabetes induces cardiovascular dysregulation but the extent to which the vasodilatatory capacity of nucleotides and nucleosides are affected in type 2 diabetes is unknown. The present...... study investigated: 1) the vasodilatatory effect of ATP, UTP, and adenosine (ADO) and 2) the expression and distribution of P2Y(2) and P2X(1) receptors in skeletal muscles of diabetic subjects. Research Design and Methods: In 10 diabetic patients and 10 age-matched controls, leg blood flow (LBF......-DM (1.5). The distribution and mRNA-expression of receptors were similar in the two groups. Conclusions: The vasodilatatory effect of the purinergic system is severely reduced in type 2 diabetic patients. The potency of nucleotides varies with the following rank order: UTP>ATP>>>ADO. This is not due...

  17. Signal Transduction Pathways of TNAP: Molecular Network Analyses.

    Science.gov (United States)

    Négyessy, László; Györffy, Balázs; Hanics, János; Bányai, Mihály; Fonta, Caroline; Bazsó, Fülöp

    2015-01-01

    Despite the growing body of evidence pointing on the involvement of tissue non-specific alkaline phosphatase (TNAP) in brain function and diseases like epilepsy and Alzheimer's disease, our understanding about the role of TNAP in the regulation of neurotransmission is severely limited. The aim of our study was to integrate the fragmented knowledge into a comprehensive view regarding neuronal functions of TNAP using objective tools. As a model we used the signal transduction molecular network of a pyramidal neuron after complementing with TNAP related data and performed the analysis using graph theoretic tools. The analyses show that TNAP is in the crossroad of numerous pathways and therefore is one of the key players of the neuronal signal transduction network. Through many of its connections, most notably with molecules of the purinergic system, TNAP serves as a controller by funnelling signal flow towards a subset of molecules. TNAP also appears as the source of signal to be spread via interactions with molecules involved among others in neurodegeneration. Cluster analyses identified TNAP as part of the second messenger signalling cascade. However, TNAP also forms connections with other functional groups involved in neuronal signal transduction. The results indicate the distinct ways of involvement of TNAP in multiple neuronal functions and diseases.

  18. Learning Cascading

    CERN Document Server

    Covert, Michael

    2015-01-01

    This book is intended for software developers, system architects and analysts, big data project managers, and data scientists who wish to deploy big data solutions using the Cascading framework. You must have a basic understanding of the big data paradigm and should be familiar with Java development techniques.

  19. Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade

    International Nuclear Information System (INIS)

    Yung, Mingo Ming Ho; Chan, David Wai; Liu, Vincent Wing Sun; Yao, Kwok-Ming; Ngan, Hextan Yuen-Sheung

    2013-01-01

    Although advanced-stage cervical cancer can benefit from current treatments, approximately 30% patients may fail after definitive treatment eventually. Therefore, exploring alternative molecular therapeutic approaches is imperatively needed for this disease. We have recently shown that activation of AMP-activated protein kinase (AMPK), a metabolic sensor, hampers cervical cancer cell growth through blocking the Wnt/β-catenin signaling activity. Here, we report that activated AMPK (p-AMPK) also inhibits cervical cancer cell growth by counteracting FOXM1 function. Effect of the activation of AMPK on FOXM1 expression was examined by hypoxia and glucose deprivation, as well as pharmacological AMPK activators such as A23187, AICAR and metformin. RT Q-PCR and Western blot analysis were employed to investigate the activities of AMPK, FOXM1 and AKT/FOXO3a signaling. Consistent with our previous findings, the activation of AMPK by either AMPK activators such as AICAR, A23187, metformin, glucose deprivation or hypoxia significantly inhibited the cervical cancer cell growth. Importantly, we found that activated AMPK activity was concomitantly associated with the reduction of both the mRNA and protein levels of FOXM1. Mechanistically, we showed that activated AMPK was able to reduce AKT mediated phosphorylation of p-FOXO3a (Ser253). Interestingly, activated AMPK could not cause any significant changes in FOXM1 in cervical cancer cells in which endogenous FOXO3a levels were knocked down using siRNAs, suggesting that FOXO3a is involved in the suppression of FOXM1. Taken together, our results suggest the activated AMPK impedes cervical cancer cell growth through reducing the expression of FOXM1

  20. Andrographolide, a Novel NF-κB Inhibitor, Induces Vascular Smooth Muscle Cell Apoptosis via a Ceramide-p47phox-ROS Signaling Cascade

    Directory of Open Access Journals (Sweden)

    Yu-Ying Chen

    2013-01-01

    Full Text Available Atherosclerosis is linked with the development of many cardiovascular complications. Abnormal proliferation of vascular smooth muscle cells (VSMCs plays a crucial role in the development of atherosclerosis. Accordingly, the apoptosis of VSMCs, which occurs in the progression of vascular proliferation, may provide a beneficial strategy for managing cardiovascular diseases. Andrographolide, a novel nuclear factor-κB inhibitor, is the most active and critical constituent isolated from the leaves of Andrographis paniculata. Recent studies have indicated that andrographolide is a potential therapeutic agent for treating cancer through the induction of apoptosis. In this study, the apoptosis-inducing activity and mechanisms in andrographolide-treated rat VSMCs were characterized. Andrographolide significantly induced reactive oxygen species (ROS formation, p53 activation, Bax, and active caspase-3 expression, and these phenomena were suppressed by pretreating the cells with N-acetyl-L-cysteine, a ROS scavenger, or diphenylene iodonium, a nicotinamide adenine dinucleotide phosphate (NADPH oxidase (Nox inhibitor. Furthermore, p47phox, a Nox subunit protein, was phosphorylated in andrographolide-treated rat VSMCs. However, pretreatment with 3-O-methyl-sphingomyelin, a neutral sphingomyelinase inhibitor, significantly inhibited andrographolide-induced p47phox phosphorylation as well as Bax and active caspase-3 expression. Our results collectively demonstrate that andrographolide-reduced cell viability can be attributed to apoptosis in VSMCs, and this apoptosis-inducing activity was associated with the ceramide-p47phox-ROS signaling cascade.

  1. Andrographolide Inhibits Nuclear Factor-κB Activation through JNK-Akt-p65 Signaling Cascade in Tumor Necrosis Factor-α-Stimulated Vascular Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Yu-Ying Chen

    2014-01-01

    Full Text Available Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α. Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK, Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

  2. Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils

    Directory of Open Access Journals (Sweden)

    Jing Zhu

    2018-06-01

    Full Text Available IL-1 family regulatory cytokine IL-37b can suppress innate immunity and inflammatory activity in inflammatory diseases. In this study, IL-37b showed remarkable in vitro suppression of inflammatory tumor necrosis factor-α, IL-1β, IL-6, CCL2, and CXCL8 production in the coculture of human primary eosinophils and human bronchial epithelial BEAS-2B cells with the stimulation of bacterial toll-like receptor-2 ligand peptidoglycan, while antagonizing the activation of intracellular nuclear factor-κB, PI3K–Akt, extracellular signal-regulated kinase 1/2, and suppressing the gene transcription of allergic inflammation-related PYCARD, S100A9, and CAMP as demonstrated by flow cytometry, RNA-sequencing, and bioinformatics. Results therefore elucidated the novel anti-inflammation-related molecular mechanisms mediated by IL-37b. Using the house dust mite (HDM-induced humanized asthmatic NOD/SCID mice for preclinical study, intravenous administration of IL-37b restored the normal plasma levels of eosinophil activators CCL11 and IL-5, suppressed the elevated concentrations of Th2 and asthma-related cytokines IL-4, IL-6, and IL-13 and inflammatory IL-17, CCL5, and CCL11 in lung homogenate of asthmatic mice. Histopathological results of lung tissue illustrated that IL-37b could mitigate the enhanced mucus, eosinophil infiltration, thickened airway wall, and goblet cells. Together with similar findings using the ovalbumin- and HDM-induced allergic asthmatic mice further validated the therapeutic potential of IL-37b in allergic asthma. The above results illustrate the novel IL-37-mediated regulation of intracellular inflammation mechanism linking bacterial infection and the activation of human eosinophils and confirm the in vivo anti-inflammatory activity of IL-37b on human allergic asthma.

  3. Dopamine elevates intracellular zinc concentration in cultured rat embryonic cortical neurons through the cAMP-nitric oxide signaling cascade.

    Science.gov (United States)

    Hung, Hui-Hsing; Kao, Lung-Sen; Liu, Pei-Shan; Huang, Chien-Chang; Yang, De-Ming; Pan, Chien-Yuan

    2017-07-01

    Zinc ion (Zn 2+ ), the second most abundant transition metal after iron in the body, is essential for neuronal activity and also induces toxicity if the concentration is abnormally high. Our previous results show that exposure of cultured cortical neurons to dopamine elevates intracellular Zn 2+ concentrations ([Zn 2+ ] i ) and induces autophagosome formation but the mechanism is not clear. In this study, we characterized the signaling pathway responsible for the dopamine-induced elevation of [Zn 2+ ] i and the effect of [Zn 2+ ] i in modulating the autophagy in cultured rat embryonic cortical neurons. N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a membrane-permeable Zn 2+ chelator, could rescue the cell death and suppress the autophagosome puncta number induced by dopamine. Dopamine treatment increased the lipidation level of the endogenous microtubule-associated protein 1A/1B-light chain 3 (LC3 II), an autophagosome marker. TPEN added 1h before, but not after, dopamine treatment suppressed the dopamine-induced elevation of LC3 II level. Inhibitors of the dopamine D1-like receptor, protein kinase A (PKA), and NOS suppressed the dopamine-induced elevation of [Zn 2+ ] i . PKA activators and NO generators directly increased [Zn 2+ ] i in cultured neurons. Through cell fractionation, proteins with m.w. values between 5 and 10kD were found to release Zn 2+ following NO stimulation. In addition, TPEN pretreatment and an inhibitor against PKA could suppress the LC3 II level increased by NO and dopamine, respectively. Therefore, our results demonstrate that dopamine-induced elevation of [Zn 2+ ] i is mediated by the D1-like receptor-PKA-NO pathway and is important in modulating the cell death and autophagy. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Effects of high-orbit spaceflight on signaling cascades and apoptosis in immune cells from mice flied on board the BION-M1 satellite

    Science.gov (United States)

    Novoselova, Elena; Shenkman, Boris; Lunin, Sergey; Parfenyuk, Svetlana; Novoselova, Tatyana; Fesenko, Eugeny

    The study was designed to evaluate immune cell activity in male C57bl mice after a 30-day high-orbit spaceflight (550 km, higher than conventional manned spaceflights) on board the BION-M1 satellite (Roskosmos Program, Russia). For the present study, thymus, spleens and plasma samples were collected from mice 12 h after landing and, additionally, 7 days subsequently. Assessing the activity of NF-kappaB signaling cascade by measuring Rel A (p65) protein phosphorylation in splenic lymphocytes, we showed that the NF-kappaB activity was significantly increased at 12 h after landing. Contrariwise, one week after landing, the NF-kappaB activity was markedly decreased, even below to the control values. Interestingly, after landing there were no significant changes in SAPK/JNK cascade activity in splenic lymphocytes as well as in the expression of transcription factor IRF3 in thymus cells. To assess the apoptosis status in thymus lymphocytes, levels of p53 protein and its phosphorylated form were measured in thymic lymphocytes. It is known that p53 plays an important role in the cellular response to DNA damage, genomic aberrations, and other characteristic of apoptosis. The results showed that the high-orbit spaceflight environment caused some increase in level of p53 protein, but most notably, activated phosphorylated form of p53 protein. Calculated ratio of active and inactive forms of the protein (ph-p53/p53) 12 h after landing increased by more than 2-fold, indicating the apparent induction of apoptosis in thymus cells. Interestingly, 7 days after the landing, this ratio was not restored, but rather increased: the specified ratio was 4 times higher as compared to the ground-based control. We can conclude that response to the prolonged high-orbit spaceflight is not like the classic "stress response", which is usually observed under various stressful factors. It is known that the stress response is surely accompanied by increased SAPK/JNK cascade activity as well as the

  5. Agonist-mediated activation of Bombyx mori diapause hormone receptor signals to extracellular signal-regulated kinases 1 and 2 through Gq-PLC-PKC-dependent cascade.

    Science.gov (United States)

    Jiang, Xue; Yang, Jingwen; Shen, Zhangfei; Chen, Yajie; Shi, Liangen; Zhou, Naiming

    2016-08-01

    Diapause is a developmental strategy adopted by insects to survive in challenging environments such as the low temperatures of a winter. This unique process is regulated by diapause hormone (DH), which is a neuropeptide hormone that induces egg diapause in Bombyx mori and is involved in terminating pupal diapause in heliothis moths. An G protein-coupled receptor from the silkworm, B. mori, has been identified as a specific cell surface receptor for DH. However, the detailed information on the DH-DHR system and its mechanism(s) involved in the induction of embryonic diapause remains unknown. Here, we combined functional assays with various specific inhibitors to elucidate the DHR-mediated signaling pathways. Upon activation by DH, B. mori DHR is coupled to the Gq protein, leading to a significant increase of intracellular Ca(2+) and cAMP response element-driven luciferase activity in an UBO-QIC, a specific Gq inhibitor, sensitive manner. B. mori DHR elicited ERK1/2 phosphorylation in a dose- and time-dependent manner in response to DH. This effect was almost completely inhibited by co-incubation with UBO-QIC and was also significantly suppressed by PLC inhibitor U73122, PKC inhibitors Gö6983 and the Ca(2+) chelator EGTA. Moreover, DHR-induced activation of ERK1/2 was significantly attenuated by treatment with the Gβγ specific inhibitors gallein and M119K and the PI3K specific inhibitor Wortmannin, but not by the Src specific inhibitor PP2. Our data also demonstrates that the EGFR-transactivation pathway is not involved in the DHR-mediated ERK1/2 phosphorylation. Future efforts are needed to clarify the role of the ERK1/2 signaling pathway in the DH-mediated induction of B. mori embryonic diapause. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Lipopolysaccharide stimulates endogenous β-glucuronidase via PKC/NF-κB/c-myc signaling cascade: a possible factor in hepatolithiasis formation.

    Science.gov (United States)

    Yao, Dianbo; Dong, Qianze; Tian, Yu; Dai, Chaoliu; Wu, Shuodong

    2017-11-29

    Hepatolithiasis is commonly encountered in Southeastern and Eastern Asian countries, but the pathogenesis mechanism of stone formation is still not well understood. Now, the role of endogenous β-glucuronidase in pigment stones formation is being gradually recognized. In this study, the mechanism of increased expression and secretion of endogenous β-glucuronidase during hepatolithiasis formation was investigated. We assessed the endogenous β-glucuronidase, c-myc, p-p65, and p-PKC expression in liver specimens with hepatolithiasis by immunohistochemical staining, and found that compared with that in normal liver samples, the expression of endogenous β-glucuronidase, c-myc, p-p65, and p-PKC in liver specimens with hepatolithiasis significantly increased, and their expressions were positively correlated with each other. Lipopolysaccharide (LPS) induced increased expression of endogenous β-glucuronidase and c-myc in hepatocytes and intrahepatic biliary epithelial cells in a dose- and time-dependent manner, and endogenous β-glucuronidase secretion increased, correspondingly. C-myc siRNA transfection effectively inhibited the LPS-induced expression of endogenous β-glucuronidase. Furthermore, NF-κB inhibitor pyrrolidine dithiocarbamate or PKC inhibitor chelerythrine could effectively inhibit the LPS-induced expression of c-myc and endogenous β-glucuronidase, and the expression of p-p65 was also partly inhibited by chelerythrine. Our clinical observations and experimental data indicate that LPS could induce the increased expression and secretion of endogenous β-glucuronidase via a signaling cascade of PKC/NF-κB/c-myc in hepatocytes and intrahepatic biliary epithelial cells, and endogenous β-glucuronidase might play a possible role in the formation of hepatolithiasis.

  7. Bitter Melon (Momordica charantia) Extract Inhibits Tumorigenicity and Overcomes Cisplatin-Resistance in Ovarian Cancer Cells Through Targeting AMPK Signaling Cascade.

    Science.gov (United States)

    Yung, Mingo M H; Ross, Fiona A; Hardie, D Grahame; Leung, Thomas H Y; Zhan, Jinbiao; Ngan, Hextan Y S; Chan, David W

    2016-09-01

    Objective Acquired chemoresistance is a major obstacle in the clinical management of ovarian cancer. Therefore, searching for alternative therapeutic modalities is urgently needed. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal values in human diabetes and cancers. Here, we sought to investigate the extract of bitter melon (BME) in antitumorigenic and cisplatin-induced cytotoxicity in ovarian cancer cells. Three varieties of bitter melon were used to prepare the BME. Ovarian cancer cell lines, human immortalized epithelial ovarian cells (HOSEs), and nude mice were used to evaluate the cell cytotoxicity, cisplatin resistance, and tumor inhibitory effect of BME. The molecular mechanism of BME was examined by Western blotting. Cotreatment with BME and cisplatin markedly attenuated tumor growth in vitro and in vivo in a mouse xenograft model, whereas there was no observable toxicity in HOSEs or in nude mice in vivo Interestingly, the antitumorigenic effects of BME varied with different varieties of bitter melon, suggesting that the amount of antitumorigenic substances may vary. Studies of the molecular mechanism demonstrated that BME activates AMP-activated protein kinase (AMPK) in an AMP-independent but CaMKK (Ca(2+)/calmodulin-dependent protein kinase)-dependent manner, exerting anticancer effects through activation of AMPK and suppression of the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade. BME functions as a natural AMPK activator in the inhibition of ovarian cancer cell growth and might be useful as a supplement to improve the efficacy of cisplatin-based chemotherapy in ovarian cancer. © The Author(s) 2015.

  8. The Role of Purinergic Receptors in Cancer-Induced Bone Pain

    Directory of Open Access Journals (Sweden)

    Sarah Falk

    2012-01-01

    Full Text Available Cancer-induced bone pain severely compromises the quality of life of many patients suffering from bone metastasis, as current therapies leave some patients with inadequate pain relief. The recent development of specific animal models has increased the understanding of the molecular and cellular mechanisms underlying cancer-induced bone pain including the involvement of ATP and the purinergic receptors in the progression of the pain state. In nociception, ATP acts as an extracellular messenger to transmit sensory information both at the peripheral site of tissue damage and in the spinal cord. Several of the purinergic receptors have been shown to be important for the development and maintenance of neuropathic and inflammatory pain, and studies have demonstrated the importance of both peripheral and central mechanisms. We here provide an overview of the current literature on the role of purinergic receptors in cancer-induced bone pain with emphasis on some of the difficulties related to studying this complex pain state.

  9. LincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through miR-9/E-cadherin cascade signaling pathway molecular mechanism

    Directory of Open Access Journals (Sweden)

    Ding G

    2017-06-01

    Full Text Available Gangqiang Ding, Zhen Peng, Jia Shang, Yi Kang, Huibin Ning, Chongshan Mao Department of Infectious Diseases, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China Abstract: In the previous study, it was found that long intergenic noncoding RNA-p21 (lincRNA-p21 was downregulated in hepatocellular carcinoma (HCC and lincRNA-p21 overexpression inhibited tumor invasion through inducing epithelial–mesenchymal transition. However, the underlying mechanism was not fully elaborated. In this study, lincRNA-p21 expression was measured in 12 paired HCC and nontumor adjacent normal tissues by ­quantitative real-time polymerase chain reaction. The effects of lincRNA-p21 on HCC cells were studied using lentivirus expressing lincRNA-p21 vector in vitro. The association between lincRNA-p21 level and miR-9 level was tested with the Spearman rank correlation. The effects of miR-9 on HCC cells were studied by using miR-9 inhibitor in vitro. Luciferase assay was used to validate the target of miR-9. The results showed that lincRNA-p21 was downregulated in human HCC tissues and cell lines. LincRNA-p21 overexpression significantly inhibited HCC cell migration and invasion in vitro. Besides, lincRNA-p21 negatively regulated miR-9 expression level, and miR-9 was upregulated in human HCC tissues and cells. MiR-9 knockdown inhibited HCC cell migration and invasion in vitro. Finally, the luciferase assay results showed that E-cadherin was a direct target of miR-9. The expression level of E-cadherin was found to be regulated by lincRNA-p21 and miR-9. Altogether, the results suggested that lincRNA-p21 inhibits migration and invasion of HCC cells through regulating miR-9-mediated E-cadherin cascade signaling pathway. Keywords: hepatocellular carcinoma, lincRNA-p21, miR-9, E-cadherin, epithelial–mesenchymal transition

  10. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

    Energy Technology Data Exchange (ETDEWEB)

    Abhilash, P.A.; Harikrishnan, R.; Indira, M., E-mail: indiramadambath@gmail.com

    2014-01-15

    Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4 g/kg b.wt for 90 days. After 90 days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250 mg/kg b.wt) and AA (250 mg/kg b.wt) supplemented groups and maintained for 30 days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β{sub 1} and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α{sub 1} (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis. - Highlights: • Alcohol increases intestinal bacterial overgrowth and permeability of endotoxin. • Endotoxin mediated inflammation plays a major role in alcoholic liver fibrosis. • Ascorbic acid reduces endotoxemia, NF-κB activation and proinflammatory cytokines. • AA's action is by inhibition of SIBO, IKKβ and alteration of

  11. P2X4: A fast and sensitive purinergic receptor

    Directory of Open Access Journals (Sweden)

    Jaanus Suurväli

    2017-10-01

    Full Text Available Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors. P2 receptors comprise P2X ionotropic receptors and G protein-coupled P2Y receptors. P2X receptors are expressed in many tissues, where they are involved in a number of functions including synaptic transmission, muscle contraction, platelet aggregation, inflammation, macrophage activation, differentiation and proliferation, neuropathic and inflammatory pain. P2X4 is one of the most sensitive purinergic receptors (at nanomolar ATP concentrations, about one thousand times more than the archetypal P2X7. P2X4 is widely expressed in central and peripheral neurons, in microglia, and also found in various epithelial tissues and endothelial cells. It localizes on the plasma membrane, but also in intracellular compartments. P2X4 is preferentially localized in lysosomes, where it is protected from proteolysis by its glycosylation. High ATP concentration in the lysosomes does not activate P2X4 at low pH; P2X4 gets activated by intra-lysosomal ATP only in its fully dissociated tetra-anionic form, when the pH increases to 7.4. Thus, P2X4 is functioning as a Ca2+-channel after the fusion of late endosomes and lysosomes. P2X4 modulates major neurotransmitter systems and regulates alcohol-induced responses in microglia. P2X4 is one of the key receptors mediating neuropathic pain. However, injury-induced upregulation of P2X4 expression is gender dependent and plays a key role in pain difference between males and females. P2X4 is also involved in inflammation. Extracellular ATP being a pro-inflammatory molecule, P2X4 can trigger inflammation in response to high ATP release. It is therefore involved in multiple pathologies, like post-ischemic inflammation, rheumatoid arthritis, airways inflammation in asthma, neurodegenerative diseases and even metabolic syndrome. Although P2X4 remains poorly

  12. Dynamics robustness of cascading systems.

    Directory of Open Access Journals (Sweden)

    Jonathan T Young

    2017-03-01

    Full Text Available A most important property of biochemical systems is robustness. Static robustness, e.g., homeostasis, is the insensitivity of a state against perturbations, whereas dynamics robustness, e.g., homeorhesis, is the insensitivity of a dynamic process. In contrast to the extensively studied static robustness, dynamics robustness, i.e., how a system creates an invariant temporal profile against perturbations, is little explored despite transient dynamics being crucial for cellular fates and are reported to be robust experimentally. For example, the duration of a stimulus elicits different phenotypic responses, and signaling networks process and encode temporal information. Hence, robustness in time courses will be necessary for functional biochemical networks. Based on dynamical systems theory, we uncovered a general mechanism to achieve dynamics robustness. Using a three-stage linear signaling cascade as an example, we found that the temporal profiles and response duration post-stimulus is robust to perturbations against certain parameters. Then analyzing the linearized model, we elucidated the criteria of when signaling cascades will display dynamics robustness. We found that changes in the upstream modules are masked in the cascade, and that the response duration is mainly controlled by the rate-limiting module and organization of the cascade's kinetics. Specifically, we found two necessary conditions for dynamics robustness in signaling cascades: 1 Constraint on the rate-limiting process: The phosphatase activity in the perturbed module is not the slowest. 2 Constraints on the initial conditions: The kinase activity needs to be fast enough such that each module is saturated even with fast phosphatase activity and upstream changes are attenuated. We discussed the relevance of such robustness to several biological examples and the validity of the above conditions therein. Given the applicability of dynamics robustness to a variety of systems, it

  13. Cascade annealing: an overview

    International Nuclear Information System (INIS)

    Doran, D.G.; Schiffgens, J.O.

    1976-04-01

    Concepts and an overview of radiation displacement damage modeling and annealing kinetics are presented. Short-term annealing methodology is described and results of annealing simulations performed on damage cascades generated using the Marlowe and Cascade programs are included. Observations concerning the inconsistencies and inadequacies of current methods are presented along with simulation of high energy cascades and simulation of longer-term annealing

  14. Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway

    Directory of Open Access Journals (Sweden)

    Freeman Robert S

    2011-02-01

    Full Text Available Abstract Background Thrombolytic therapy with tissue plasminogen activator (tPA benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM (Tyro3, Axl, Mer receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult. Results We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase-deficient Akt mutant AktK179A and a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM, we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates

  15. Distinct Upstream Role of Type I IFN Signaling in Hematopoietic Stem Cell-Derived and Epithelial Resident Cells for Concerted Recruitment of Ly-6Chi Monocytes and NK Cells via CCL2-CCL3 Cascade.

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    Erdenebileg Uyangaa

    Full Text Available Type I interferon (IFN-I-dependent orchestrated mobilization of innate cells in inflamed tissues is believed to play a critical role in controlling replication and CNS-invasion of herpes simplex virus (HSV. However, the crucial regulators and cell populations that are affected by IFN-I to establish the early environment of innate cells in HSV-infected mucosal tissues are largely unknown. Here, we found that IFN-I signaling promoted the differentiation of CCL2-producing Ly-6Chi monocytes and IFN-γ/granzyme B-producing NK cells, whereas deficiency of IFN-I signaling induced Ly-6Clo monocytes producing CXCL1 and CXCL2. More interestingly, recruitment of Ly-6Chi monocytes preceded that of NK cells with the levels peaked at 24 h post-infection in IFN-I-dependent manner, which was kinetically associated with the CCL2-CCL3 cascade response. Early Ly-6Chi monocyte recruitment was governed by CCL2 produced from hematopoietic stem cell (HSC-derived leukocytes, whereas NK cell recruitment predominantly depended on CC chemokines produced by resident epithelial cells. Also, IFN-I signaling in HSC-derived leukocytes appeared to suppress Ly-6Ghi neutrophil recruitment to ameliorate immunopathology. Finally, tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ dendritic cells appeared to produce initial CCL2 for migration-based self-amplification of early infiltrated Ly-6Chi monocytes upon stimulation by IFN-I produced from infected epithelial cells. Ultimately, these results decipher a detailed IFN-I-dependent pathway that establishes orchestrated mobilization of Ly-6Chi monocytes and NK cells through CCL2-CCL3 cascade response of HSC-derived leukocytes and epithelium-resident cells. Therefore, this cascade response of resident-to-hematopoietic-to-resident cells that drives cytokine-to-chemokine-to-cytokine production to recruit orchestrated innate cells is critical for attenuation of HSV replication in inflamed tissues.

  16. A Ca2+-calmodulin-eEF2K-eEF2 signalling cascade, but not AMPK, contributes to the suppression of skeletal muscle protein synthesis during contractions

    DEFF Research Database (Denmark)

    Rose, Adam John; Alsted, Thomas Junker; Jensen, Thomas Elbenhardt

    2009-01-01

    Skeletal muscle protein synthesis rate decreases during contractions but the underlying regulatory mechanisms are poorly understood. It was hypothesised that there would be a coordinated regulation of eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1......) phosphorylation by signalling cascades downstream of rises in intracellular [Ca(2+)] and decreased energy charge via AMP activated protein kinase (AMPK) in contracting skeletal muscle. When fast-twitch skeletal muscles were contracted ex vivo using different protocols, the suppression of protein synthesis...... correlated more closely with changes in eEF2 rather than 4EBP1 phosphorylation. Using a combination of Ca(2+) release agents and ATPase inhibitors it was shown that the 60-70% suppression of fast-twitch skeletal muscle protein synthesis during contraction was equally distributed between Ca(2+) and energy...

  17. Pleiotrophin Signaling Through PTNR in Breast Cancer

    National Research Council Canada - National Science Library

    Powers, Ciaron

    2001-01-01

    ... of intracellular signaling cascades. The pleiotrophin signaling pathway is known to be important in angiogenesis and breast cancer growth, but the exact mechanisms of pleiotrophin signaling remain undefined...

  18. Short-range intercellular calcium signaling in bone

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye

    2005-01-01

    different mechanisms for this propagation. One mechanism involves the secretion of a nucleotide, possibly ATP, acting in an autocrine action to purinergic P2Y2 receptors on the neighboring cells, leading to intracellular IP3 generation and subsequent release of calcium from intracellular stores. The other...... to osteoclasts as well. We demonstrated that paracrine action of ATP was responsible for the wave propagation, but now the purinergic P2X7 receptor was involved. Thus, the studies demonstrate that calcium signals can be propagated not only among osteoblasts, but also between osteoblasts and osteoclasts...

  19. Effect of electroacupuncture on the cervicospinal P2X7 receptor/fractalkine/CX3CR1 signaling pathway in a rat neck-incision pain model.

    Science.gov (United States)

    Gao, Y H; Li, C W; Wang, J Y; Tan, L H; Duanmu, C L; Jing, X H; Chang, X R; Liu, J L

    2017-06-01

    Increasing evidence supports that acupuncture intervention is an effective approach for intraoperative and postoperative pain. Neuron-microglia crosstalk, mediated by the purinergic P2X7 receptor (R)/fractalkine/CX3CR1 cascade in the spinal cord dorsal horn, plays a pivotal role in pain processing. However, its involvement in the analgesic effect of electroacupuncture (EA) remains unclear. In this study, a rat neck-incision pain model was established by making a longitudinal incision along the midline of the neck and subsequent repeated mechanical stimulation. EA stimulation was applied to bilateral LI18, LI4-PC6, or ST36-GB34. The thermal pain threshold, cervicospinal ATP concentration, expression levels of purinergic P2XR and P2YR subunits mRNAs, and fractalkine, CX3CR1 and p38 MAPK proteins, were detected separately. The neck incision induced strong thermal hyperalgesia and upregulation of spinal ATP within 48 h. No significant change was found in thermal hyperalgesia after a single session of EA intervention. However, a single session of EA dramatically enhanced the neck incision-induced upregulation of ATP and upregulated the expression of P2X7R, which was reversed by two sessions of EA. Two sessions of EA at bilateral LI18 or LI4-PC6 attenuated hyperalgesia significantly, accompanied with downregulation of P2X7R/fractalkine/ CX3CR1 signaling after three sessions of EA. EA stimulation of LI18 or LI4-PC6 alleviates thermal hyperalgesia in neck-incision pain rats, which may be associated with its effects in regulating the neck incision-induced increase of ATP and P2X7R and subsequently suppressing fractalkine/CX3CR1 signaling in the cervical spinal cord.

  20. Noise propagation in two-step series MAPK cascade.

    Directory of Open Access Journals (Sweden)

    Venkata Dhananjaneyulu

    Full Text Available Series MAPK enzymatic cascades, ubiquitously found in signaling networks, act as signal amplifiers and play a key role in processing information during signal transduction in cells. In activated cascades, cell-to-cell variability or noise is bound to occur and thereby strongly affects the cellular response. Commonly used linearization method (LM applied to Langevin type stochastic model of the MAPK cascade fails to accurately predict intrinsic noise propagation in the cascade. We prove this by using extensive stochastic simulations for various ranges of biochemical parameters. This failure is due to the fact that the LM ignores the nonlinear effects on the noise. However, LM provides a good estimate of the extrinsic noise propagation. We show that the correct estimate of intrinsic noise propagation in signaling networks that contain at least one enzymatic step can be obtained only through stochastic simulations. Noise propagation in the cascade depends on the underlying biochemical parameters which are often unavailable. Based on a combination of global sensitivity analysis (GSA and stochastic simulations, we developed a systematic methodology to characterize noise propagation in the cascade. GSA predicts that noise propagation in MAPK cascade is sensitive to the total number of upstream enzyme molecules and the total number of molecules of the two substrates involved in the cascade. We argue that the general systematic approach proposed and demonstrated on MAPK cascade must accompany noise propagation studies in biological networks.

  1. Neuronal Regulation of Schwann Cell Mitochondrial Ca2+ Signaling during Myelination

    Directory of Open Access Journals (Sweden)

    Daisuke Ino

    2015-09-01

    Full Text Available Schwann cells (SCs myelinate peripheral neurons to promote the rapid conduction of action potentials, and the process of myelination is known to be regulated by signals from axons to SCs. Given that SC mitochondria are one of the potential regulators of myelination, we investigated whether SC mitochondria are regulated by axonal signaling. Here, we show a purinergic mechanism that sends information from neurons to SC mitochondria during myelination. Our results show that electrical stimulation of rat sciatic nerve increases extracellular ATP levels enough to activate purinergic receptors. Indeed, electrical stimulation of sciatic nerves induces Ca2+ increases in the cytosol and the mitochondrial matrix of surrounding SCs via purinergic receptor activation. Chronic suppression of this pathway during active myelination suppressed the longitudinal and radial development of myelinating SCs and caused hypomyelination. These results demonstrate a neuron-to-SC mitochondria signaling, which is likely to have an important role in proper myelination.

  2. Neuropharmacology of purinergic receptors in human submucous plexus: Involvement of P2X₁, P2X₂, P2X₃ channels, P2Y and A₃ metabotropic receptors in neurotransmission.

    Science.gov (United States)

    Liñán-Rico, A; Wunderlich, J E; Enneking, J T; Tso, D R; Grants, I; Williams, K C; Otey, A; Michel, K; Schemann, M; Needleman, B; Harzman, A; Christofi, F L

    2015-08-01

    The role of purinergic signaling in human ENS is not well understood. We sought to further characterize the neuropharmacology of purinergic receptors in human ENS and test the hypothesis that endogenous purines are critical regulators of neurotransmission. LSCM-Fluo-4/(Ca(2+))-imaging of postsynaptic Ca(2+) transients (PSCaTs) was used as a reporter of synaptic transmission evoked by fiber tract electrical stimulation in human SMP surgical preparations. Pharmacological analysis of purinergic signaling was done in 1,556 neurons (identified by HuC/D-immunoreactivity) in 235 ganglia from 107 patients; P2XR-immunoreactivity was evaluated in 19 patients. Real-time MSORT (Di-8-ANEPPS) imaging tested effects of adenosine on fast excitatory synaptic potentials (fEPSPs). Synaptic transmission is sensitive to pharmacological manipulations that alter accumulation of extracellular purines: Apyrase blocks PSCaTs in a majority of neurons. An ecto-NTPDase-inhibitor 6-N,N-diethyl-D-β,γ-dibromomethyleneATP or adenosine deaminase augments PSCaTs. Blockade of reuptake/deamination of eADO inhibits PSCaTs. Adenosine inhibits fEPSPs and PSCaTs (IC50 = 25 µM), sensitive to MRS1220-antagonism (A3AR). A P2Y agonist ADPβS inhibits PSCaTs (IC50 = 111 nM) in neurons without stimulatory ADPbS responses (EC50 = 960 nM). ATP or a P2X1,2,2/3 (α,β-MeATP) agonist evokes fast, slow, biphasic Ca(2+) transients or Ca(2+) oscillations (ATP,EC50 = 400 mM). PSCaTs are sensitive to P2X1 antagonist NF279. Low (20 nM) or high (5 µM) concentrations of P2X antagonist TNP-ATP block PSCaTs in different neurons; proportions of neurons with P2XR-immunoreactivity follow the order P2X2 > P2X1 > P2X3; P2X1 + P2X2 and P2X3 + P2X2 are co-localized. RT-PCR identified mRNA-transcripts for P2X1-7, P2Y1,2,12-14R. Purines are critical regulators of neurotransmission in human ENS. Purinergic signaling involves P2X1, P2X2, P2X3 channels, P2X1 + P2X2 co-localization and inhibitory P2Y or A3 receptors. These are

  3. Regulation of P450-mediated permethrin resistance in Culex quinquefasciatus by the GPCR/Gαs/AC/cAMP/PKA signaling cascade.

    Science.gov (United States)

    Li, Ting; Liu, Nannan

    2017-12-01

    This study explores the role of G-protein-coupled receptor-intracellular signaling in the development of P450-mediated insecticide resistance in mosquitoes, Culex quinquefasciatus , focusing on the essential function of the GPCRs and their downstream effectors of Gs alpha subunit protein (Gαs) and adenylyl cyclase (ACs) in P450-mediated insecticide resistance of Culex mosquitoes. Our RNAi-mediated functional study showed that knockdown of Gαs caused the decreased expression of the downstream effectors of ACs and PKAs in the GPCR signaling pathway and resistance P450 genes, whereas knockdown of ACs decreased the expression of PKAs and resistance P450 genes. Knockdown of either Gαs or ACs resulted in an increased susceptibility of mosquitoes to permethrin. These results add significantly to our understanding of the molecular basis of resistance P450 gene regulation through GPCR/Gαs/AC/cAMP-PKA signaling pathways in the insecticide resistance of mosquitoes. The temporal and spatial dynamic analyses of GPCRs, Gαs, ACs, PKAs, and P450s in two insecticide resistant mosquito strains revealed that all the GPCR signaling pathway components tested, namely GPCRs, Gαs, ACs and PKAs, were most highly expressed in the brain for both resistant strains, suggesting the role played by these genes in signaling transduction and regulation. The resistance P450 genes were mainly expressed in the brain, midgut and malpighian tubules (MTs), suggesting their critical function in the central nervous system and importance for detoxification. The temporal dynamics analysis for the gene expression showed a diverse expression profile during mosquito development, indicating their initially functional importance in response to exposure to insecticides during their life stages.

  4. Effect of Hyperglycemia on Purinergic and Nitrergic Inhibitory Neuromuscular Transmission in the Antrum of the Stomach: Implications for Fast Gastric Emptying

    Directory of Open Access Journals (Sweden)

    Xue-Dao He

    2018-01-01

    Full Text Available BackgroundHyperglycemia has been reported to enhance vagovagal reflex that causes the release of inhibitory neurotransmitter, nitric oxide (NO, at the neuromuscular junction in the antrum to relax the antrum and slow gastric emptying by stimulating glucose-sensitive afferent neurons. However, hyperglycemia has also been reported to cause fast gastric emptying that may be due to suppression of the inhibitory motor neurons.AimsThe purpose of the present study was to investigate changes in inhibitory neuromuscular transmission in the gastric antrum due to hyperglycemia.MethodsInhibitory electrical junction potentials were recorded from gastric antral muscle strips, using intracellular electrodes under non-adrenergic, non-cholinergic conditions. Studies were performed in non-hyperglycemic NOD (NH-NOD, NOD mice as they develop hyperglycemia (H-NOD and their age-matched controls. The purinergic inhibitory junction potential (pIJP and nitrergic IJP (nIJP were isolated pharmacologically.ResultsThe control pIJP was large, around −18 mV and nIJP was small, around −9 mV. In NH-NOD the IJPs were not affected, but in H-NOD pIJP was nearly abolished and nIJP was significantly reduced. In H-NOD mice, membrane hyperpolarization caused by exogenous α,β-MeATP or diethylenetriamine NO adduct was similar to that in wild-type controls (P > 0.05. H-NOD smooth muscles were significantly depolarized as compared to NH-NOD smooth muscles.ConclusionThese observations show that hyperglycemia causes suppression of purinergic and nitrergic transmission by acting on the motor neurons that form the last neuron in the vagovagal circuit. Moreover, the loss the neurotransmission is due to a defect in neurotransmitter release rather than a defect in signal transduction. Hyperglycemia also causes depolarization of smooth muscles that may increase their excitability.

  5. The Wnt/β-catenin signaling/Id2 cascade mediates the effects of hypoxia on the hierarchy of colorectal-cancer stem cells.

    Science.gov (United States)

    Dong, Hye-Jin; Jang, Gyu-Beom; Lee, Hwa-Yong; Park, Se-Ra; Kim, Ji-Young; Nam, Jeong-Seok; Hong, In-Sun

    2016-03-11

    Hypoxia, a feature common to most solid tumors, is known to regulate many aspects of tumorigenesis. Recently, it was suggested that hypoxia increased the size of the cancer stem-cell (CSC) subpopulations and promoted the acquisition of a CSC-like phenotype. However, candidate hypoxia-regulated mediators specifically relevant to the stemness-related functions of colorectal CSCs have not been examined in detail. In the present study, we showed that hypoxia specifically promoted the self-renewal potential of CSCs. Through various in vitro studies, we found that hypoxia-induced Wnt/β-catenin signaling increased the occurrence of CSC-like phenotypes and the level of Id2 expression in colorectal-cancer cells. Importantly, the levels of hypoxia-induced CSC-sphere formation and Id2 expression were successfully attenuated by treatment with a Wnt/β-catenin-signaling inhibitor. We further demonstrated, for the first time, that the degree of hypoxia-induced CSC-sphere formation (CD44(+) subpopulation) in vitro and of tumor metastasis/dissemination in vivo were markedly suppressed by knocking down Id2 expression. Taken together, these data suggested that Wnt/β-catenin signaling mediated the hypoxia-induced self-renewal potential of colorectal-cancer CSCs through reactivating Id2 expression.

  6. Cascade quantum teleportation

    Institute of Scientific and Technical Information of China (English)

    ZHOU Nan-run; GONG Li-hua; LIU Ye

    2006-01-01

    In this letter a cascade quantum teleportation scheme is proposed. The proposed scheme needs less local quantum operations than those of quantum multi-teleportation. A quantum teleportation scheme based on entanglement swapping is presented and compared with the cascade quantum teleportation scheme. Those two schemes can effectively teleport quantum information and extend the distance of quantum communication.

  7. Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium

    DEFF Research Database (Denmark)

    Poulsen, Asser Nyander; Klausen, Thomas Levin; Pedersen, Peter Steen

    2005-01-01

    and unidirectional Cl- fluxes decreased significantly. The results suggest that nucleotides released to the airway surface liquid exert an autocrine regulation of epithelial NaCl absorption mainly by inhibiting the amiloride-sensitive epithelial Na+ channel (ENaC) and paracellular anion conductance via a P2Y......We investigated purinergic receptors involved in ion transport regulation in the intact rabbit nasal airway epithelium. Stimulation of apical membrane P2Y receptors with ATP or UTP (200 microM) induced transient increases in short-circuit current (Isc) of 13 and 6% followed by sustained inhibitions...

  8. Mechanisms of cascade collapse

    International Nuclear Information System (INIS)

    Diaz de la Rubia, T.; Smalinskas, K.; Averback, R.S.; Robertson, I.M.; Hseih, H.; Benedek, R.

    1988-12-01

    The spontaneous collapse of energetic displacement cascades in metals into vacancy dislocation loops has been investigated by molecular dynamics (MD) computer simulation and transmission electron microscopy (TEM). Simulations of 5 keV recoil events in Cu and Ni provide the following scenario of cascade collapse: atoms are ejected from the central region of the cascade by replacement collision sequences; the central region subsequently melts; vacancies are driven to the center of the cascade during resolidification where they may collapse into loops. Whether or not collapse occurs depends critically on the melting temperature of the metal and the energy density and total energy in the cascade. Results of TEM are presented in support of this mechanism. 14 refs., 4 figs., 1 tab

  9. The regulatory role of the NO/cGMP signal transduction cascade during larval attachment and metamorphosis of the barnacle Balanus (=Amphibalanus) amphitrite

    KAUST Repository

    Zhang, Y.

    2012-08-01

    The barnacle Balanus amphitrite is among the most dominant fouling species on intertidal rocky shores in tropical and subtropical areas and is thus a target organism in antifouling research. After being released from adults, the swimming nauplius undertakes six molting cycles and then transforms into a cyprid. Using paired antennules, a competent cyprid actively explores and selects a suitable substratum for attachment and metamorphosis (collectively known as settlement). This selection process involves the reception of exogenous signals and subsequent endogenous signal transduction. To investigate the involvement of nitric oxide (NO) and cyclic GMP (cGMP) during larval settlement of B. amphitrite, we examined the effects of an NO donor and an NO scavenger, two nitric oxide synthase (NOS) inhibitors and a soluble guanylyl cyclase (sGC) inhibitor on settling cyprids. We found that the NO donor sodium nitroprusside (SNP) inhibited larval settlement in a dose-dependent manner. In contrast, both the NO scavenger carboxy-PTIO and the NOS inhibitors aminoguanidine hemisulfate (AGH) and S-methylisothiourea sulfate (SMIS) significantly accelerated larval settlement. Suppression of the downstream guanylyl cyclase (GC) activity using a GC-selective inhibitor ODQ could also significantly accelerate larval settlement. Interestingly, the settlement inhibition effects of SNP could be attenuated by ODQ at all concentrations tested. In the developmental expression profiling of NOS and sGC, the lowest expression of both genes was detected in the cyprid stage, a crucial stage for the larval decision to attach and metamorphose. In summary, we concluded that NO regulates larval settlement via mediating downstream cGMP signaling.

  10. Distinctive functions of Syk N-terminal and C-terminal SH2 domains in the signaling cascade elicited by oxidative stress in B cells.

    Science.gov (United States)

    Ding, J; Takano, T; Hermann, P; Gao, S; Han, W; Noda, C; Yanagi, S; Yamamura, H

    2000-05-01

    Syk plays a crucial role in the transduction of oxidative stress signaling. In this paper, we investigated the roles of Src homology 2 (SH2) domains of Syk in oxidative stress signaling, using Syk-negative DT40 cells expressing the N- or C-terminal SH2 domain mutant [mSH2(N) or mSH2(C)] of Syk. Tyrosine phosphorylation of Syk in cells expressing mSH2(N) Syk after H(2)O(2) treatment was higher than that in cells expressing wild-type Syk or mSH2(C) Syk. The tyrosine phosphorylation of wild-type Syk and mSH2(C) Syk, but not that of mSH2(N), was sensitive to PP2, a specific inhibitor of Src-family protein-tyrosine kinase. In oxidative stress, the C-terminal SH2 domain of Syk was demonstrated to be required for induction of tyrosine phosphorylation of cellular proteins, phospholipase C (PLC)-gamma2 phosphorylation, inositol 1,4, 5-triphosphate (IP(3)) generation, Ca(2)(+) release from intracellular stores, and c-Jun N-terminal kinase activation. In contrast, in mSH2(N) Syk-expressing cells, tyrosine phosphorylation of intracellular proteins including PLC-gamma2 was markedly induced in oxidative stress. The enhanced phosphorylation of mSH2(N) Syk and PLC-gamma2, however, did not link to Ca(2)(+) mobilization from intracellular pools and IP(3) generation. Thus, the N- and C-terminal SH2 domains of Syk possess distinctive functions in oxidative stress signaling.

  11. The regulatory role of the NO/cGMP signal transduction cascade during larval attachment and metamorphosis of the barnacle Balanus (=Amphibalanus) amphitrite

    KAUST Repository

    Zhang, Y.; He, L.-S.; Zhang, G.; Xu, Y.; Lee, O.-O.; Matsumura, K.; Qian, P.-Y.

    2012-01-01

    The barnacle Balanus amphitrite is among the most dominant fouling species on intertidal rocky shores in tropical and subtropical areas and is thus a target organism in antifouling research. After being released from adults, the swimming nauplius undertakes six molting cycles and then transforms into a cyprid. Using paired antennules, a competent cyprid actively explores and selects a suitable substratum for attachment and metamorphosis (collectively known as settlement). This selection process involves the reception of exogenous signals and subsequent endogenous signal transduction. To investigate the involvement of nitric oxide (NO) and cyclic GMP (cGMP) during larval settlement of B. amphitrite, we examined the effects of an NO donor and an NO scavenger, two nitric oxide synthase (NOS) inhibitors and a soluble guanylyl cyclase (sGC) inhibitor on settling cyprids. We found that the NO donor sodium nitroprusside (SNP) inhibited larval settlement in a dose-dependent manner. In contrast, both the NO scavenger carboxy-PTIO and the NOS inhibitors aminoguanidine hemisulfate (AGH) and S-methylisothiourea sulfate (SMIS) significantly accelerated larval settlement. Suppression of the downstream guanylyl cyclase (GC) activity using a GC-selective inhibitor ODQ could also significantly accelerate larval settlement. Interestingly, the settlement inhibition effects of SNP could be attenuated by ODQ at all concentrations tested. In the developmental expression profiling of NOS and sGC, the lowest expression of both genes was detected in the cyprid stage, a crucial stage for the larval decision to attach and metamorphose. In summary, we concluded that NO regulates larval settlement via mediating downstream cGMP signaling.

  12. p115 RhoGEF activates the Rac1 GTPase signaling cascade in MCP1 chemokine-induced vascular smooth muscle cell migration and proliferation.

    Science.gov (United States)

    Singh, Nikhlesh K; Janjanam, Jagadeesh; Rao, Gadiparthi N

    2017-08-25

    Although the involvement of Rho proteins in the pathogenesis of vascular diseases is well studied, little is known about the role of their upstream regulators, the Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular wall remodeling. We found that, among the RhoGEFs tested, MCP1 induced tyrosine phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or leukemia-associated RhoGEF in human aortic smooth muscle cells (HASMCs). Moreover, p115 RhoGEF inhibition suppressed MCP1-induced HASMC migration and proliferation. Consistent with these observations, balloon injury (BI) induced p115 RhoGEF tyrosine phosphorylation in rat common carotid arteries, and siRNA-mediated down-regulation of its levels substantially attenuated BI-induced smooth muscle cell migration and proliferation, resulting in reduced neointima formation. Furthermore, depletion of p115 RhoGEF levels also abrogated MCP1- or BI-induced Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling, which, as we reported previously, is involved in vascular wall remodeling. Our findings also show that protein kinase N1 (PKN1) downstream of Rac1-cyclin D1/CDK6 and upstream of CDK4-PAK1 in the p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling axis is involved in the modulation of vascular wall remodeling. Of note, we also observed that CCR2-G i/o -Fyn signaling mediates MCP1-induced p115 RhoGEF and Rac1 GTPase activation. These findings suggest that p115 RhoGEF is critical for MCP1-induced HASMC migration and proliferation in vitro and for injury-induced neointima formation in vivo by modulating Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Hyperactivity and memory/learning deficits evoked by developmental exposure to nicotine and/or ethanol are mitigated by cAMP and cGMP signaling cascades activation.

    Science.gov (United States)

    Abreu-Villaça, Yael; Carvalho-Graça, Anna C; Skinner, Gabriela; Lotufo, Bruna M; Duarte-Pinheiro, Vitor H S; Ribeiro-Carvalho, Anderson; Manhães, Alex C; Filgueiras, Claudio C

    2018-04-10

    Pregnant smoking women are frequently episodic drinkers. Here, we investigated whether ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to nicotine aggravates memory/learning deficits and hyperactivity, and associated cAMP and cGMP signaling disruption. To further investigate the role of these signaling cascades, we verified whether vinpocetine (a phosphodiesterase inhibitor) ameliorates the neurochemical and behavioral outcomes. Swiss mice had free access to nicotine (NIC, 50 μg/ml) or water to drink during gestation and until the 8th postnatal day (PN8). Ethanol (ETOH, 5 g/kg, i.p.) or saline were injected in the pups every other day from PN2 to PN8. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or vehicle before being tested in the step-down passive avoidance or open field. Memory/learning was impaired in NIC, ETOH and NIC + ETOH mice, and vinpocetine mitigated ETOH- and NIC + ETOH-induced deficits. Locomotor hyperactivity identified in ETOH and NIC + ETOH mice was ameliorated by vinpocetine. While cyclic nucleotides levels in cerebral cortex and hippocampus were reduced by NIC, ETOH and NIC + ETOH, this outcome was more consistent in the latter group. As observed for behavior, vinpocetine normalized NIC + ETOH nucleotides levels. pCREB levels were also increased in response to vinpocetine, with stronger effects in the NIC + ETOH group. Exposure to both drugs of abuse worsens behavioral and neurochemical disruption. These findings and the amelioration of deleterious effects by vinpocetine support the idea that cAMP and cGMP signaling contribute to nicotine- and ethanol-induced hyperactivity and memory/learning deficits. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Hybrid Modulation Scheme for Cascaded H-Bridge Inverter Cells ...

    African Journals Online (AJOL)

    This work proposes a switching technique for cascaded H-Bridge (CHB) cells. Single carrier Sinusoidal PWM (SCSPWM) scheme is employed in the generation of the gating signals. A sequential switching and base PWM circulation schemes are presented for this fundamental cascaded multilevel inverter topology.

  15. Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver

    Directory of Open Access Journals (Sweden)

    Arne Hinrichs

    2018-05-01

    Full Text Available Objective: Laron syndrome (LS is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR gene. To establish a large animal model for LS, pigs with GHR knockout (KO mutations were generated and characterized. Methods: CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue. Results: GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1 levels and reduced IGF-binding protein 3 (IGFBP3 activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was

  16. A novel PTP1B inhibitor extracted from Ganoderma lucidum ameliorates insulin resistance by regulating IRS1-GLUT4 cascades in the insulin signaling pathway.

    Science.gov (United States)

    Yang, Zhou; Wu, Fan; He, Yanming; Zhang, Qiang; Zhang, Yuan; Zhou, Guangrong; Yang, Hongjie; Zhou, Ping

    2018-01-24

    Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extracted from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels. We found that FYGL can decrease blood glucose, reduce body weight and ameliorate insulin resistance in ob/ob mice. Decrease of PTP1B expression and increase of the phosphorylation of PTP1B targets in the insulin signaling pathway of skeletal muscles were observed. In order to clearly reveal the underlying mechanism of the hypoglycemic effect caused by FYGL, we further investigated the effects of FYGL on the PTP1B-involved insulin signaling pathway in rat myoblast L6 cells. We demonstrated that FYGL had excellent cell permeability by using a confocal laser scanning microscope and a flow cytometer. We found that FYGL had a positive effect on insulin-stimulated glucose uptake by using the 2-deoxyglucose (2-DG) method. FYGL could inhibit PTP1B expression at the mRNA level, phosphorylating insulin receptor substrate-1 (IRS1), as well as activating phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt). Finally, FYGL increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and consequently up-regulated the expression of glucose transporter type 4 (GLUT4), promoting GLUT4 transportation to the plasma membrane in PTP1B-transfected L6 cells. Our study provides theoretical evidence for FYGL to be potentially used in T2D management.

  17. Effect of hypothyroidism on the purinergic responses of corpus cavernosal smooth muscle in rabbits.

    Science.gov (United States)

    Yildirim, M K; Bagcivan, I; Sarac, B; Kilicarslan, H; Yildirim, S; Kaya, T

    2008-01-01

    Several studies have reported evidence of hormonal abnormalities in 25-35% of impotent men. Hypothyroidism has been reported to occur in 6% of impotent men. In the present study, we examined purinergic relaxation responses in hypothyroidism in an experimental rabbit model and compared them with controls to evaluate the possible involvement of the purinergic pathway. The study comprised 20 male New Zealand white rabbits. The rabbits were divided into two equal groups. We tested the effects of ATP, alpha beta ATP, and adenosine precontracted with phenylephrine on the isolated corpus cavernosum preparations from control and hypothyroid rabbits. We also evaluated the effects of ATP, alpha beta ATP, and adenosine on the cGMP levels in the isolated corpus cavernosum preparations from control and hypothyroid rabbits. T3, T4, and testosterone levels were significantly lower in hypothyroid rabbits. ATP, alpha beta ATP, carbachol, and electrical field stimulation (EFS)-induced frequency-dependent relaxation responses in the isolated rabbit corpus cavernosum strips precontracted with phenylephrine reduced significantly (Phypothyroid rabbits. Reduction of relaxation response in hypothyroid rabbits corpus cavernosum can depend on a decreased release of nitric oxide (NO) from nitrergic nerves and endothelium.

  18. Gene regulation by MAP kinase cascades

    DEFF Research Database (Denmark)

    Fiil, Berthe Katrine; Petersen, Klaus; Petersen, Morten

    2009-01-01

    Mitogen-activated protein kinase (MAPK) cascades are signaling modules that transduce extracellular stimuli to a range of cellular responses. Research in yeast and metazoans has shown that MAPK-mediated phosphorylation directly or indirectly regulates the activity of transcription factors. Plant ...

  19. Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver.

    Science.gov (United States)

    Hinrichs, Arne; Kessler, Barbara; Kurome, Mayuko; Blutke, Andreas; Kemter, Elisabeth; Bernau, Maren; Scholz, Armin M; Rathkolb, Birgit; Renner, Simone; Bultmann, Sebastian; Leonhardt, Heinrich; de Angelis, Martin Hrabĕ; Nagashima, Hiroshi; Hoeflich, Andreas; Blum, Werner F; Bidlingmaier, Martin; Wanke, Rüdiger; Dahlhoff, Maik; Wolf, Eckhard

    2018-05-01

    Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized. CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue. GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation

  20. Resveratrol Ameliorates Tau Hyperphosphorylation at Ser396 Site and Oxidative Damage in Rat Hippocampal Slices Exposed to Vanadate: Implication of ERK1/2 and GSK-3β Signaling Cascades.

    Science.gov (United States)

    Jhang, Kyoung A; Park, Jin-Sun; Kim, Hee-Sun; Chong, Young Hae

    2017-11-08

    The objective of this study was to investigate the effect of resveratrol (a natural polyphenolic phytostilbene) on tau hyperphosphorylation and oxidative damage induced by sodium orthovanadate (Na 3 VO 4 ), the prevalent species of vanadium (vanadate), in rat hippocampal slices. Our results showed that resveratrol significantly inhibited Na 3 VO 4 -induced hyperphosphorylation of tau at the Ser396 (p-S396-tau) site, which is upregulated in the hippocampus of Alzheimer's disease (AD) brains and principally linked to AD-associated cognitive dysfunction. Subsequent mechanistic studies revealed that reduction of ERK1/2 activation was involved in the inhibitory effect of resveratrol by inhibiting the ERK1/2 pathway with SL327 mimicking the aforementioned effect of resveratrol. Moreover, resveratrol potently induced GSK-3β Ser9 phosphorylation and reduced Na 3 VO 4 -induced p-S396-tau levels, which were markedly replicated by pharmacologic inhibition of GSK-3β with LiCl. These results indicate that resveratrol could suppress Na 3 VO 4 -induced p-S396-tau levels via downregulating ERK1/2 and GSK-3β signaling cascades in rat hippocampal slices. In addition, resveratrol diminished the increased extracellular reactive oxygen species generation and hippocampal toxicity upon long-term exposure to Na 3 VO 4 or FeCl 2 . Our findings strongly support the notion that resveratrol may serve as a potential nutraceutical agent for AD.

  1. Function of RSKS-1-AAK-2-DAF-16 signaling cascade in enhancing toxicity of multi-walled carbon nanotubes can be suppressed by mir-259 activation in Caenorhabditis elegans

    Science.gov (United States)

    Zhuang, Ziheng; Li, Min; Liu, Hui; Luo, Libo; Gu, Weidong; Wu, Qiuli; Wang, Dayong

    2016-08-01

    Caenorhabditis elegans is an important non-mammalian alternative assay model for toxicological study. Previous study has indicated that exposure to multi-walled carbon nanotubes (MWCNTs) dysregulated the transcriptional expression of mir-259. In this study, we examined the molecular basis for mir-259 in regulating MWCNTs toxicity in nematodes. Mutation of mir-259 induced a susceptible property to MWCNTs toxicity, and MWCNTs exposure induced a significant increase in mir-259::GFP in pharyngeal/intestinal valve and reproductive tract, implying that mir-259 might mediate a protection mechanisms for nematodes against MWCNTs toxicity. RSKS-1, a putative ribosomal protein S6 kinase, acted as the target for mir-259 in regulating MWCNTs toxicity, and mutation of rsks-1 suppressed the susceptible property of mir-259 mutant to MWCNTs toxicity. Moreover, mir-259 functioned in pharynx-intestinal valve and RSKS-1 functioned in pharynx to regulate MWCNTs toxicity. Furthermore, RSKS-1 regulated MWCNTs toxicity by suppressing the function of AAK-2-DAF-16 signaling cascade. Our results will strengthen our understanding the microRNAs mediated protection mechanisms for animals against the toxicity from certain nanomaterials.

  2. Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

    DEFF Research Database (Denmark)

    Mathiasen, D.P.; Egebjerg, C.; Andersen, S.H.

    2012-01-01

    are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene...... that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue...... the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation.Oncogene advance online publication, 27 June 2011; doi:10.1038/onc.2011.230....

  3. Evaluation of Purinergic Mechanism for the Treatment of Voiding Dysfunction: A Study in Conscious Spinal Cord-injured Rats

    Directory of Open Access Journals (Sweden)

    Shing-Hwa Lu

    2007-10-01

    Conclusion: These results indicate that purinergic mechanisms, presumably involving P2X3 or P2X2/3 receptors on bladder C-fiber afferent nerves, play an important role in the detrusor hyperreflexia that occurs after spinal cord injury in rats.

  4. Conjugation of cascades

    International Nuclear Information System (INIS)

    San Martin, Jesus; Rodriguez-Perez, Daniel

    2009-01-01

    Presented in this work are some results relative to sequences found in the logistic equation bifurcation diagram, which is the unimodal quadratic map prototype. All of the different saddle-node bifurcation cascades, associated with every last appearance p-periodic orbit (p=3,4,5,...), can also be generated from the very Feigenbaum cascade. In this way it is evidenced the relationship between both cascades. The orbits of every saddle-node bifurcation cascade, mentioned above, are located in different chaotic bands, and this determines a sequence of orbits converging to every band-merging Misiurewicz point. In turn, these accumulation points form a sequence whose accumulation point is the Myrberg-Feigenbaum point. It is also proven that the first appearance orbits in the n-chaotic band converge to the same point as the last appearance orbits of the (n + 1)-chaotic band. The symbolic sequences of band-merging Misiurewicz points are computed for any window.

  5. Learning optimal embedded cascades.

    Science.gov (United States)

    Saberian, Mohammad Javad; Vasconcelos, Nuno

    2012-10-01

    The problem of automatic and optimal design of embedded object detector cascades is considered. Two main challenges are identified: optimization of the cascade configuration and optimization of individual cascade stages, so as to achieve the best tradeoff between classification accuracy and speed, under a detection rate constraint. Two novel boosting algorithms are proposed to address these problems. The first, RCBoost, formulates boosting as a constrained optimization problem which is solved with a barrier penalty method. The constraint is the target detection rate, which is met at all iterations of the boosting process. This enables the design of embedded cascades of known configuration without extensive cross validation or heuristics. The second, ECBoost, searches over cascade configurations to achieve the optimal tradeoff between classification risk and speed. The two algorithms are combined into an overall boosting procedure, RCECBoost, which optimizes both the cascade configuration and its stages under a detection rate constraint, in a fully automated manner. Extensive experiments in face, car, pedestrian, and panda detection show that the resulting detectors achieve an accuracy versus speed tradeoff superior to those of previous methods.

  6. Cascade Organic Solar Cells

    KAUST Repository

    Schlenker, Cody W.

    2011-09-27

    We demonstrate planar organic solar cells consisting of a series of complementary donor materials with cascading exciton energies, incorporated in the following structure: glass/indium-tin-oxide/donor cascade/C 60/bathocuproine/Al. Using a tetracene layer grown in a descending energy cascade on 5,6-diphenyl-tetracene and capped with 5,6,11,12-tetraphenyl- tetracene, where the accessibility of the π-system in each material is expected to influence the rate of parasitic carrier leakage and charge recombination at the donor/acceptor interface, we observe an increase in open circuit voltage (Voc) of approximately 40% (corresponding to a change of +200 mV) compared to that of a single tetracene donor. Little change is observed in other parameters such as fill factor and short circuit current density (FF = 0.50 ± 0.02 and Jsc = 2.55 ± 0.23 mA/cm2) compared to those of the control tetracene-C60 solar cells (FF = 0.54 ± 0.02 and Jsc = 2.86 ± 0.23 mA/cm2). We demonstrate that this cascade architecture is effective in reducing losses due to polaron pair recombination at donor-acceptor interfaces, while enhancing spectral coverage, resulting in a substantial increase in the power conversion efficiency for cascade organic photovoltaic cells compared to tetracene and pentacene based devices with a single donor layer. © 2011 American Chemical Society.

  7. Energy cascades in Canada

    Energy Technology Data Exchange (ETDEWEB)

    Hayden, A. C.; Brown, T. D.

    1979-03-15

    Combining energy uses in a cascade can result in significant overall reductions in fuel requirements. The simplest applications for a cascade are in the recovery of waste heat from existing processes using special boilers or turbines. Specific applications of more-complex energy cascades for Canada are discussed. A combined-cycle plant at a chemical refinery in Ontario is world leader in energy efficiency. Total-energy systems for commercial buildings, such as one installed in a school in Western Canada, offer attractive energy and operating cost benefits. A cogeneration plant proposed for the National Capital Region, generating electricity as well as steam for district heating, allows the use of a low-grade fossil fuel (coal), greatly improves energy-transformation efficiency, and also utilizes an effectively renewable resource (municipal garbage). Despite the widespread availability of equipment and technology of energy cascades, the sale of steam and electricity across plant boundaries presents a barrier. More widespread use of cascades will require increased cooperation among industry, electric utilities and the various levels of government if Canada is to realize the high levels of energy efficiency potential available.

  8. Cascade Organic Solar Cells

    KAUST Repository

    Schlenker, Cody W.; Barlier, Vincent S.; Chin, Stephanie W.; Whited, Matthew T.; McAnally, R. Eric; Forrest, Stephen R.; Thompson, Mark E.

    2011-01-01

    We demonstrate planar organic solar cells consisting of a series of complementary donor materials with cascading exciton energies, incorporated in the following structure: glass/indium-tin-oxide/donor cascade/C 60/bathocuproine/Al. Using a tetracene layer grown in a descending energy cascade on 5,6-diphenyl-tetracene and capped with 5,6,11,12-tetraphenyl- tetracene, where the accessibility of the π-system in each material is expected to influence the rate of parasitic carrier leakage and charge recombination at the donor/acceptor interface, we observe an increase in open circuit voltage (Voc) of approximately 40% (corresponding to a change of +200 mV) compared to that of a single tetracene donor. Little change is observed in other parameters such as fill factor and short circuit current density (FF = 0.50 ± 0.02 and Jsc = 2.55 ± 0.23 mA/cm2) compared to those of the control tetracene-C60 solar cells (FF = 0.54 ± 0.02 and Jsc = 2.86 ± 0.23 mA/cm2). We demonstrate that this cascade architecture is effective in reducing losses due to polaron pair recombination at donor-acceptor interfaces, while enhancing spectral coverage, resulting in a substantial increase in the power conversion efficiency for cascade organic photovoltaic cells compared to tetracene and pentacene based devices with a single donor layer. © 2011 American Chemical Society.

  9. The effect of purinergic P2 receptor blockade on skeletal muscle exercise hyperemia in miniature swine

    DEFF Research Database (Denmark)

    Mortensen, Stefan Peter; McAllister, R M; Yang, H T

    2014-01-01

    PURPOSE: ATP could play an important role in skeletal muscle blood flow regulation by inducing vasodilation via purinergic P2 receptors. This study investigated the role of P2 receptors in exercise hyperemia in miniature swine. METHODS: We measured regional blood flow with radiolabeled......-microsphere technique and systemic hemodynamics before and after arterial infusion of the P2 receptor antagonist reactive blue 2 during treadmill exercise (5.2 km/h, ~60 % VO2max) and arterial ATP infusion in female Yucatan miniature swine (~29 kg). RESULTS: Mean blood flow during exercise from the 16 sampled skeletal...... muscle tissues was 138 ± 18 mL/min/100 g (mean ± SEM), and it was reduced in 11 (~25 %) of the 16 sampled skeletal muscles after RB2 was infused. RB2 also lowered diaphragm blood flow and kidney blood flow, whereas lung tissue blood flow was increased (all P

  10. A chimeric receptor of the insulin-like growth factor receptor type 1 (IGFR1) and a single chain antibody specific to myelin oligodendrocyte glycoprotein activates the IGF1R signalling cascade in CG4 oligodendrocyte progenitors.

    Science.gov (United States)

    Annenkov, Alexander; Rigby, Anne; Amor, Sandra; Zhou, Dun; Yousaf, Nasim; Hemmer, Bernhard; Chernajovsky, Yuti

    2011-08-01

    In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 ‎‎(IGF1R) signalling cascade. Activation of this pro-survival pathway in response to ligand broadly available in the brain might increase neuroregenerative potential of transplanted precursors. The ChR was produced by fusing a MOG-specific single ‎chain antibody with the extracellular boundary of the IGF1R transmembrane segment. The ChR is expressed on the cellular surface, predominantly as a monomer, and is not N-glycosylated. To show MOG-dependent functionality of the ChR, neuroblastoma cells B104 expressing this ChR were stimulated with monolayers of cells expressing recombinant MOG. The ChR undergoes MOG-dependent tyrosine phosphorylation and homodimerisation. It promotes insulin and IGF-independent growth of the oligodendrocyte progenitor cell line CG4. The proposed mode of the ChR activation is by MOG-induced dimerisation which promotes kinase domain transphosphorylation, by-passing the requirement of conformation changes known to be important for IGF1R activation. Another ChR, which contains a segment of the β-chain ectodomain, was produced in an attempt to recapitulate some of these conformational changes, but proved non-functional. 2011 Elsevier B.V. All rights reserved.

  11. Hadron cascades produced by electromagnetic cascades

    International Nuclear Information System (INIS)

    Nelson, W.R.; Jenkins, T.M.; Ranft, J.

    1986-12-01

    A method for calculating high energy hadron cascades induced by multi-GeV electron and photon beams is described. Using the EGS4 computer program, high energy photons in the EM shower are allowed to interact hadronically according to the vector meson dominance (VMD) model, facilitated by a Monte Carlo version of the dual multistring fragmentation model which is used in the hadron cascade code FLUKA. The results of this calculation compare very favorably with experimental data on hadron production in photon-proton collisions and on the hadron production by electron beams on targets (i.e., yields in secondary particle beam lines). Electron beam induced hadron star density contours are also presented and are compared with those produced by proton beams. This FLUKA-EGS4 coupling technique could find use in the design of secondary beams, in the determination high energy hadron source terms for shielding purposes, and in the estimation of induced radioactivity in targets, collimators and beam dumps

  12. Volcano geodesy in the Cascade arc, USA

    Science.gov (United States)

    Poland, Michael; Lisowski, Michael; Dzurisin, Daniel; Kramer, Rebecca; McLay, Megan; Pauk, Benjamin

    2017-01-01

    Experience during historical time throughout the Cascade arc and the lack of deep-seated deformation prior to the two most recent eruptions of Mount St. Helens might lead one to infer that Cascade volcanoes are generally quiescent and, specifically, show no signs of geodetic change until they are about to erupt. Several decades of geodetic data, however, tell a different story. Ground- and space-based deformation studies have identified surface displacements at five of the 13 major Cascade arc volcanoes that lie in the USA (Mount Baker, Mount St. Helens, South Sister, Medicine Lake, and Lassen volcanic center). No deformation has been detected at five volcanoes (Mount Rainier, Mount Hood, Newberry Volcano, Crater Lake, and Mount Shasta), and there are not sufficient data at the remaining three (Glacier Peak, Mount Adams, and Mount Jefferson) for a rigorous assessment. In addition, gravity change has been measured at two of the three locations where surveys have been repeated (Mount St. Helens and Mount Baker show changes, while South Sister does not). Broad deformation patterns associated with heavily forested and ice-clad Cascade volcanoes are generally characterized by low displacement rates, in the range of millimeters to a few centimeters per year, and are overprinted by larger tectonic motions of several centimeters per year. Continuous GPS is therefore the best means of tracking temporal changes in deformation of Cascade volcanoes and also for characterizing tectonic signals so that they may be distinguished from volcanic sources. Better spatial resolution of volcano deformation can be obtained through the use of campaign GPS, semipermanent GPS, and interferometric synthetic aperture radar observations, which leverage the accumulation of displacements over time to improve signal to noise. Deformation source mechanisms in the Cascades are diverse and include magma accumulation and withdrawal, post-emplacement cooling of recent volcanic deposits, magmatic

  13. Volcano geodesy in the Cascade arc, USA

    Science.gov (United States)

    Poland, Michael P.; Lisowski, Michael; Dzurisin, Daniel; Kramer, Rebecca; McLay, Megan; Pauk, Ben

    2017-08-01

    Experience during historical time throughout the Cascade arc and the lack of deep-seated deformation prior to the two most recent eruptions of Mount St. Helens might lead one to infer that Cascade volcanoes are generally quiescent and, specifically, show no signs of geodetic change until they are about to erupt. Several decades of geodetic data, however, tell a different story. Ground- and space-based deformation studies have identified surface displacements at five of the 13 major Cascade arc volcanoes that lie in the USA (Mount Baker, Mount St. Helens, South Sister, Medicine Lake, and Lassen volcanic center). No deformation has been detected at five volcanoes (Mount Rainier, Mount Hood, Newberry Volcano, Crater Lake, and Mount Shasta), and there are not sufficient data at the remaining three (Glacier Peak, Mount Adams, and Mount Jefferson) for a rigorous assessment. In addition, gravity change has been measured at two of the three locations where surveys have been repeated (Mount St. Helens and Mount Baker show changes, while South Sister does not). Broad deformation patterns associated with heavily forested and ice-clad Cascade volcanoes are generally characterized by low displacement rates, in the range of millimeters to a few centimeters per year, and are overprinted by larger tectonic motions of several centimeters per year. Continuous GPS is therefore the best means of tracking temporal changes in deformation of Cascade volcanoes and also for characterizing tectonic signals so that they may be distinguished from volcanic sources. Better spatial resolution of volcano deformation can be obtained through the use of campaign GPS, semipermanent GPS, and interferometric synthetic aperture radar observations, which leverage the accumulation of displacements over time to improve signal to noise. Deformation source mechanisms in the Cascades are diverse and include magma accumulation and withdrawal, post-emplacement cooling of recent volcanic deposits, magmatic

  14. Cascade reactor: introduction

    International Nuclear Information System (INIS)

    Pitts, J.H.

    1985-01-01

    Cascade is a concept for an ultrasafe, highly efficient, easily built reactor to convert inertial-confinement fusion energy into electrical power. The Cascade design includes a rotating double-cone-shaped chamber in which a moving, 1-m-thick ceramic granular blanket is held against the reactor wall by centrifugal action. The granular material absorbs energy from the fusion reactions. Accomplishments this year associated with Cascade included improvements to simplify chamber design and lower activation. The authors switched from a steel chamber wall to one made from silicon-carbide (SiC) panels held in compression by SiC-fiber/Al-composite tendons that gird the chamber both circumferentially and axially. The authors studies a number of heat-exchanger designs and selected a gravity-flow cascade design with a vacuum on the primary side. This design allows granules leaving the chamber to be transported to the heat exchangers using their own peripheral speed. The granules transfer their thermal energy and return to the chamber gravitationally: no vacuum locks or conveyors are needed

  15. Stability of cascade search

    Energy Technology Data Exchange (ETDEWEB)

    Fomenko, Tatiana N [M. V. Lomonosov Moscow State University, Faculty of Computational Mathematics and Cybernetics, Moscow (Russian Federation)

    2010-10-22

    We find sufficient conditions on a searching multi-cascade for a modification of the set of limit points of the cascade that satisfy an assessing inequality for the distance from each of these points to the initial point to be small, provided that the modifications of the initial point and the initial set-valued functionals or maps used to construct the multi-cascade are small. Using this result, we prove the stability (in the above sense) of the cascade search for the set of common pre-images of a closed subspace under the action of n set-valued maps, n{>=}1 (in particular, for the set of common roots of these maps and for the set of their coincidences). For n=2 we obtain generalizations of some results of A. V. Arutyunov; the very statement of the problem comes from a recent paper of his devoted to the study of the stability of the subset of coincidences of a Lipschitz map and a covering map.

  16. Hadronic cascade processes

    International Nuclear Information System (INIS)

    Ilgenfritz, E.M.; Kripfganz, J.; Moehring, H.J.

    1977-01-01

    The analytical treatment of hadronic decay cascades within the framework of the statistical bootstrap model is demonstrated on the basis of a simple variant. Selected problems for a more comprehensive formulation of the model such as angular momentum conservation, quantum statistical effects, and the immediate applicability to particle production processes at high energies are discussed in detail

  17. Enteric Glia Mediate Neuron Death in Colitis Through Purinergic Pathways That Require Connexin-43 and Nitric OxideSummary

    Directory of Open Access Journals (Sweden)

    Isola A.M. Brown

    2016-01-01

    Full Text Available Background & Aims: The concept of enteric glia as regulators of intestinal homeostasis is slowly gaining acceptance as a central concept in neurogastroenterology. Yet how glia contribute to intestinal disease is still poorly understood. Purines generated during inflammation drive enteric neuron death by activating neuronal P2X7 purine receptors (P2X7R; triggering adenosine triphosphate (ATP release via neuronal pannexin-1 channels that subsequently recruits intracellular calcium ([Ca2+]i in surrounding enteric glia. We tested the hypothesis that the activation of enteric glia contributes to neuron death during inflammation. Methods: We studied neuroinflammation in vivo using the 2,4-dinitrobenzene sulfonic acid model of colitis and in situ using whole-mount preparations of human and mouse intestine. Transgenic mice with a targeted deletion of glial connexin-43 (Cx43 [GFAP::CreERT2+/−/Cx43f/f] were used to specifically disrupt glial signaling pathways. Mice deficient in inducible nitric oxide (NO synthase (iNOS−/− were used to study NO production. Protein expression and oxidative stress were measured using immunohistochemistry and in situ Ca2+ and NO imaging were used to monitor glial [Ca2+]i and [NO]i. Results: Purinergic activation of enteric glia drove [Ca2+]i responses and enteric neuron death through a Cx43-dependent mechanism. Neurotoxic Cx43 activity, driven by NO production from glial iNOS, was required for neuron death. Glial Cx43 opening liberated ATP and Cx43-dependent ATP release was potentiated by NO. Conclusions: Our results show that the activation of glial cells in the context of neuroinflammation kills enteric neurons. Mediators of inflammation that include ATP and NO activate neurotoxic pathways that converge on glial Cx43 hemichannels. The glial response to inflammatory mediators might contribute to the development of motility disorders. Keywords: Enteric Nervous System, Hemichannels

  18. Integrated Broadband Quantum Cascade Laser

    Science.gov (United States)

    Mansour, Kamjou (Inventor); Soibel, Alexander (Inventor)

    2016-01-01

    A broadband, integrated quantum cascade laser is disclosed, comprising ridge waveguide quantum cascade lasers formed by applying standard semiconductor process techniques to a monolithic structure of alternating layers of claddings and active region layers. The resulting ridge waveguide quantum cascade lasers may be individually controlled by independent voltage potentials, resulting in control of the overall spectrum of the integrated quantum cascade laser source. Other embodiments are described and claimed.

  19. Ion Transport in Human Pancreatic Duct Epithelium, Capan-1 Cells, Is Regulated by Secretin, VIP, Acetylcholine, and Purinergic Receptors

    DEFF Research Database (Denmark)

    Wang, Jing; Novak, Ivana

    2013-01-01

    OBJECTIVES: The objective of the study was to establish a solid model of polarized epithelium for human pancreatic ducts, where electrical parameters could be measured as indicators of ion transport. Further, we aimed to determine functional expression of several receptors, in particular, puriner...... transport in human pancreatic duct epithelium, Capan-1 cells, is regulated by secretin, VIP, acetylcholine, adenosine, and purinergic P2 receptors; and this human model has a good potential for studies of physiology and pathophysiology of pancreatic duct ion transport....

  20. Roles of purinergic P2X receptors as pacemaking channels and modulators of calcium-mobilizing pathway in pituitary gonadotrophs

    Czech Academy of Sciences Publication Activity Database

    Zemková, Hana; Balík, Aleš; Jiang, Y.; Kretschmannová, K.; Stojilkovic, S. S.

    2006-01-01

    Roč. 20, č. 6 (2006), s. 1423-1436 ISSN 0888-8809 R&D Projects: GA AV ČR(CZ) IAA5011408; GA AV ČR(CZ) IAA5011103; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : purinergic receptors * electrical activity * pituitary Subject RIV: FH - Neurology Impact factor: 4.967, year: 2006

  1. UTP-induced ATP release is a fine-tuned signalling pathway in osteocytes

    DEFF Research Database (Denmark)

    Kringelbach, Tina M.; Aslan, Derya; Novak, Ivana

    2014-01-01

    Osteocytes reside as a cellular network throughout the mineralised matrix of bone and are considered the primary mechanosensors of this tissue. They sense mechanical stimulation such as fluid flow and are able to regulate osteoblast and osteoclast functions on the bone surface. Previously, we fou...... signals may be propagated by P2 receptor activation and further ATP release in the osteocyte network and implicate purinergic signalling as a central signalling pathway in osteocyte mechanotransduction....

  2. Modeling of Bit Error Rate in Cascaded 2R Regenerators

    DEFF Research Database (Denmark)

    Öhman, Filip; Mørk, Jesper

    2006-01-01

    and the regenerating nonlinearity is investigated. It is shown that an increase in nonlinearity can compensate for an increase in noise figure or decrease in signal power. Furthermore, the influence of the improvement in signal extinction ratio along the cascade and the importance of choosing the proper threshold......This paper presents a simple and efficient model for estimating the bit error rate in a cascade of optical 2R-regenerators. The model includes the influences of of amplifier noise, finite extinction ratio and nonlinear reshaping. The interplay between the different signal impairments...

  3. Information cascade on networks

    Science.gov (United States)

    Hisakado, Masato; Mori, Shintaro

    2016-05-01

    In this paper, we discuss a voting model by considering three different kinds of networks: a random graph, the Barabási-Albert (BA) model, and a fitness model. A voting model represents the way in which public perceptions are conveyed to voters. Our voting model is constructed by using two types of voters-herders and independents-and two candidates. Independents conduct voting based on their fundamental values; on the other hand, herders base their voting on the number of previous votes. Hence, herders vote for the majority candidates and obtain information relating to previous votes from their networks. We discuss the difference between the phases on which the networks depend. Two kinds of phase transitions, an information cascade transition and a super-normal transition, were identified. The first of these is a transition between a state in which most voters make the correct choices and a state in which most of them are wrong. The second is a transition of convergence speed. The information cascade transition prevails when herder effects are stronger than the super-normal transition. In the BA and fitness models, the critical point of the information cascade transition is the same as that of the random network model. However, the critical point of the super-normal transition disappears when these two models are used. In conclusion, the influence of networks is shown to only affect the convergence speed and not the information cascade transition. We are therefore able to conclude that the influence of hubs on voters' perceptions is limited.

  4. Cascade ICF power reactor

    International Nuclear Information System (INIS)

    Hogan, W.J.; Pitts, J.H.

    1986-01-01

    The double-cone-shaped Cascade reaction chamber rotates at 50 rpm to keep a blanket of ceramic granules in place against the wall as they slide from the poles to the exit slots at the equator. The 1 m-thick blanket consists of layers of carbon, beryllium oxide, and lithium aluminate granules about 1 mm in diameter. The x rays and debris are stopped in the carbon granules; the neutrons are multiplied and moderated in the BeO and breed tritium in the LiAlO 2 . The chamber wall is made up of SiO tiles held in compression by a network of composite SiC/Al tendons. Cascade operates at a 5 Hz pulse rate with 300 MJ in each pulse. The temperature in the blanket reaches 1600 K on the inner surface and 1350 K at the outer edge. The granules are automatically thrown into three separate vacuum heat exchangers where they give up their energy to high pressure helium. The helium is used in a Brayton cycle to obtain a thermal-to-electric conversion efficiency of 55%. Studies have been done on neutron activation, debris recovery, vaporization and recondensation of blanket material, tritium control and recovery, fire safety, and cost. These studies indicate that Cascade appears to be a promising ICF reactor candidate from all standpoints. At the 1000 MWe size, electricity could be made for about the same cost as in a future fission reactor

  5. Neuropharmacology of Purinergic Receptors in Human Submucous Plexus: Involvement of P2X1, P2X2, P2X3 Channels, P2Y and A3 Metabotropic Receptors in Neurotransmission

    Science.gov (United States)

    Liñán-Rico, A.; Wunderlich, JE.; Enneking, JT.; Tso, DR.; Grants, I.; Williams, KC.; Otey, A.; Michel, K.; Schemann, M.; Needleman, B.; Harzman, A.; Christofi, FL.

    2015-01-01

    Rationale The role of purinergic signaling in the human ENS is not well understood. We sought to further characterize the neuropharmacology of purinergic receptors in human ENS and test the hypothesis that endogenous purines are critical regulators of neurotransmission. Experimental Approach LSCM-Fluo-4-(Ca2+)-imaging of postsynaptic Ca2+ transients (PSCaTs) was used as a reporter of neural activity. Synaptic transmission was evoked by fiber tract electrical stimulation in human SMP surgical preparations. Pharmacological analysis of purinergic signaling was done in 1,556 neurons from 234 separate ganglia 107 patients; immunochemical labeling for P2XRs of neurons in ganglia from 19 patients. Real-time MSORT (Di-8-ANEPPS) imaging was used to test effects of adenosine on fast excitatory synaptic potentials (fEPSPs). Results Synaptic transmission is sensitive to pharmacological manipulations that alter accumulation of extracellular purines. Apyrase blocks PSCaTs in a majority of neurons. An ecto-NTPDase-inhibitor 6-N,N-diethyl-D-β,γ-dibromomethyleneATP or adenosine deaminase augments PSCaTs. Blockade of reuptake/deamination of eADO inhibits PSCaTs. Adenosine inhibits fEPSPs and PSCaTs (IC50=25μM), sensitive to MRS1220-antagonism (A3AR). A P2Y agonist ADPβS inhibits PSCaTs (IC50=111nM) in neurons without stimulatory ADPβS responses (EC50=960nM). ATP or a P2X1,2,2/3 (α,β-MeATP) agonist evokes fast, slow, biphasic Ca2+ transients or Ca2+ oscillations (EC50=400μM). PSCaTs are sensitive to P2X1 antagonist NF279. Low (20nM) or high (5μM) concentrations of P2X antagonist TNP-ATP block PSCaTs in different neurons; proportions of neurons with P2XR-ir follow the order P2X2>P2X1≫P2X3; P2X1+ P2X2 and P2X3+P2X2 are co-localized. RT-PCR identified mRNA-transcripts for P2X1-7,P2Y1,2,12-14R. Responsive neurons were also identified by HuC/D-ir. Conclusions Purines are critical regulators of neurotransmission in the human enteric nervous system. Purinergic signaling involves

  6. Purinergic P2Y12 Receptor Activation in Eosinophils and the Schistosomal Host Response.

    Science.gov (United States)

    Muniz, Valdirene S; Baptista-Dos-Reis, Renata; Benjamim, Claudia F; Mata-Santos, Hilton A; Pyrrho, Alexandre S; Strauch, Marcelo A; Melo, Paulo A; Vicentino, Amanda R R; Silva-Paiva, Juliana; Bandeira-Melo, Christianne; Weller, Peter F; Figueiredo, Rodrigo T; Neves, Josiane S

    2015-01-01

    Identifying new target molecules through which eosinophils secrete their stored proteins may reveal new therapeutic approaches for the control of eosinophilic disorders such as host immune responses to parasites. We have recently reported the expression of the purinergic P2Y12 receptor (P2Y12R) in human eosinophils; however, its functional role in this cell type and its involvement in eosinophilic inflammation remain unknown. Here, we investigated functional roles of P2Y12R in isolated human eosinophils and in a murine model of eosinophilic inflammation induced by Schistosoma mansoni (S. mansoni) infection. We found that adenosine 5'-diphosphate (ADP) induced human eosinophils to secrete eosinophil peroxidase (EPO) in a P2Y12R dependent manner. However, ADP did not interfere with human eosinophil apoptosis or chemotaxis in vitro. In vivo, C57Bl/6 mice were infected with cercariae of the Belo Horizonte strain of S. mansoni. Analyses performed 55 days post infection revealed that P2Y12R blockade reduced the granulomatous hepatic area and the eosinophilic infiltrate, collagen deposition and IL-13/IL-4 production in the liver without affecting the parasite oviposition. As found for humans, murine eosinophils also express the P2Y12R. P2Y12R inhibition increased blood eosinophilia, whereas it decreased the bone marrow eosinophil count. Our results suggest that P2Y12R has an important role in eosinophil EPO secretion and in establishing the inflammatory response in the course of a S. mansoni infection.

  7. Cascading Corruption News

    DEFF Research Database (Denmark)

    Damgaard, Mads

    2018-01-01

    Through a content analysis of 8,800 news items and six months of front pages in three Brazilian newspapers, all dealing with corruption and political transgression, this article documents the remarkable skew of media attention to corruption scandals. The bias is examined as an information...... phenomenon, arising from systemic and commercial factors of Brazil’s news media: An information cascade of news on corruption formed, destabilizing the governing coalition and legitimizing the impeachment process of Dilma Rousseff. As this process gained momentum, questions of accountability were disregarded...

  8. Cascading Corruption News

    DEFF Research Database (Denmark)

    Damgaard, Mads

    2018-01-01

    Through a content analysis of 8,800 news items and six months of front pages in three Brazilian newspapers, all dealing with corruption and political transgression, this article documents the remarkable skew of media attention to corruption scandals. The bias is examined as an information...... phenomenon, arising from systemic and commercial factors of Brazil’s news media: An information cascade of news on corruption formed, destabilizing the governing coalition and legitimizing the impeachment process of Dilma Rousseff. As this process gained momentum, questions of accountability were disregarded...... by the media, with harmful effects on democracy....

  9. Cascade Structure of Digital Predistorter for Power Amplifier Linearization

    Directory of Open Access Journals (Sweden)

    E. B. Solovyeva

    2015-12-01

    Full Text Available In this paper, a cascade structure of nonlinear digital predistorter (DPD synthesized by the direct learning adaptive algorithm is represented. DPD is used for linearization of power amplifier (PA characteristic, namely for compensation of PA nonlinear distortion. Blocks of the cascade DPD are described by different models: the functional link artificial neural network (FLANN, the polynomial perceptron network (PPN and the radially pruned Volterra model (RPVM. At synthesis of the cascade DPD there is possibility to overcome the ill conditionality problem due to reducing the dimension of DPD nonlinear operator approximation. Results of compensating nonlinear distortion in Wiener–Hammerstein model of PA at the GSM–signal with four carriers are shown. The highest accuracy of PA linearization is produced by the cascade DPD containing PPN and RPVM.

  10. Neuronal Regulation of Schwann Cell Mitochondrial Ca2+ Signaling during Myelination

    OpenAIRE

    Daisuke Ino; Hiroshi Sagara; Junji Suzuki; Kazunori Kanemaru; Yohei Okubo; Masamitsu Iino

    2015-01-01

    Schwann cells (SCs) myelinate peripheral neurons to promote the rapid conduction of action potentials, and the process of myelination is known to be regulated by signals from axons to SCs. Given that SC mitochondria are one of the potential regulators of myelination, we investigated whether SC mitochondria are regulated by axonal signaling. Here, we show a purinergic mechanism that sends information from neurons to SC mitochondria during myelination. Our results show that electrical stimulati...

  11. Interaction of GABAA receptors with purinergic P2X2 receptors

    International Nuclear Information System (INIS)

    Shrivastava, A.

    2010-01-01

    GABA A Rs in the spinal cord are evolving as an important target for drug development against pain. Purinergic P2X 2 Rs are also expressed in spinal cord neurons and are known to cross-talk with GABA A Rs. Here we investigated a possible 'dynamic' interaction between GABA A Rs and P2X 2 Rs using co-immunoprecipitation and FRET studies in HEK cells along with co-localization and single particle tracking studies in spinal cord neurons. Our results suggest that a significant proportion of P2X 2 Rs forms a transient complex with GABA A Rs inside the cell, thus stabilizing these receptors and using them for co-trafficking to the cell surface. P2X 2 Rs and GABA A Rs are then co-inserted into the cell membrane and are primarily located extra-synaptically. Furthermore, agonist induced activation of P2X 2 Rs results in disassembly of the receptor complex and destabilization of GABA A Rs whereas P2X 2 Rs are stabilized and form larger clusters. Antagonist-induced blocking of P2XRs results in co-stabilization of this receptor complex at the cell surface. These results suggest a novel mechanism where association of P2XRs with other receptors could be used for specific targeting to the neuronal membrane, thus providing an extrasynaptic receptor reserve that could regulate the excitability of neurons. We further conclude that blocking the excitatory activity of excessively released ATP under diseased state by P2XR antagonists could simultaneously enhance synaptic inhibition mediated by GABA A Rs.(author) (author) [de

  12. The roles of P2Y2 purinergic receptors in osteoblasts and mechanotransduction.

    Directory of Open Access Journals (Sweden)

    Yanghui Xing

    Full Text Available We previously demonstrated, using osteoblastic MC3T3-E1 cells, that P2Y2 purinergic receptors are involved in osteoblast mechanotransduction. In this study, our objective was to further investigate, using a knockout mouse model, the roles of P2Y2 receptors in bone mechanobiology. We first examined bone structure with micro-CT and measured bone mechanical properties with three point bending experiments in both wild type mice and P2Y2 knockout mice. We found that bones from P2Y2 knockout mice have significantly decreased bone volume, bone thickness, bone stiffness and bone ultimate breaking force at 17 week old age. In order to elucidate the mechanisms by which P2Y2 receptors contribute to bone biology, we examined differentiation and mineralization of bone marrow cells from wild type and P2Y2 knockout mice. We found that P2Y2 receptor deficiency reduces the differentiation and mineralization of bone marrow cells. Next, we compared the response of primary osteoblasts, from both wild type and P2Y2 knockout mice, to ATP and mechanical stimulation (oscillatory fluid flow, and found that osteoblasts from wild type mice have a stronger response, in terms of ERK1/2 phosphorylation, to both ATP and fluid flow, relative to P2Y2 knockout mice. However, we did not detect any difference in ATP release in response to fluid flow between wild type and P2Y2 knock out osteoblasts. Our findings suggest that P2Y2 receptors play important roles in bone marrow cell differentiation and mineralization as well as in bone cell mechanotransduction, leading to an osteopenic phenotype in P2Y2 knockout mice.

  13. Cascade Error Projection Learning Algorithm

    Science.gov (United States)

    Duong, T. A.; Stubberud, A. R.; Daud, T.

    1995-01-01

    A detailed mathematical analysis is presented for a new learning algorithm termed cascade error projection (CEP) and a general learning frame work. This frame work can be used to obtain the cascade correlation learning algorithm by choosing a particular set of parameters.

  14. Interband cascade lasers

    International Nuclear Information System (INIS)

    Vurgaftman, I; Meyer, J R; Canedy, C L; Kim, C S; Bewley, W W; Merritt, C D; Abell, J; Weih, R; Kamp, M; Kim, M; Höfling, S

    2015-01-01

    We review the current status of interband cascade lasers (ICLs) emitting in the midwave infrared (IR). The ICL may be considered the hybrid of a conventional diode laser that generates photons via electron–hole recombination, and an intersubband-based quantum cascade laser (QCL) that stacks multiple stages for enhanced current efficiency. Following a brief historical overview, we discuss theoretical aspects of the active region and core designs, growth by molecular beam epitaxy, and the processing of broad-area, narrow-ridge, and distributed feedback (DFB) devices. We then review the experimental performance of pulsed broad area ICLs, as well as the continuous-wave (cw) characteristics of narrow ridges having good beam quality and DFBs producing output in a single spectral mode. Because the threshold drive powers are far lower than those of QCLs throughout the λ = 3–6 µm spectral band, ICLs are increasingly viewed as the laser of choice for mid-IR laser spectroscopy applications that do not require high output power but need to be hand-portable and/or battery operated. Demonstrated ICL performance characteristics to date include threshold current densities as low as 106 A cm −2 at room temperature (RT), cw threshold drive powers as low as 29 mW at RT, maximum cw operating temperatures as high as 118 °C, maximum cw output powers exceeding 400 mW at RT, maximum cw wallplug efficiencies as high as 18% at RT, maximum cw single-mode output powers as high as 55 mW at RT, and single-mode output at λ = 5.2 µm with a cw drive power of only 138 mW at RT. (topical review)

  15. Extracellular ATP in the Exocrine Pancreas – ATP Release, Signalling and Metabolism

    DEFF Research Database (Denmark)

    Kowal, Justyna Magdalena

    release. So far, the contribution of duct cells in purinergic signalling has never been studied. This work presents that both acinar and duct cells are sources of extracellular ATP in the exocrine pancreas. Here we show that duct cells release ATP in response to several physiological......ATP plays an important role as an autocrine/paracrine signalling molecule, being released from a number of tissues, in response to physiological and pathophysiological stimuli. Released ATP induces Ca2+ - and/or cAMP - dependent cellular responses via activation of ubiquitously expressed P2X and P2......, particularly during Ca2+ stress conditions. In conclusion, these studies demonstrate a complex regulation of purinergic signalling in exocrine pancreas. A crucial role for duct cells in mediating extracellular nucleotides homeostasis, involving ATP release, subsequent hydrolysis and conversion via...

  16. Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.

    Directory of Open Access Journals (Sweden)

    Wei Zheng

    2010-12-01

    Full Text Available Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5' diphosphate (2-MeSADP, an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y(1R. At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP(3-dependent Ca(2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries.

  17. Evaluation of purinergic mechanism for the treatment of voiding dysfunction: a study in conscious spinal cord-injured rats.

    Science.gov (United States)

    Lu, Shing-Hwa; Groat, William C de; Lin, Alex T L; Chen, Kuang-Kuo; Chang, Luke S

    2007-10-01

    To investigate the effect of a selective P2X(3-)P2X(2/3) purinergic receptor antagonist (a-317491) on detrusor hyperreflexia in conscious chronic spinal cord-injured female rats. Six chronic spinal cord-transected female Sprague-Dawley rats (290-336 g) were used in this study. Spinal transection at the T8-T9 segmental level was performed using aseptic techniques under halothane anesthesia. Fourteen to 16 weeks after spinal transection, A-317491, a selective P2X(3-)P2X(2/3) purinergic receptor antagonist, was administered intravenously in cystometry studies at increasing doses of 0.03, 0.1, 0.3, 1, 3, 10 and 30 micromol/kg at 40-50 minute intervals. Cystometrograms (CMGs) were performed before and after the administration of each dose of the drug. The continuous filling of CMGs revealed a large number of small-amplitude (> 8 cmH(2)O), non-voiding contractions (NVCs) (average, 9.7 per voiding cycle) preceding voiding contractions (mean amplitude, 31 cmH(2)O; duration, 2.5 minutes), which occurred at an interval of 539 seconds and at a pressure threshold of 5.7 cmH(2)O. When tested in a range of doses (0.03-30 micromol/kg, intravenous), A-317491 in doses between 1 and 30 micromol/kg significantly (p spinal cord injury in rats.

  18. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role...... using insulin signalling as a model system....

  19. Apical membrane P2Y4 purinergic receptor controls K+ secretion by strial marginal cell epithelium

    Directory of Open Access Journals (Sweden)

    Scofield Margaret A

    2005-11-01

    Full Text Available Abstract Background It was previously shown that K+ secretion by strial marginal cell epithelium is under the control of G-protein coupled receptors of the P2Y family in the apical membrane. Receptor activation by uracil nucleotides (P2Y2, P2Y4 or P2Y6 leads to a decrease in the electrogenic K+ secretion. The present study was conducted to determine the subtype of the functional purinergic receptor in gerbil stria vascularis, to test if receptor activation leads to elevation of intracellular [Ca2+] and to test if the response to these receptors undergoes desensitization. Results The transepithelial short circuit current (Isc represents electrogenic K+ secretion and was found to be decreased by uridine 5'-triphosphate (UTP, adenosine 5'-triphosphate (ATP and diadenosine tetraphosphate (Ap4A but not uridine 5'-diphosphate (UDP at the apical membrane of marginal cells of the gerbil stria vascularis. The potencies of these agonists were consistent with rodent P2Y4 and P2Y2 but not P2Y6 receptors. Activation caused a biphasic increase in intracellular [Ca2+] that could be partially blocked by 2-aminoethoxy-diphenyl borate (2-APB, an inhibitor of the IP3 receptor and store-operated channels. Suramin (100 μM did not inhibit the effect of UTP (1 μM. The ineffectiveness of suramin at the concentration used was consistent with P2Y4 but not P2Y2. Transcripts for both P2Y2 and P2Y4 were found in the stria vascularis. Sustained exposure to ATP or UTP for 15 min caused a depression of Isc that appeared to have two components but with apparently no chronic desensitization. Conclusion The results support the conclusion that regulation of K+ secretion across strial marginal cell epithelium occurs by P2Y4 receptors at the apical membrane. The apparent lack of desensitization of the response is consistent with two processes: a rapid-onset phosphorylation of KCNE1 channel subunit and a slower-onset of regulation by depletion of plasma membrane PIP2.

  20. Inferring network structure from cascades

    Science.gov (United States)

    Ghonge, Sushrut; Vural, Dervis Can

    2017-07-01

    Many physical, biological, and social phenomena can be described by cascades taking place on a network. Often, the activity can be empirically observed, but not the underlying network of interactions. In this paper we offer three topological methods to infer the structure of any directed network given a set of cascade arrival times. Our formulas hold for a very general class of models where the activation probability of a node is a generic function of its degree and the number of its active neighbors. We report high success rates for synthetic and real networks, for several different cascade models.

  1. Cascade energy amplifier

    International Nuclear Information System (INIS)

    Barzilov, A.P.; Gulevich, A.V.; Kukharchuk, O.F.

    2000-01-01

    The technical problem of long-life fission product and minor actinide incineration and production of plutonium fuel in the prospective nuclear systems will arise at significant scales of nuclear power industry development. Subcritical nuclear reactors driven by extemal neutron sources (energy amplifiers) are considered as incinerators of toxicity of complete nuclear industry. In the frames of this concept, the subcritical reactor part consisting of two coupled blanket regions (inner fast neutron spectrum core and outer thermal core) driven by extemal neutron source is discussed. Two types of source are studied: spallation target and 14-MeV fusion bum of micropellets. Liquid metal Pb-Bi is considered as target material and coolant of inner fast core. Thermal core is a heavy-water subcritical reactor of the Candu-type. The fast core is protected from thermal neutrons influence with the boron shield. All reactor technologies used in this concept are tested during years of operation and commercially available. Thus, the cascade energy amplifiers have a set of advantages in comparison with traditional concepts: in energy production, in transmutation efficiency, and in economics. (authors)

  2. mGluR1 receptors contribute to non-purinergic slow excitatory transmission to submucosal VIP neurons of guinea-pig ileum

    Directory of Open Access Journals (Sweden)

    Jaime Pei Pei Foong

    2009-05-01

    Full Text Available Vasoactive intestinal peptide (VIP immunoreactive secretomotor neurons in the submucous plexus are involved in mediating bacterial toxin-induced hypersecretion leading to diarrhoea. VIP neurons become hyperexcitable after the mucosa is exposed to cholera toxin, which suggests that the manipulation of the excitability of these neurons may be therapeutic. This study used standard intracellular recording methods to systematically characterize slow excitatory postsynaptic potentials (EPSPs evoked in submucosal VIP neurons by different stimulus regimes (1, 3 and 15 pulse 30 Hz stimulation, together with their associated input resistances and pharmacology. All slow EPSPs were associated with a significant increase in input resistance compared to baseline values. Slow EPSPs evoked by a single stimulus were confirmed to be purinergic, however, slow EPSPs evoked by 15 pulse trains were non-purinergic and those evoked by 3 pulse trains were mixed. NK1 or NK3 receptor antagonists did not affect slow EPSPs. The group I mGluR receptor antagonist, PHCCC reduced the amplitude of purinergic and non-purinergic slow EPSPs. Blocking mGluR1 receptors depressed the overall response to 3 and 15 pulse trains, but this effect was inconsistent, while blockade of mGluR5 receptors had no effect on the non-purinergic slow EPSPs. Thus, although other receptors are almost certainly involved, our data indicate that there are at least two pharmacologically distinct types of slow EPSPs in the VIP secretomotor neurons: one mediated by P2Y receptors and the other in part by mGluR1 receptors.

  3. Ultrarelativistic cascades and strangeness production

    Energy Technology Data Exchange (ETDEWEB)

    Kahana, D.E. [State Univ. of New York, Stony Brook, NY (United States). Dept. of Physics; Kahana, S.H. [Brookhaven National Lab., Upton, NY (United States). Physics Dept.

    1998-08-24

    A two-phase cascade code, LUCIFER II, developed for the treatment of ultra high energy-ion-ion collisions is applied to the production of strangeness at SPS energies {radical}(s)=17-20. This simulation is able to simultaneously describe both hard processes such as Drell-Yan and slower, soft processes such as the production of light mesons by separating the dynamics into two steps, a fast cascade involving only the nucleons in the original colliding relativistic ions followed, after an appropriate delay, by a normal multiscattering of the resulting excited baryons and mesons produced virtually in the first step. No energy loss can take place in the short time interval over which the first cascade takes place. The chief result is a reconciliation of the important Drell-Yan measurements with the apparent success of standard cascades to describe the nucleon stopping and meson production in heavy-ion experiments at the CERN SPS. (orig.) 26 refs.

  4. Ultrarelativistic cascades and strangeness production

    International Nuclear Information System (INIS)

    Kahana, D.E.; Kahana, S.H.

    1998-01-01

    A two-phase cascade code, LUCIFER II, developed for the treatment of ultra high energy-ion-ion collisions is applied to the production of strangeness at SPS energies √(s)=17-20. This simulation is able to simultaneously describe both hard processes such as Drell-Yan and slower, soft processes such as the production of light mesons by separating the dynamics into two steps, a fast cascade involving only the nucleons in the original colliding relativistic ions followed, after an appropriate delay, by a normal multiscattering of the resulting excited baryons and mesons produced virtually in the first step. No energy loss can take place in the short time interval over which the first cascade takes place. The chief result is a reconciliation of the important Drell-Yan measurements with the apparent success of standard cascades to describe the nucleon stopping and meson production in heavy-ion experiments at the CERN SPS. (orig.)

  5. Ultrarelativistic cascades and strangeness production

    International Nuclear Information System (INIS)

    Kahana, D.E.; Kahana, S.H.

    1998-02-01

    A two phase cascade, LUCIFER II, developed for the treatment of ultra high energy Ion-Ion collisions is applied to the production of strangeness at SPS energies. This simulation is able to simultaneously describe both hard processes such as Drell-Yan and slower, soft processes such as the production of light mesons by separating the dynamics into two steps, a fast cascade involving only the nucleons in the original colliding relativistic ions followed, after an appropriate delay, by a normal multiscattering of the resulting excited baryons and mesons produced virtually in the first step. No energy loss can take place in the short time interval over which the first cascade takes place. The chief result is a reconciliation of the important Drell-Yan measurements with the apparent success of standard cascades to describe the nucleon stopping and meson production in heavy ion experiments at the CERN SPS

  6. Cascade redox flow battery systems

    Science.gov (United States)

    Horne, Craig R.; Kinoshita, Kim; Hickey, Darren B.; Sha, Jay E.; Bose, Deepak

    2014-07-22

    A reduction/oxidation ("redox") flow battery system includes a series of electrochemical cells arranged in a cascade, whereby liquid electrolyte reacts in a first electrochemical cell (or group of cells) before being directed into a second cell (or group of cells) where it reacts before being directed to subsequent cells. The cascade includes 2 to n stages, each stage having one or more electrochemical cells. During a charge reaction, electrolyte entering a first stage will have a lower state-of-charge than electrolyte entering the nth stage. In some embodiments, cell components and/or characteristics may be configured based on a state-of-charge of electrolytes expected at each cascade stage. Such engineered cascades provide redox flow battery systems with higher energy efficiency over a broader range of current density than prior art arrangements.

  7. The cascaded amplifier and saturable absorber (CASA) all-optical switch

    DEFF Research Database (Denmark)

    Hilliger, E.; Berger, J.; Weber, H. G.

    2001-01-01

    The cascaded amplifier and saturable absorber is presented as a new all-optical switching scheme for optical signal processing applications. First demultiplexing experiments demonstrate the principle of operation of this scheme....

  8. Stochastic background of atmospheric cascades

    International Nuclear Information System (INIS)

    Wilk, G.; Wlodarczyk, Z.

    1993-01-01

    Fluctuations in the atmospheric cascades developing during the propagation of very high energy cosmic rays through the atmosphere are investigated using stochastic branching model of pure birth process with immigration. In particular, we show that the multiplicity distributions of secondaries emerging from gamma families are much narrower than those resulting from hadronic families. We argue that the strong intermittent like behaviour found recently in atmospheric families results from the fluctuations in the cascades themselves and are insensitive to the details of elementary interactions

  9. Computation of inverse magnetic cascades

    International Nuclear Information System (INIS)

    Montgomery, D.

    1981-10-01

    Inverse cascades of magnetic quantities for turbulent incompressible magnetohydrodynamics are reviewed, for two and three dimensions. The theory is extended to the Strauss equations, a description intermediate between two and three dimensions appropriate to tokamak magnetofluids. Consideration of the absolute equilibrium Gibbs ensemble for the system leads to a prediction of an inverse cascade of magnetic helicity, which may manifest itself as a major disruption. An agenda for computational investigation of this conjecture is proposed

  10. Frequency division using a micromechanical resonance cascade

    Energy Technology Data Exchange (ETDEWEB)

    Qalandar, K. R., E-mail: kamala@engineering.ucsb.edu; Gibson, B.; Sharma, M.; Ma, A.; Turner, K. L. [Department of Mechanical Engineering, University of California at Santa Barbara, Santa Barbara, California 93106 (United States); Strachan, B. S. [Department of Mechanical Engineering, Michigan State University, East Lansing, Michigan 48823 (United States); Department of Electrical Engineering, Michigan State University, East Lansing, Michigan 48823 (United States); Shaw, S. W. [Department of Mechanical Engineering, Michigan State University, East Lansing, Michigan 48823 (United States); Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan 48823 (United States)

    2014-12-15

    A coupled micromechanical resonator array demonstrates a mechanical realization of multi-stage frequency division. The mechanical structure consists of a set of N sequentially perpendicular microbeams that are connected by relatively weak elastic elements such that the system vibration modes are localized to individual microbeams and have natural frequencies with ratios close to 1:2:⋯:2{sup N}. Conservative (passive) nonlinear inter-modal coupling provides the required energy transfer between modes and is achieved by finite deformation kinematics. When the highest frequency beam is excited, this arrangement promotes a cascade of subharmonic resonances that achieve frequency division of 2{sup j} at microbeam j for j = 1, …, N. Results are shown for a capacitively driven three-stage divider in which an input signal of 824 kHz is passively divided through three modal stages, producing signals at 412 kHz, 206 kHz, and 103 kHz. The system modes are characterized and used to delineate the range of AC input voltages and frequencies over which the cascade occurs. This narrow band frequency divider has simple design rules that are scalable to higher frequencies and can be extended to a larger number of modal stages.

  11. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

    OpenAIRE

    Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R. Douglas

    2004-01-01

    Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron–glia communication are not known. Recent research shows that adenosine is a neuron–glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility...

  12. The purinergic P2X7 ion channel receptor — a ‘repair’ receptor in bone

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye

    2018-01-01

    A strong skeleton relies on adaptation to varying physical demands and on maintenance of the bone tissue in order to avoid accumulation of micro-damage. In bone, the purinergic P2X7 ion channel receptor is expressed on both cells of the stromal lineage such as the bone forming osteoblasts...... and the mechano-sensing osteocytes and on cells belonging to the immune-related monocyte–macrophage lineage, the bone resorbing osteoclasts. Recent studies have demonstrated that the receptor plays important roles in the anabolic responses to mechanical loading on bone and, together with the pannexin1 hemi......-channel, in the process of initiating bone remodeling in response to micro-damage. Thus, the receptor is crucial in skeletal mechano-transduction and in the continuous repair process. However, under pathophysiological conditions such as diabetes with high glucose concentrations or glucocorticoid-treatment the receptor...

  13. Communication between corneal epithelial cells and trigeminal neurons is facilitated by purinergic (P2) and glutamatergic receptors.

    Science.gov (United States)

    Oswald, Duane J; Lee, Albert; Trinidad, Monique; Chi, Cheryl; Ren, Ruiyi; Rich, Celeste B; Trinkaus-Randall, Vickery

    2012-01-01

    Previously, we demonstrated that nucleotides released upon mechanical injury to corneal epithelium activate purinergic (P2) receptors resulting in mobilization of a Ca(2+) wave. However, the tissue is extensively innervated and communication between epithelium and neurons is critical and not well understood. Therefore, we developed a co-culture of primary trigeminal neurons and human corneal limbal epithelial cells. We demonstrated that trigeminal neurons expressed a repertoire of P2Yand P2X receptor transcripts and responded to P2 agonists in a concentration-dependent manner. Mechanical injuries to epithelia in the co-cultures elicited a Ca(2+) wave that mobilized to neurons and was attenuated by Apyrase, an ectonucleotidase. To elucidate the role of factors released from each cell type, epithelial and neuronal cells were cultured, injured, and the wound media from one cell type was collected and added to the other cell type. Epithelial wound media generated a rapid Ca(2+) mobilization in neuronal cells that was abrogated in the presence of Apyrase, while neuronal wound media elicited a complex response in epithelial cells. The rapid Ca(2+) mobilization was detected, which was abrogated with Apyrase, but it was followed by Ca(2+) waves that occurred in cell clusters. When neuronal wound media was preincubated with a cocktail of N-methyl-D-aspartate (NMDA) receptor inhibitors, the secondary response in epithelia was diminished. Glutamate was detected in the neuronal wound media and epithelial expression of NMDA receptor subunit transcripts was demonstrated. Our results indicate that corneal epithelia and neurons communicate via purinergic and NMDA receptors that mediate the wound response in a highly orchestrated manner.

  14. Communication between corneal epithelial cells and trigeminal neurons is facilitated by purinergic (P2 and glutamatergic receptors.

    Directory of Open Access Journals (Sweden)

    Duane J Oswald

    Full Text Available Previously, we demonstrated that nucleotides released upon mechanical injury to corneal epithelium activate purinergic (P2 receptors resulting in mobilization of a Ca(2+ wave. However, the tissue is extensively innervated and communication between epithelium and neurons is critical and not well understood. Therefore, we developed a co-culture of primary trigeminal neurons and human corneal limbal epithelial cells. We demonstrated that trigeminal neurons expressed a repertoire of P2Yand P2X receptor transcripts and responded to P2 agonists in a concentration-dependent manner. Mechanical injuries to epithelia in the co-cultures elicited a Ca(2+ wave that mobilized to neurons and was attenuated by Apyrase, an ectonucleotidase. To elucidate the role of factors released from each cell type, epithelial and neuronal cells were cultured, injured, and the wound media from one cell type was collected and added to the other cell type. Epithelial wound media generated a rapid Ca(2+ mobilization in neuronal cells that was abrogated in the presence of Apyrase, while neuronal wound media elicited a complex response in epithelial cells. The rapid Ca(2+ mobilization was detected, which was abrogated with Apyrase, but it was followed by Ca(2+ waves that occurred in cell clusters. When neuronal wound media was preincubated with a cocktail of N-methyl-D-aspartate (NMDA receptor inhibitors, the secondary response in epithelia was diminished. Glutamate was detected in the neuronal wound media and epithelial expression of NMDA receptor subunit transcripts was demonstrated. Our results indicate that corneal epithelia and neurons communicate via purinergic and NMDA receptors that mediate the wound response in a highly orchestrated manner.

  15. Time structure of cascade showers

    International Nuclear Information System (INIS)

    Nakatsuka, Takao

    1984-01-01

    Interesting results have been reported on the time structure of the electromagnetic components of air showers which have been obtained by using recent fast electronic circuit technology. However, these analyses and explanations seem not very persuasive. One of the reasons is that there is not satisfactory theoretical calculation yet to explain the delay of electromagnetic components in cascade processes which are the object of direct observation. Therefore, Monte Carlo calculation was attempted for examining the relationship between the altitude at which high energy γ-ray is generated up in the air and the time structure of cascade showers at the level of observation. The investigation of a dominant factor over the delay of electromagnetic components indicated that the delay due to the multiple scattering of electrons was essential. The author used the analytical solution found by himself of C. N. Yang's equation for the study on the delay due to multiple scattering. The results were as follows: The average delay time and the spread of distribution of electromagnetic cascades were approximately in linear relationship with the mass of a material having passed in a thin uniform medium; the rise time of arrival time distribution for electromagnetic cascade showers was very steep under the condition that they were generated up in the air and observed on the ground; the subpeaks delayed by tens of ns in arrival time may sometimes appear due to the perturbation in electromagnetic cascade processes. (Wakatsuki, Y.)

  16. Presynaptic Dopamine D2 Receptors Modulate [3H]GABA Release at StriatoPallidal Terminals via Activation of PLC → IP3 → Calcineurin and Inhibition of AC → cAMP → PKA Signaling Cascades.

    Science.gov (United States)

    Jijón-Lorenzo, Rafael; Caballero-Florán, Isaac Hiram; Recillas-Morales, Sergio; Cortés, Hernán; Avalos-Fuentes, José Arturo; Paz-Bermúdez, Francisco Javier; Erlij, David; Florán, Benjamín

    2018-02-21

    Striatal dopamine D2 receptors activate the PLC → IP3 → Calcineurin-signaling pathway to modulate the neural excitability of En+ Medium-sized Spiny GABAergic neurons (MSN) through the regulation of L-type Ca 2+ channels. Presynaptic dopaminergic D2 receptors modulate GABA release at striatopallidal terminals through L-type Ca 2+ channels as well, but their signaling pathway is still undetermined. Since D2 receptors are Gi/o-coupled and negatively modulate adenylyl cyclase (AC), we investigated whether presynaptic D2 receptors modulate GABA release through the same signaling cascade that controls excitability in the striatum or by the inhibition of AC and decreased PKA activity. Activation of D2 receptors stimulated formation of [ 3 H]IP 1 and decreased Forskolin-stimulated [ 3 H]cAMP accumulation in synaptosomes from rat Globus Pallidus. D2 receptor activation with Quinpirole in the presence of L 745,870 decreased, in a dose-dependent manner, K + -induced [ 3 H]GABA release in pallidal slices. The effect was prevented by the pharmacological blockade of Gi/o βγ subunit effects with Gallein, PLC with U 73122, IP3 receptor activation with 4-APB, Calcineurin with FK506. In addition, when release was stimulated with Forskolin to activate AC, D2 receptors also decreased K + -induced [ 3 H]GABA release, an effect occluded with the effect of the blockade of PKA with H89 or stimulation of release with the cAMP analog 8-Br-cAMP. These data indicate that D2 receptors modulate [ 3 H]GABA release at striatopallidal terminals by activating the PLC → IP3 → Calcineurin-signaling cascade, the same one that modulates excitability in soma. Additionally, D2 receptors inhibit release when AC is active. Both mechanisms appear to converge to regulate the activity of presynaptic L-type Ca 2+ channels. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Neuronal Regulation of Schwann Cell Mitochondrial Ca(2+) Signaling during Myelination.

    Science.gov (United States)

    Ino, Daisuke; Sagara, Hiroshi; Suzuki, Junji; Kanemaru, Kazunori; Okubo, Yohei; Iino, Masamitsu

    2015-09-29

    Schwann cells (SCs) myelinate peripheral neurons to promote the rapid conduction of action potentials, and the process of myelination is known to be regulated by signals from axons to SCs. Given that SC mitochondria are one of the potential regulators of myelination, we investigated whether SC mitochondria are regulated by axonal signaling. Here, we show a purinergic mechanism that sends information from neurons to SC mitochondria during myelination. Our results show that electrical stimulation of rat sciatic nerve increases extracellular ATP levels enough to activate purinergic receptors. Indeed, electrical stimulation of sciatic nerves induces Ca(2+) increases in the cytosol and the mitochondrial matrix of surrounding SCs via purinergic receptor activation. Chronic suppression of this pathway during active myelination suppressed the longitudinal and radial development of myelinating SCs and caused hypomyelination. These results demonstrate a neuron-to-SC mitochondria signaling, which is likely to have an important role in proper myelination. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Rescuing Ecosystems from Extinction Cascades

    Science.gov (United States)

    Sahasrabudhe, Sagar; Motter, Adilson

    2010-03-01

    Food web perturbations stemming from climate change, overexploitation, invasive species, and natural disasters often cause an initial loss of species that results in a cascade of secondary extinctions. Using a predictive modeling framework, here we will present a systematic network-based approach to reduce the number of secondary extinctions. We will show that the extinction of one species can often be compensated by the concurrent removal of a second specific species, which is a counter-intuitive effect not previously tested in complex food webs. These compensatory perturbations frequently involve long-range interactions that are not a priori evident from local predator-prey relationships. Strikingly, in numerous cases even the early removal of a species that would eventually be extinct by the cascade is found to significantly reduce the number of cascading extinctions. Other nondestructive interventions based on partial removals and growth suppression and/or mortality increase are shown to sometimes prevent all secondary extinctions.

  19. Cascaded FSO-VLC Communication System

    KAUST Repository

    Gupta, Akash

    2017-08-28

    The proposed cascaded free space optics (FSO)-visible light communication (VLC) system consists of multiple VLC access points which caters the end users connected via a decode and forward (DF) relay to the FSO backhaul link. The FSO link is assumed to be affected by path-loss, pointing error and atmospheric turbulence while the end-to-end signal-to-noise ratio (SNR) of VLC downlinks are statistically characterized considering the randomness of users position. In this study, the novel closed form expressions of the statistics like probability density function (PDF) and cumulative distribution function (CDF) of the equivalent SNR are derived. Capitalizing on these, the closed form expressions for various performance metrics such as outage probability and error probability are provided. The simulation results are provided to verify the functional curves of mathematical analysis.

  20. Seeking heavy Higgs bosons through cascade decays

    Science.gov (United States)

    Coleppa, Baradhwaj; Fuks, Benjamin; Poulose, P.; Sahoo, Shibananda

    2018-04-01

    We investigate the LHC discovery prospects for a heavy Higgs boson decaying into the standard model Higgs boson and additional weak bosons. We consider a generic model-independent new physics configuration where this decay proceeds via a cascade involving other intermediate scalar bosons and focus on an LHC final-state signature comprised either of four b -jets and two charged leptons or of four charged leptons and two b -jets. We design two analyses of the corresponding signals, and demonstrate that a 5 σ discovery at the 14 TeV LHC is possible for various combinations of the parent and daughter Higgs-boson masses. We moreover find that the standard model backgrounds can be sufficiently rejected to guarantee the reconstruction of the parent Higgs boson mass. We apply our analyses to the Type-II two-Higgs-doublet model and identify the regions of the parameter space to which the LHC is sensitive.

  1. Cell membrane disruption stimulates cAMP and Ca2+ signaling to potentiate cell membrane resealing in neighboring cells

    Directory of Open Access Journals (Sweden)

    Tatsuru Togo

    2017-12-01

    Full Text Available Disruption of cellular plasma membranes is a common event in many animal tissues, and the membranes are usually rapidly resealed. Moreover, repeated membrane disruptions within a single cell reseal faster than the initial wound in a protein kinase A (PKA- and protein kinase C (PKC-dependent manner. In addition to wounded cells, recent studies have demonstrated that wounding of Madin-Darby canine kidney (MDCK cells potentiates membrane resealing in neighboring cells in the short-term by purinergic signaling, and in the long-term by nitric oxide/protein kinase G signaling. In the present study, real-time imaging showed that cell membrane disruption stimulated cAMP synthesis and Ca2+ mobilization from intracellular stores by purinergic signaling in neighboring MDCK cells. Furthermore, inhibition of PKA and PKC suppressed the ATP-mediated short-term potentiation of membrane resealing in neighboring cells. These results suggest that cell membrane disruption stimulates PKA and PKC via purinergic signaling to potentiate cell membrane resealing in neighboring MDCK cells.

  2. Multiplicity distributions in QCD cascades

    International Nuclear Information System (INIS)

    Gustafson, G.

    1992-03-01

    Multiplicity distributions for hadrons and for jets are studied in QCD parton cascades. The colour dipole formalism is used and earlier results in the double log approximation are generalized to include terms which are suppressed by colour factors or factors of ln s. The result is a set of coupled differential equations, together with appropriate boundary conditions

  3. A comparison of methods for cascade prediction

    OpenAIRE

    Guo, Ruocheng; Shakarian, Paulo

    2016-01-01

    Information cascades exist in a wide variety of platforms on Internet. A very important real-world problem is to identify which information cascades can go viral. A system addressing this problem can be used in a variety of applications including public health, marketing and counter-terrorism. As a cascade can be considered as compound of the social network and the time series. However, in related literature where methods for solving the cascade prediction problem were proposed, the experimen...

  4. Computer simulation of displacement cascades in copper

    International Nuclear Information System (INIS)

    Heinisch, H.L.

    1983-06-01

    More than 500 displacement cascades in copper have been generated with the computer simulation code MARLOWE over an energy range pertinent to both fission and fusion neutron spectra. Three-dimensional graphical depictions of selected cascades, as well as quantitative analysis of cascade shapes and sizes and defect densities, illustrate cascade behavior as a function of energy. With increasing energy, the transition from production of single compact damage regions to widely spaced multiple damage regions is clearly demonstrated

  5. Penalty-free transmission at 10 Gbit/s through 40 cascaded 1-nm arrayed waveguide multiplexers

    DEFF Research Database (Denmark)

    Nissov, Morten; Jørgensen, Bo Foged; Pedersen, Rune Johan Skullerud

    1997-01-01

    Cascaded optical add-drop multiplexers (OADM) and optical cross connects (OXC) are key components in optical wavelength-division multiplex networks. OADMs with filtering of the passing signals and OXCs can be constructed by the use of wavelength-division multiplexers. Cascadability of multiplexers...

  6. Cascaded Bragg scattering in fiber optics.

    Science.gov (United States)

    Xu, Y Q; Erkintalo, M; Genty, G; Murdoch, S G

    2013-01-15

    We report on a theoretical and experimental study of cascaded Bragg scattering in fiber optics. We show that the usual energy-momentum conservation of Bragg scattering can be considerably relaxed via cascade-induced phase-matching. Experimentally we demonstrate frequency translation over six- and 11-fold cascades, in excellent agreement with derived phase-matching conditions.

  7. Retroactive signaling in short signaling pathways.

    Directory of Open Access Journals (Sweden)

    Jacques-Alexandre Sepulchre

    Full Text Available In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles.

  8. Digital Speed Cascade Control, using Scilab / Xcos Environment

    Directory of Open Access Journals (Sweden)

    Petru Chioncel

    2016-10-01

    Full Text Available This paper presents an application of digital cascade control implemented in Scilab / Xcos environment, using a P type regulator for the position adjustment circuit, a PI controller for the speed circuit adjustment; the current respectively moments control circuits are rendered by elements of PT1 type. On this basis the program is done in Scilab and the related signal block diagram implemented in Xcos; through simulation, the step response of the system is analyzed for different sampling times.

  9. A new cascade NN based method to short-term load forecast in deregulated electricity market

    International Nuclear Information System (INIS)

    Kouhi, Sajjad; Keynia, Farshid

    2013-01-01

    Highlights: • We are proposed a new hybrid cascaded NN based method and WT to short-term load forecast in deregulated electricity market. • An efficient preprocessor consist of normalization and shuffling of signals is presented. • In order to select the best inputs, a two-stage feature selection is presented. • A new cascaded structure consist of three cascaded NNs is used as forecaster. - Abstract: Short-term load forecasting (STLF) is a major discussion in efficient operation of power systems. The electricity load is a nonlinear signal with time dependent behavior. The area of electricity load forecasting has still essential need for more accurate and stable load forecast algorithm. To improve the accuracy of prediction, a new hybrid forecast strategy based on cascaded neural network is proposed for STLF. This method is consists of wavelet transform, an intelligent two-stage feature selection, and cascaded neural network. The feature selection is used to remove the irrelevant and redundant inputs. The forecast engine is composed of three cascaded neural network (CNN) structure. This cascaded structure can be efficiently extract input/output mapping function of the nonlinear electricity load data. Adjustable parameters of the intelligent feature selection and CNN is fine-tuned by a kind of cross-validation technique. The proposed STLF is tested on PJM and New York electricity markets. It is concluded from the result, the proposed algorithm is a robust forecast method

  10. Astrocyte Sodium Signalling and Panglial Spread of Sodium Signals in Brain White Matter.

    Science.gov (United States)

    Moshrefi-Ravasdjani, Behrouz; Hammel, Evelyn L; Kafitz, Karl W; Rose, Christine R

    2017-09-01

    In brain grey matter, excitatory synaptic transmission activates glutamate uptake into astrocytes, inducing sodium signals which propagate into neighboring astrocytes through gap junctions. These sodium signals have been suggested to serve an important role in neuro-metabolic coupling. So far, it is unknown if astrocytes in white matter-that is in brain regions devoid of synapses-are also able to undergo such intra- and intercellular sodium signalling. In the present study, we have addressed this question by performing quantitative sodium imaging in acute tissue slices of mouse corpus callosum. Focal application of glutamate induced sodium transients in SR101-positive astrocytes. These were largely unaltered in the presence of ionotropic glutamate receptors blockers, but strongly dampened upon pharmacological inhibition of glutamate uptake. Sodium signals induced in individual astrocytes readily spread into neighboring SR101-positive cells with peak amplitudes decaying monoexponentially with distance from the stimulated cell. In addition, spread of sodium was largely unaltered during pharmacological inhibition of purinergic and glutamate receptors, indicating gap junction-mediated, passive diffusion of sodium between astrocytes. Using cell-type-specific, transgenic reporter mice, we found that sodium signals also propagated, albeit less effectively, from astrocytes to neighboring oligodendrocytes and NG2 cells. Again, panglial spread was unaltered with purinergic and glutamate receptors blocked. Taken together, our results demonstrate that activation of sodium-dependent glutamate transporters induces sodium signals in white matter astrocytes, which spread within the astrocyte syncytium. In addition, we found a panglial passage of sodium signals from astrocytes to NG2 cells and oligodendrocytes, indicating functional coupling between these macroglial cells in white matter.

  11. 3,5,4′-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/β-catenin signaling cascades and reversal of epithelial–mesenchymal transition

    International Nuclear Information System (INIS)

    Tsai, Jie-Heng; Hsu, Li-Sung; Lin, Chih-Li; Hong, Hui-Mei; Pan, Min-Hsiung; Way, Tzong-Der; Chen, Wei-Jen

    2013-01-01

    The molecular basis of epithelial–mesenchymal transition (EMT) functions as a potential therapeutic target for breast cancer because EMT may endow breast tumor-initiating cells with stem-like characteristics and enable the dissemination of breast cancer cells. We have recently verified the antitumor activity of 3,5,4′-trimethoxystilbene (MR-3), a naturally methoxylated derivative of resveratrol, in colorectal cancer xenografts via an induction of apoptosis. The effect of MR-3 on EMT and the invasiveness of human MCF-7 breast adenocarcinoma cell line were also explored. We found that MR-3 significantly increased epithelial marker E-cadherin expression and triggered a cobblestone-like morphology of MCF-7 cells, while reciprocally decreasing the expression of mesenchymal markers, such as snail, slug, and vimentin. In parallel with EMT reversal, MR-3 downregulated the invasion and migration of MCF-7 cells. Exploring the action mechanism of MR-3 on the suppression of EMT and invasion indicates that MR-3 markedly reduced the expression and nuclear translocation of β-catenin, accompanied with the downregulation of β-catenin target genes and the increment of membrane-bound β-catenin. These results suggest the involvement of Wnt/β-catenin signaling in the MR-3-induced EMT reversion of MCF-7 cells. Notably, MR-3 restored glycogen synthase kinase-3β activity by inhibiting the phosphorylation of Akt, the event required for β-catenin destruction via a proteasome-mediated system. Overall, these findings indicate that the anti-invasive activity of MR-3 on MCF-7 cells may result from the suppression of EMT via down-regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling, and consequently, β-catenin nuclear translocation. These occurrences ultimately lead to the blockage of EMT and the invasion of breast cancer cells. - Highlights: • MR-3 blocked MCF-7 cell invasion by inducing a reversal of EMT. • Wnt/β-catenin signaling is involved in MR-3-induced EMT

  12. 3,5,4′-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/β-catenin signaling cascades and reversal of epithelial–mesenchymal transition

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, Jie-Heng [Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, ROC (China); Hsu, Li-Sung [Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, ROC (China); Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan, ROC (China); Lin, Chih-Li [Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, ROC (China); Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan, ROC (China); Hong, Hui-Mei [Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan, ROC (China); Department of Biomedical Sciences, Chung Shan Medical University, Taichung 402, Taiwan, ROC (China); Pan, Min-Hsiung [Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung 811, Taiwan, ROC (China); Way, Tzong-Der [Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 40402, Taiwan, ROC (China); Chen, Wei-Jen, E-mail: cwj519@csmu.edu.tw [Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan, ROC (China); Department of Biomedical Sciences, Chung Shan Medical University, Taichung 402, Taiwan, ROC (China)

    2013-11-01

    The molecular basis of epithelial–mesenchymal transition (EMT) functions as a potential therapeutic target for breast cancer because EMT may endow breast tumor-initiating cells with stem-like characteristics and enable the dissemination of breast cancer cells. We have recently verified the antitumor activity of 3,5,4′-trimethoxystilbene (MR-3), a naturally methoxylated derivative of resveratrol, in colorectal cancer xenografts via an induction of apoptosis. The effect of MR-3 on EMT and the invasiveness of human MCF-7 breast adenocarcinoma cell line were also explored. We found that MR-3 significantly increased epithelial marker E-cadherin expression and triggered a cobblestone-like morphology of MCF-7 cells, while reciprocally decreasing the expression of mesenchymal markers, such as snail, slug, and vimentin. In parallel with EMT reversal, MR-3 downregulated the invasion and migration of MCF-7 cells. Exploring the action mechanism of MR-3 on the suppression of EMT and invasion indicates that MR-3 markedly reduced the expression and nuclear translocation of β-catenin, accompanied with the downregulation of β-catenin target genes and the increment of membrane-bound β-catenin. These results suggest the involvement of Wnt/β-catenin signaling in the MR-3-induced EMT reversion of MCF-7 cells. Notably, MR-3 restored glycogen synthase kinase-3β activity by inhibiting the phosphorylation of Akt, the event required for β-catenin destruction via a proteasome-mediated system. Overall, these findings indicate that the anti-invasive activity of MR-3 on MCF-7 cells may result from the suppression of EMT via down-regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling, and consequently, β-catenin nuclear translocation. These occurrences ultimately lead to the blockage of EMT and the invasion of breast cancer cells. - Highlights: • MR-3 blocked MCF-7 cell invasion by inducing a reversal of EMT. • Wnt/β-catenin signaling is involved in MR-3-induced EMT

  13. Atom-atom collision cascades localization

    International Nuclear Information System (INIS)

    Kirsanov, V.V.

    1980-01-01

    The presence of an impurity and thermal vibration influence on the atom-atom collision cascade development is analysed by the computer simulation method (the modificated dynamic model). It is discovered that the relatively low energetic cascades are localized with the temperature increase of an irradiated crystal. On the basis of the given effect the mechanism of splitting of the high energetic cascades into subcascades is proposed. It accounts for two factors: the primary knocked atom energy and the irradiated crystal temperature. Introduction of an impurity also localizes the cascades independently from the impurity atom mass. The cascades localization leads to intensification of the process of annealing in the cascades and reduction of the post-cascade vacancy cluster sizes. (author)

  14. Cascade Chaotic System With Applications.

    Science.gov (United States)

    Zhou, Yicong; Hua, Zhongyun; Pun, Chi-Man; Chen, C L Philip

    2015-09-01

    Chaotic maps are widely used in different applications. Motivated by the cascade structure in electronic circuits, this paper introduces a general chaotic framework called the cascade chaotic system (CCS). Using two 1-D chaotic maps as seed maps, CCS is able to generate a huge number of new chaotic maps. Examples and evaluations show the CCS's robustness. Compared with corresponding seed maps, newly generated chaotic maps are more unpredictable and have better chaotic performance, more parameters, and complex chaotic properties. To investigate applications of CCS, we introduce a pseudo-random number generator (PRNG) and a data encryption system using a chaotic map generated by CCS. Simulation and analysis demonstrate that the proposed PRNG has high quality of randomness and that the data encryption system is able to protect different types of data with a high-security level.

  15. Cascade reactor: granule fabrication processes

    International Nuclear Information System (INIS)

    Erlandson, O.D.; Winkler, E.O.; Maya, I.; Pitts, J.H.

    1985-01-01

    A key feature of Cascade is the granular blanket. Of the many blanket material options open to Cascade, fabrication of Li 2 O granules was felt to offer the greatest challenge. The authors explored available methods for initial Li 2 O granule fabrication. They identified three cost-effective processes for fabricating Li 2 O granules: the VSM drop-melt furnace process, which is based on melting and spheroidizing irregularly shaped Li 2 O feed granules; the LiOH process, which spheroidizes liquefied LiOH and uses GA Technologies' sphere-forming procedures; and the Li 2 CO 3 sol-gel process, used for making spherical fuel particles for the high-temperature gas-cooled reactor (HTGR). Each process is described below

  16. Bankruptcy cascades in interbank markets.

    Directory of Open Access Journals (Sweden)

    Gabriele Tedeschi

    Full Text Available We study a credit network and, in particular, an interbank system with an agent-based model. To understand the relationship between business cycles and cascades of bankruptcies, we model a three-sector economy with goods, credit and interbank market. In the interbank market, the participating banks share the risk of bad debits, which may potentially spread a bank's liquidity problems through the network of banks. Our agent-based model sheds light on the correlation between bankruptcy cascades and the endogenous economic cycle of booms and recessions. It also demonstrates the serious trade-off between, on the one hand, reducing risks of individual banks by sharing them and, on the other hand, creating systemic risks through credit-related interlinkages of banks. As a result of our study, the dynamics underlying the meltdown of financial markets in 2008 becomes much better understandable.

  17. Phase locking of a 2.7 THz quantum cascade laser to a microwave reference

    NARCIS (Netherlands)

    Khosropanah, P.; Baryshev, A.; Zhang, W.; Jellema, W.; Hovenier, J.N.; Gao, J.R.; Klapwijk, T.M.; Paveliev, D.G.; Williams, B.S.; Kumar, S.; Hu, Q.; Reno, J.L.; Klein, B.; Hesler, J.L.

    2009-01-01

    We demonstrate the phase locking of a 2.7 THz metal–metal waveguide quantum cascade laser (QCL) to an external microwave signal. The reference is the 15th harmonic, generated by a semiconductor superlattice nonlinear device, of a signal at 182 GHz, which itself is generated by a multiplier chain

  18. Phase locking of a 2.7 THz quantum cascade laser to a microwave reference

    NARCIS (Netherlands)

    Khosropanah, P.; Baryshev, A.; Zhang, W.; Jellema, W.; Hovenier, J. N.; Gao, J. R.; Klapwijk, T. M.; Paveliev, D. G.; Williams, B. S.; Kumar, S.; Hu, Q.; Reno, J. L.; Klein, B.; Hesler, J. L.

    2009-01-01

    We demonstrate the phase locking of a 2.7 THz metal-metal waveguide quantum cascade laser (QCL) to an external microwave signal. The reference is the 15th harmonic, generated by a semiconductor superlattice nonlinear device, of a signal at 182 GHz, which itself is generated by a multiplier chain

  19. Lens Coupled Quantum Cascade Laser

    Science.gov (United States)

    Hu, Qing (Inventor); Lee, Alan Wei Min (Inventor)

    2013-01-01

    Terahertz quantum cascade (QC) devices are disclosed that can operate, e.g., in a range of about 1 THz to about 10 THz. In some embodiments, QC lasers are disclosed in which an optical element (e.g., a lens) is coupled to an output facet of the laser's active region to enhance coupling of the lasing radiation from the active region to an external environment. In other embodiments, terahertz amplifier and tunable terahertz QC lasers are disclosed.

  20. Subfailure overstretch injury leads to reversible functional impairment and purinergic P2X7 receptor activation in intact vascular tissue

    Directory of Open Access Journals (Sweden)

    Weifeng Luo

    2016-09-01

    Full Text Available Vascular stretch injury is associated with blunt trauma, vascular surgical procedures, and harvest of human saphenous vein for use in vascular bypass grafting. A model of subfailure overstretch in rat abdominal aorta was developed to characterize surgical vascular stretch injury. Longitudinal stretch of rat aorta was characterized ex vivo. Stretch to the haptic endpoint where the tissues would no longer lengthen, occurred at twice the resting length. The stress produced at this length was greater than physiologic mechanical forces but well below the level of mechanical disruption. Functional responses were determined in a muscle bath and this subfailure overstretch injury led to impaired smooth muscle function that was partially reversed by treatment with purinergic receptor (P2X7R antagonists. These data suggest that vasomotor dysfunction caused by subfailure overstretch injury may be due to activation of P2X7R. These studies have implications for our understanding of mechanical stretch injury of blood vessels and offer novel therapeutic opportunities.

  1. Effect of hyperthyroidism on circulating prolactin and hypothalamic expression of tyrosine hydroxylase, prolactin signaling cascade members and estrogen and progesterone receptors during late pregnancy and lactation in the rat.

    Science.gov (United States)

    Pennacchio, Gisela E; Neira, Flavia J; Soaje, Marta; Jahn, Graciela A; Valdez, Susana R

    2017-02-15

    Hyperthyroidism (HyperT) compromises pregnancy and lactation, hindering suckling-induced PRL release. We studied the effect of HyperT on hypothalamic mRNA (RT-qPCR) and protein (Western blot) expression of tyrosine hydroxylase (TH), PRL receptor (PRLR) and signaling pathway members, estrogen-α (ERα) and progesterone (PR) receptors on late pregnancy (days G19, 20 and 21) and early lactation (L2) in rats. HyperT advanced pre-partum PRL release, reduced circulating PRL on L2 and increased TH mRNA (G21 and L2), p-TH, PRLR mRNA, STAT5 protein (G19 and L2), PRLR protein (G21) and CIS protein (G19). PRs mRNAs and protein decreased on G19 but afterwards PRA mRNA (G20), PRB mRNA (G21) and PRA mRNA and protein (L2) increased. ERα protein increased on G19 and decreased on G20. Thus, the altered hypothalamic PRLR, STAT5, PR and ERα expression in hyperthyroid rats may induce elevated TH expression and activation, that consequently, elevate dopaminergic tone during lactation, blunting suckling-induced PRL release and litter growth. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Cascade DNA nanomachine and exponential amplification biosensing.

    Science.gov (United States)

    Xu, Jianguo; Wu, Zai-Sheng; Shen, Weiyu; Xu, Huo; Li, Hongling; Jia, Lee

    2015-11-15

    DNA is a versatile scaffold for the assembly of multifunctional nanostructures, and potential applications of various DNA nanodevices have been recently demonstrated for disease diagnosis and treatment. In the current study, a powerful cascade DNA nanomachine was developed that can execute the exponential amplification of p53 tumor suppressor gene. During the operation of the newly-proposed DNA nanomachine, dual-cyclical nucleic acid strand-displacement polymerization (dual-CNDP) was ingeniously introduced, where the target trigger is repeatedly used as the fuel molecule and the nicked fragments are dramatically accumulated. Moreover, each displaced nicked fragment is able to activate the another type of cyclical strand-displacement amplification, increasing exponentially the value of fluorescence intensity. Essentially, one target binding event can induce considerable number of subsequent reactions, and the nanodevice was called cascade DNA nanomachine. It can implement several functions, including recognition element, signaling probe, polymerization primer and template. Using the developed autonomous operation of DNA nanomachine, the p53 gene can be quantified in the wide concentration range from 0.05 to 150 nM with the detection limit of 50 pM. If taking into account the final volume of mixture, the detection limit is calculated as lower as 6.2 pM, achieving an desirable assay ability. More strikingly, the mutant gene can be easily distinguished from the wild-type one. The proof-of-concept demonstrations reported herein is expected to promote the development and application of DNA nanomachine, showing great potential value in basic biology and medical diagnosis. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Lack of the purinergic receptor P2X7 results in resistance to contact hypersensitivity

    Science.gov (United States)

    Weber, Felix C.; Esser, Philipp R.; Müller, Tobias; Ganesan, Jayanthi; Pellegatti, Patrizia; Simon, Markus M.; Zeiser, Robert; Idzko, Marco; Jakob, Thilo

    2010-01-01

    Sensitization to contact allergens requires activation of the innate immune system by endogenous danger signals. However, the mechanisms through which contact allergens activate innate signaling pathways are incompletely understood. In this study, we demonstrate that mice lacking the adenosine triphosphate (ATP) receptor P2X7 are resistant to contact hypersensitivity (CHS). P2X7-deficient dendritic cells fail to induce sensitization to contact allergens and do not release IL-1β in response to lipopolysaccharide (LPS) and ATP. These defects are restored by pretreatment with LPS and alum in an NLRP3- and ASC-dependent manner. Whereas pretreatment of wild-type mice with P2X7 antagonists, the ATP-degrading enzyme apyrase or IL-1 receptor antagonist, prevents CHS, IL-1β injection restores CHS in P2X7-deficient mice. Thus, P2X7 is a crucial receptor for extracellular ATP released in skin in response to contact allergens. The lack of P2X7 triggering prevents IL-1β release, which is an essential step in the sensitization process. Interference with P2X7 signaling may be a promising strategy for the prevention of allergic contact dermatitis. PMID:21059855

  4. Abnormal cascading failure spreading on complex networks

    International Nuclear Information System (INIS)

    Wang, Jianwei; Sun, Enhui; Xu, Bo; Li, Peng; Ni, Chengzhang

    2016-01-01

    Applying the mechanism of the preferential selection of the flow destination, we develop a new method to quantify the initial load on an edge, of which the flow is transported along the path with the shortest edge weight between two nodes. Considering the node weight, we propose a cascading model on the edge and investigate cascading dynamics induced by the removal of the edge with the largest load. We perform simulated attacks on four types of constructed networks and two actual networks and observe an interesting and counterintuitive phenomenon of the cascading spreading, i.e., gradually improving the capacity of nodes does not lead to the monotonous increase in the robustness of these networks against cascading failures. The non monotonous behavior of cascading dynamics is well explained by the analysis on a simple graph. We additionally study the effect of the parameter of the node weight on cascading dynamics and evaluate the network robustness by a new metric.

  5. Cascades of pile-up and dead time

    International Nuclear Information System (INIS)

    Pomme, S.

    2008-01-01

    Count loss through a cascade of pile-up and dead time is studied. Time interval density-distribution functions and throughput factors are presented for counters with a series arrangement of pile-up and extending or non-extending dead time. A counter is considered, where an artificial dead time is imposed on every counted event, in order to control the length and type of dead time. For such a system, it is relatively easy to determine an average count-loss correction factor via a live-time clock gated by the imposed dead-time signal ('live-time mode'), or otherwise to apply a correction factor based on the inversion of the throughput function ('real-time mode'). However, these techniques do not account for additional loss through pulse pile-up. In this work, counting errors associated with neglecting cascade effects are calculated for measurements in live-time and real-time mode

  6. Disaster Mythology and Availability Cascades

    Directory of Open Access Journals (Sweden)

    Lisa Grow Sun

    2013-04-01

    Full Text Available Sociological research conducted in the aftermath of natural disasters has uncovered a number of “disaster myths” – widely shared misconceptions about typical post-disaster human behavior. This paper discusses the possibility that perpetuation of disaster mythology reflects an “availability cascade,” defined in prior scholarship as a “self-reinforcing process of collective belief formation by which an expressed perception triggers a chain reaction that gives the perception increasing plausibility through its rising availability in public discourse.” (Kuran and Sunstein 1999. Framing the spread of disaster mythology as an availability cascade suggests that certain tools may be useful in halting the myths’ continued perpetuation. These tools include changing the legal and social incentives of so-called “availability entrepreneurs” – those principally responsible for beginning and perpetuating the cascade, as well as insulating decision-makers from political pressures generated by the availability cascade. This paper evaluates the potential effectiveness of these and other solutions for countering disaster mythology. Las investigaciones sociológicas realizadas tras los desastres naturales han hecho evidentes una serie de “mitos del desastre”, conceptos erróneos ampliamente compartidos sobre el comportamiento humano típico tras un desastre. Este artículo analiza la posibilidad de que la perpetuación de los mitos del desastre refleje una “cascada de disponibilidad”, definida en estudios anteriores como un “proceso de auto-refuerzo de la formación de una creencia colectiva, a través del que una percepción expresada produce una reacción en cadena que hace que la percepción sea cada vez más verosímil, a través de una mayor presencia en el discurso público” (Kuran y Sunstein 1999. Enmarcar la propagación de los mitos del desastre como una cascada de disponibilidad sugiere que ciertas herramientas pueden ser

  7. Ion-implantation dense cascade data

    International Nuclear Information System (INIS)

    Winterbon, K.B.

    1983-04-01

    A tabulation is given of data useful in estimating various aspects of ion-implantation cascades in the nuclear stopping regime, particularly with respect to nonlinearity of the cascade at high energy densities. The tabulation is restricted to self-ion implantation. Besides power-cross-section cascade dimensions, various material properties are included. Scaling of derived quantities with input data is noted, so one is not limited to the values assumed by the author

  8. A non-conventional isotope separation cascade without any mixing: net cascade

    International Nuclear Information System (INIS)

    Zeng Shi; Jiang Dongjun; Ying Zhengen

    2012-01-01

    A component has different concentrations in the incoming flows at a confluent point in all existing isotope separations cascades for multi-component isotope separation and mixing is inevitable, which results in deterioration of separation performance of the separation cascade. However, realization of no-mixing at a confluent point is impossible with a conventional cascade. A non-conventional isotope separation cascade, net cascade, is found to be able to realize no mixings for all components at confluent points, and its concept is further developed here. No-mixing is fulfilled by requiring symmetrical separation of two specified key components at every stage, and the procedure of realizing no-mixing is presented in detail. Some properties of net cascade are investigated preliminarily, and the results demonstrated the no-mixing property is indeed realized. Net cascade is the only separation cascade that so far possesses the no-mixing property. (authors)

  9. Contingency Analysis of Cascading Line Outage Events

    Energy Technology Data Exchange (ETDEWEB)

    Thomas L Baldwin; Magdy S Tawfik; Miles McQueen

    2011-03-01

    As the US power systems continue to increase in size and complexity, including the growth of smart grids, larger blackouts due to cascading outages become more likely. Grid congestion is often associated with a cascading collapse leading to a major blackout. Such a collapse is characterized by a self-sustaining sequence of line outages followed by a topology breakup of the network. This paper addresses the implementation and testing of a process for N-k contingency analysis and sequential cascading outage simulation in order to identify potential cascading modes. A modeling approach described in this paper offers a unique capability to identify initiating events that may lead to cascading outages. It predicts the development of cascading events by identifying and visualizing potential cascading tiers. The proposed approach was implemented using a 328-bus simplified SERC power system network. The results of the study indicate that initiating events and possible cascading chains may be identified, ranked and visualized. This approach may be used to improve the reliability of a transmission grid and reduce its vulnerability to cascading outages.

  10. Neurotransmitter signaling in white matter.

    Science.gov (United States)

    Butt, Arthur M; Fern, Robert F; Matute, Carlos

    2014-11-01

    White matter (WM) tracts are bundles of myelinated axons that provide for rapid communication throughout the CNS and integration in grey matter (GM). The main cells in myelinated tracts are oligodendrocytes and astrocytes, with small populations of microglia and oligodendrocyte precursor cells. The prominence of neurotransmitter signaling in WM, which largely exclude neuronal cell bodies, indicates it must have physiological functions other than neuron-to-neuron communication. A surprising aspect is the diversity of neurotransmitter signaling in WM, with evidence for glutamatergic, purinergic (ATP and adenosine), GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic and serotonergic signaling, acting via a wide range of ionotropic and metabotropic receptors. Both axons and glia are potential sources of neurotransmitters and may express the respective receptors. The physiological functions of neurotransmitter signaling in WM are subject to debate, but glutamate and ATP-mediated signaling have been shown to evoke Ca(2+) signals in glia and modulate axonal conduction. Experimental findings support a model of neurotransmitters being released from axons during action potential propagation acting on glial receptors to regulate the homeostatic functions of astrocytes and myelination by oligodendrocytes. Astrocytes also release neurotransmitters, which act on axonal receptors to strengthen action potential propagation, maintaining signaling along potentially long axon tracts. The co-existence of multiple neurotransmitters in WM tracts suggests they may have diverse functions that are important for information processing. Furthermore, the neurotransmitter signaling phenomena described in WM most likely apply to myelinated axons of the cerebral cortex and GM areas, where they are doubtless important for higher cognitive function. © 2014 Wiley Periodicals, Inc.

  11. Theobromine-Induced Changes in A1 Purinergic Receptor Gene Expression and Distribution in a Rat Brain Alzheimer's Disease Model.

    Science.gov (United States)

    Mendiola-Precoma, Jesus; Padilla, Karla; Rodríguez-Cruz, Alfredo; Berumen, Laura C; Miledi, Ricardo; García-Alcocer, Guadalupe

    2017-01-01

    Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.

  12. Purinergic 2X receptors play a role in evoking the exercise pressor reflex in rats with peripheral artery insufficiency.

    Science.gov (United States)

    Stone, Audrey J; Yamauchi, Katsuya; Kaufman, Marc P

    2014-02-01

    Purinergic 2X (P2X) receptors on the endings of thin fiber afferents have been shown to play a role in evoking the exercise pressor reflex in cats. In this study, we attempted to extend this finding to decerebrated, unanesthetized rats whose femoral arteries were either freely perfused or were ligated 72 h before the start of the experiment. We first established that our dose of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 10 mg/kg), a P2X receptor antagonist, attenuated the pressor response to α,β-methylene ATP (10 μg/kg), a P2X receptor agonist. We then compared the exercise pressor reflex before and after infusing PPADS into the arterial supply of the hindlimb muscles that were statically contracted. In rats with freely perfused femoral arteries, the peak pressor responses to contraction were not significantly attenuated by PPADS (before PPADS: 19 ± 2 mmHg, 13 min after PPADS: 17 ± 2 mmHg, and 25 min after PPADS: 17 ± 3 mmHg). Likewise, the cardioaccelerator and renal sympathetic nerve responses were not significantly attenuated. In contrast, we found that in rats whose femoral arteries were ligated PPADS significantly attenuated the peak pressor responses to contraction (before PPADS: 37 ± 5 mmHg, 13 min after PPADS: 27 ± 6 mmHg, and 25 min after PPADS: 25 ± 5 mmHg; P reflex in rats whose femoral arteries were ligated but play only a minimal role in evoking the reflex in rats whose femoral arteries were freely perfused.

  13. [Trigeminal purinergic P2X4 receptor involved in experimental occlusal interference-induced hyperalgesia in rat masseter muscle].

    Science.gov (United States)

    Xu, Xiaoxiang; Cao, Ye; Ding, Tingting; Fu, Kaiyuan; Xie, Qiufei

    2016-03-01

    To explore the expression of purinergic p2X4 receptor (P2X4R) in trigeminal ganglion of rats after occlusal interference. Investigation of peripheral receptor mechanism of occlusal interference-induced masticatory muscle pain will aid the development of drug intervention against this condition. Experimental occlusal interference was established by application of 0.4 mm metal crown to the upper right first molar of male Sprague-Dawley rats. Real-time PCR assay was used to investigate P2X4R mRNA level in trigeminal ganglion in rats with occlusal interference for 3, 7, 10 and 14 days and in control rats without occlusal interference (n=5 in each). Retrograde labelling combining immunofluorescence was performed to evaluate the percentage of P2X4R-positive cells in masseter afferent neurons (n=5 in each group). Graded concentrations of P2XR antagonist TNP-ATP (0.1, 10, 125, 250, 500 μmol/L) or saline (n=5 in each group) was administrated in right masseter and the mechanical sensitivity of bilateral masseters was measured before occlusal interference application, before the injection, and 30 min as well as 60 min after the injection. Compared with control rats (P2X4R mRNA: right side: 1.00±0.26, left side: 0.94± 0.21; percentage of P2X4R-positive masseter afferents: right side: [64.3±6.3]%, left side: [67.7±5.8]%), the level of P2X4R mRNA in bilateral trigeminal ganglia (right side: 5.98±3.56; left side: 5.06±2.88) of rats with occlusal interference for 7 days up-regulated (Pocclusal interference-induced masseter hyperalgesia.

  14. A Semisupervised Cascade Classification Algorithm

    Directory of Open Access Journals (Sweden)

    Stamatis Karlos

    2016-01-01

    Full Text Available Classification is one of the most important tasks of data mining techniques, which have been adopted by several modern applications. The shortage of enough labeled data in the majority of these applications has shifted the interest towards using semisupervised methods. Under such schemes, the use of collected unlabeled data combined with a clearly smaller set of labeled examples leads to similar or even better classification accuracy against supervised algorithms, which use labeled examples exclusively during the training phase. A novel approach for increasing semisupervised classification using Cascade Classifier technique is presented in this paper. The main characteristic of Cascade Classifier strategy is the use of a base classifier for increasing the feature space by adding either the predicted class or the probability class distribution of the initial data. The classifier of the second level is supplied with the new dataset and extracts the decision for each instance. In this work, a self-trained NB∇C4.5 classifier algorithm is presented, which combines the characteristics of Naive Bayes as a base classifier and the speed of C4.5 for final classification. We performed an in-depth comparison with other well-known semisupervised classification methods on standard benchmark datasets and we finally reached to the point that the presented technique has better accuracy in most cases.

  15. Experimental investigation of the cascadability of a cross-gain modulation wavelength converter

    DEFF Research Database (Denmark)

    Zheng, Xueyan; Liu, Fenghai; Kloch, Allan

    2000-01-01

    by adding a fiber grating-based optical add-drop multiplexer after the semiconductor optical amplifier (SOA) to enhance the high-frequency response of the wavelength converter. However, the low-frequency degradation of the signal together with amplified spontaneous emission (ASE) noise and jitter......The cascading characteristics of a wavelength converter based on cross-gain modulation (XGM) are studied experimentally using a recirculating loop at 10 Gb/s. The maximum cascaded number of the wavelength converter converting the signal to the same wavelength is improved from five to eight...

  16. Evaluation of blind signal separation methods

    NARCIS (Netherlands)

    Schobben, D.W.E.; Torkkola, K.; Smaragdis, P.

    1999-01-01

    Recently many new Blind Signal Separation BSS algorithms have been introduced Authors evaluate the performance of their algorithms in various ways Among these are speech recognition rates plots of separated signals plots of cascaded mixingunmixing impulse responses and signal to noise ratios Clearly

  17. Design concept of Hydro cascade control system

    International Nuclear Information System (INIS)

    Fustik, Vangel; Kiteva, Nevenka

    2006-01-01

    In this paper a design concept of the comple hydro cascade scheme is presented with the design parameters of the main technical features. The cascade control system architecture is designed considering up-to-date communication and information technology. The control algorithm is based on Pond Level Control and Economic Load Allocation concepts.

  18. Centrifugal separator cascade connected in zigzag manner

    International Nuclear Information System (INIS)

    Kai, Tsunetoshi; Inoue, Yoshiya; Oya, Akio; Nagakura, Masaaki.

    1974-01-01

    Object: To effectively accommodate centrifugal separators of the entire cascade within the available space in a plant by freely selecting perpendicular direction of connection of the centrifugal separator. Structure: Centrifugal separators are connected in zigzag fashion by using a single header for each stage so that in a rectangular shape the entire cascade is arranged. (Kamimura, M.)

  19. Cascaded impedance networks for NPC inverter

    DEFF Research Database (Denmark)

    Li, Ding; Gao, Feng; Loh, Poh Chiang

    2010-01-01

    they are subject to the renewable sources. To date, three distinct types of impedance networks can be summarized for implementing a hybrid source impedance network, which can in principle be combined and cascaded before connected to a NPC inverter by proposed two ways. The resulting cascaded impedance network NPC...

  20. Cascading costs: an economic nitrogen cycle.

    Science.gov (United States)

    Moomaw, William R; Birch, Melissa B L

    2005-09-01

    The chemical nitrogen cycle is becoming better characterized in terms of fluxes and reservoirs on a variety of scales. Galloway has demonstrated that reactive nitrogen can cascade through multiple ecosystems causing environmental damage at each stage before being denitrified to N(2). We propose to construct a parallel economic nitrogen cascade (ENC) in which economic impacts of nitrogen fluxes can be estimated by the costs associated with each stage of the chemical cascade. Using economic data for the benefits of damage avoided and costs of mitigation in the Chesapeake Bay basin, we have constructed an economic nitrogen cascade for the region. Since a single ton of nitrogen can cascade through the system, the costs also cascade. Therefore evaluating the benefits of mitigating a ton of reactive nitrogen released needs to consider the damage avoided in all of the ecosystems through which that ton would cascade. The analysis reveals that it is most cost effective to remove a ton of nitrogen coming from combustion since it has the greatest impact on human health and creates cascading damage through the atmospheric, terrestrial, aquatic and coastal ecosystems. We will discuss the implications of this analysis for determining the most cost effective policy option for achieving environmental quality goals.

  1. Purinergic receptors are involved in tooth-pulp evoked nocifensive behavior and brainstem neuronal activity

    Directory of Open Access Journals (Sweden)

    Sessle Barry J

    2010-09-01

    Full Text Available Abstract Background To evaluate whether P2X receptors are involved in responses to noxious pulp stimulation, the P2X3 and P2X2/3 receptor agonist α,β-methyleneATP (α,β-meATP was applied to the molar tooth pulp and nocifensive behavior and extracellular-signal regulated kinase (ERK phosphorylation in trigeminal spinal subnucleus caudalis (Vc, trigeminal spinal subnucleus interpolaris (Vi, upper cervical spinal cord (C1/C2 and paratrigeminal nucleus (Pa5 neurons were analyzed in rats. Results Genioglossus (GG muscle activity was evoked by pulpal application of 100 mM α,β-meATP and was significantly larger than GG activity following vehicle (phosphate-buffered saline PBS application (p 1, P2X3 and, P2X2/3 antagonist. A large number of pERK-LI cells were expressed in the Vc, Vi/Vc, C1/C2 and Pa5 at 5 min following pulpal application of 100 mM α,β-meATP compared to PBS application to the pulp (p Conclusions The present findings suggest that activation of P2X3 and P2X2/3 receptors in the tooth pulp is sufficient to elicit nociceptive behavioral responses and trigeminal brainstem neuronal activity.

  2. Investigation on performance of all optical buffer with large dynamical delay time based on cascaded double loop optical buffers

    International Nuclear Information System (INIS)

    Yong-Jun, Wang; Xiang-Jun, Xin; Xiao-Lei, Zhang; Chong-Qing, Wu; Kuang-Lu, Yu

    2010-01-01

    Optical buffers are critical for optical signal processing in future optical packet-switched networks. In this paper, a theoretical study as well as an experimental demonstration on a new optical buffer with large dynamical delay time is carried out based on cascaded double loop optical buffers (DLOBs). It is found that pulse distortion can be restrained by a negative optical control mode when the optical packet is in the loop. Noise analysis indicates that it is feasible to realise a large variable delay range by cascaded DLOBs. These conclusions are validated by the experiment system with 4-stage cascaded DLOBs. Both the theoretical simulations and the experimental results indicate that a large delay range of 1–9999 times the basic delay unit and a fine granularity of 25 ns can be achieved by the cascaded DLOBs. The performance of the cascaded DLOBs is suitable for the all optical networks. (classical areas of phenomenology)

  3. Cascade Error Projection: An Efficient Hardware Learning Algorithm

    Science.gov (United States)

    Duong, T. A.

    1995-01-01

    A new learning algorithm termed cascade error projection (CEP) is presented. CEP is an adaption of a constructive architecture from cascade correlation and the dynamical stepsize of A/D conversion from the cascade back propagation algorithm.

  4. Displacement cascades in diatomic materials

    International Nuclear Information System (INIS)

    Parkin, D.M.; Coulter, C.A.

    1981-01-01

    A new function, the specified-projectile displacement function p/sub ijk/ (E), is introduced to describe displacement cascades in polyatomic materials. This function describes the specific collision events that produce displacements and hence adds new information not previously available. Calculations of p/sub ijk/ (E) for MgO, Al 2 O 3 and TaO are presented and discussed. Results show that the parameters that have the largest effect on displacement collision events are the PKA energy and the mass ratio of the atom types in the material. It is further shown that the microscopic nature of the displacement events changes over the entire recoil energy range relevant to fusion neutron spectra and that these changes are different in materials whose mass ratio is near one than in those where it is far from one

  5. The Geant4 Bertini Cascade

    Energy Technology Data Exchange (ETDEWEB)

    Wright, D.H.; Kelsey, M.H.

    2015-12-21

    One of the medium energy hadron–nucleus interaction models in the GEANT4 simulation toolkit is based partly on the Bertini intranuclear cascade model. Since its initial appearance in the toolkit, this model has been largely re-written in order to extend its physics capabilities and to reduce its memory footprint. Physics improvements include extensions in applicable energy range and incident particle types, and improved hadron–nucleon cross-sections and angular distributions. Interfaces have also been developed which allow the model to be coupled with other GEANT4 models at lower and higher energies. The inevitable speed reductions due to enhanced physics have been mitigated by memory and CPU efficiency improvements. Details of these improvements, along with selected comparisons of the model to data, are discussed.

  6. Availability Cascades & the Sharing Economy

    DEFF Research Database (Denmark)

    Netter, Sarah

    2014-01-01

    attention. This conceptual paper attempts to explain the emergent focus on the sharing economy and associated business and consumption models by applying cascade theory. Risks associated with this behavior will be especially examined with regard to the sustainability claim of collaborative consumption......In search of a new concept that will provide answers to as to how modern societies should not only make sense but also resolve the social and environmental problems linked with our modes of production and consumption, collaborative consumption and the sharing economy are increasingly attracting....... With academics, practitioners, and civil society alike having a shared history in being rather fast in accepting new concepts that will not only provide business opportunities but also a good conscience, this study proposes a critical study of the implications of collaborative consumption, before engaging...

  7. Coomassie Brilliant Blue G is a more potent antagonist of P2 purinergic responses than Reactive Blue 2 (Cibacron Blue 3GA) in rat parotid acinar cells

    International Nuclear Information System (INIS)

    Soltoff, S.P.; McMillian, M.K.; Talamo, B.R.

    1989-01-01

    The ability of Brilliant Blue G (Coomassie Brilliant Blue G) and Reactive Blue 2 (Cibacron Blue 3GA) to block the effects of extracellular ATP on rat parotid acinar cells was examined by evaluating their effects on ATP-stimulated 45Ca 2+ entry and the elevation of [Ca 2+ ]i (Fura 2 fluorescence). ATP (300 microM) increased the rate of Ca 2+ entry to more than 25-times the basal rate and elevated [Ca 2+ ]i to levels more than three times the basal value. Brilliant Blue G and Reactive Blue 2 greatly reduced the entry of 45 Ca 2+ into parotid cells, but the potency of Brilliant Blue G (IC50 approximately 0.4 microM) was about 100-times that of Reactive Blue 2. Fura 2 studies demonstrated that inhibitory concentrations of these compounds did not block the cholinergic response of these cells, thus demonstrating the selectivity of the dye compounds for purinergic receptors. Unlike Reactive Blue 2, effective concentrations of Brilliant Blue G did not substantially quench Fura 2 fluorescence. The greater potency of Brilliant Blue G suggests that it may be very useful in identifying P2-type purinergic receptors, especially in studies which utilize fluorescent probes

  8. Experimental study of flow through compressor Cascade

    Directory of Open Access Journals (Sweden)

    Satyam Panchal

    2017-09-01

    Full Text Available The objective of this research work is to study the behaviour of flow at the inlet, within the blade passage and at the exit of a compressor cascade. For this purpose, a cascade with six numbers of aerofoil blades was designed and constructed. The cascade was fitted on the cascade test tunnel. Out of six blades two were instrumented for measuring the pressure distribution on the pressure and suction surface. The blades had a parabolic camber line, with a maximum camber position at 40% of the chord from the leading edge of the blade. The profile of the blade was C4, height of the blade was 160 mm, chord length was 80 mm, camber angle was 45° and stagger angle was 30°. Similarly, the length of the cascade was 300 mm, span was 160 mm, pitch was 60 mm, the actual chord of the cascade was 80 mm, the axial chord of the cascade was 70 mm, the stagger angle of the cascade was 30° and the pitch-chord ratio was 0.75. The data was taken and analyzed at −500% of the axial chord before the cascade, −25% of the axial chord before the leading edge, 25%, 50%, 75% and 150% of the axial chord from the leading edge of the blade. The readings were taken from the cascade wall to the mid span position along the pitch wise direction. The angle of incidence was also changed during the experiment and varied from i=−50°, −30°, −10° to 5°.

  9. Wnt signaling in cancer

    Science.gov (United States)

    Zhan, T; Rindtorff, N; Boutros, M

    2017-01-01

    Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches. PMID:27617575

  10. A cascaded three-phase symmetrical multistage voltage multiplier

    International Nuclear Information System (INIS)

    Iqbal, Shahid; Singh, G K; Besar, R; Muhammad, G

    2006-01-01

    A cascaded three-phase symmetrical multistage Cockcroft-Walton voltage multiplier (CW-VM) is proposed in this report. It consists of three single-phase symmetrical voltage multipliers, which are connected in series at their smoothing columns like string of batteries and are driven by three-phase ac power source. The smoothing column of each voltage multiplier is charged twice every cycle independently by respective oscillating columns and discharged in series through load. The charging discharging process completes six times a cycle and therefore the output voltage ripple's frequency is of sixth order of the drive signal frequency. Thus the proposed approach eliminates the first five harmonic components of load generated voltage ripples and sixth harmonic is the major ripple component. The proposed cascaded three-phase symmetrical voltage multiplier has less than half the voltage ripple, and three times larger output voltage and output power than the conventional single-phase symmetrical CW-VM. Experimental and simulation results of the laboratory prototype are given to show the feasibility of proposed cascaded three-phase symmetrical CW-VM

  11. An Arabidopsis kinase cascade influences auxin-responsive cell expansion.

    Science.gov (United States)

    Enders, Tara A; Frick, Elizabeth M; Strader, Lucia C

    2017-10-01

    Mitogen-activated protein kinase (MPK) cascades are conserved mechanisms of signal transduction across eukaryotes. Despite the importance of MPK proteins in signaling events, specific roles for many Arabidopsis MPK proteins remain unknown. Multiple studies have suggested roles for MPK signaling in a variety of auxin-related processes. To identify MPK proteins with roles in auxin response, we screened mpk insertional alleles and identified mpk1-1 as a mutant that displays hypersensitivity in auxin-responsive cell expansion assays. Further, mutants defective in the upstream MAP kinase kinase MKK3 also display hypersensitivity in auxin-responsive cell expansion assays, suggesting that this MPK cascade affects auxin-influenced cell expansion. We found that MPK1 interacts with and phosphorylates ROP BINDING PROTEIN KINASE 1 (RBK1), a protein kinase that interacts with members of the Rho-like GTPases from Plants (ROP) small GTPase family. Similar to mpk1-1 and mkk3-1 mutants, rbk1 insertional mutants display auxin hypersensitivity, consistent with a possible role for RBK1 downstream of MPK1 in influencing auxin-responsive cell expansion. We found that RBK1 directly phosphorylates ROP4 and ROP6, supporting the possibility that RBK1 effects on auxin-responsive cell expansion are mediated through phosphorylation-dependent modulation of ROP activity. Our data suggest a MKK3 • MPK1 • RBK1 phosphorylation cascade that may provide a dynamic module for altering cell expansion. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  12. Cascaded systems analysis of photon counting detectors.

    Science.gov (United States)

    Xu, J; Zbijewski, W; Gang, G; Stayman, J W; Taguchi, K; Lundqvist, M; Fredenberg, E; Carrino, J A; Siewerdsen, J H

    2014-10-01

    Photon counting detectors (PCDs) are an emerging technology with applications in spectral and low-dose radiographic and tomographic imaging. This paper develops an analytical model of PCD imaging performance, including the system gain, modulation transfer function (MTF), noise-power spectrum (NPS), and detective quantum efficiency (DQE). A cascaded systems analysis model describing the propagation of quanta through the imaging chain was developed. The model was validated in comparison to the physical performance of a silicon-strip PCD implemented on an experimental imaging bench. The signal response, MTF, and NPS were measured and compared to theory as a function of exposure conditions (70 kVp, 1-7 mA), detector threshold, and readout mode (i.e., the option for coincidence detection). The model sheds new light on the dependence of spatial resolution, charge sharing, and additive noise effects on threshold selection and was used to investigate the factors governing PCD performance, including the fundamental advantages and limitations of PCDs in comparison to energy-integrating detectors (EIDs) in the linear regime for which pulse pileup can be ignored. The detector exhibited highly linear mean signal response across the system operating range and agreed well with theoretical prediction, as did the system MTF and NPS. The DQE analyzed as a function of kilovolt (peak), exposure, detector threshold, and readout mode revealed important considerations for system optimization. The model also demonstrated the important implications of false counts from both additive electronic noise and charge sharing and highlighted the system design and operational parameters that most affect detector performance in the presence of such factors: for example, increasing the detector threshold from 0 to 100 (arbitrary units of pulse height threshold roughly equivalent to 0.5 and 6 keV energy threshold, respectively), increased the f50 (spatial-frequency at which the MTF falls to a value of

  13. Cascaded systems analysis of photon counting detectors

    International Nuclear Information System (INIS)

    Xu, J.; Zbijewski, W.; Gang, G.; Stayman, J. W.; Taguchi, K.; Carrino, J. A.; Lundqvist, M.; Fredenberg, E.; Siewerdsen, J. H.

    2014-01-01

    Purpose: Photon counting detectors (PCDs) are an emerging technology with applications in spectral and low-dose radiographic and tomographic imaging. This paper develops an analytical model of PCD imaging performance, including the system gain, modulation transfer function (MTF), noise-power spectrum (NPS), and detective quantum efficiency (DQE). Methods: A cascaded systems analysis model describing the propagation of quanta through the imaging chain was developed. The model was validated in comparison to the physical performance of a silicon-strip PCD implemented on an experimental imaging bench. The signal response, MTF, and NPS were measured and compared to theory as a function of exposure conditions (70 kVp, 1–7 mA), detector threshold, and readout mode (i.e., the option for coincidence detection). The model sheds new light on the dependence of spatial resolution, charge sharing, and additive noise effects on threshold selection and was used to investigate the factors governing PCD performance, including the fundamental advantages and limitations of PCDs in comparison to energy-integrating detectors (EIDs) in the linear regime for which pulse pileup can be ignored. Results: The detector exhibited highly linear mean signal response across the system operating range and agreed well with theoretical prediction, as did the system MTF and NPS. The DQE analyzed as a function of kilovolt (peak), exposure, detector threshold, and readout mode revealed important considerations for system optimization. The model also demonstrated the important implications of false counts from both additive electronic noise and charge sharing and highlighted the system design and operational parameters that most affect detector performance in the presence of such factors: for example, increasing the detector threshold from 0 to 100 (arbitrary units of pulse height threshold roughly equivalent to 0.5 and 6 keV energy threshold, respectively), increased the f 50 (spatial-frequency at

  14. Cascaded systems analysis of photon counting detectors

    Energy Technology Data Exchange (ETDEWEB)

    Xu, J.; Zbijewski, W.; Gang, G.; Stayman, J. W. [Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21205 (United States); Taguchi, K.; Carrino, J. A. [Russell H. Morgan Department of Radiology, Johns Hopkins University, Baltimore, Maryland 21205 (United States); Lundqvist, M.; Fredenberg, E. [Philips Healthcare, Solna 171 41 (Sweden); Siewerdsen, J. H., E-mail: jeff.siewerdsen@jhu.edu [Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21205 (United States); Russell H. Morgan Department of Radiology, Johns Hopkins University, Baltimore, Maryland 21205 (United States)

    2014-10-15

    Purpose: Photon counting detectors (PCDs) are an emerging technology with applications in spectral and low-dose radiographic and tomographic imaging. This paper develops an analytical model of PCD imaging performance, including the system gain, modulation transfer function (MTF), noise-power spectrum (NPS), and detective quantum efficiency (DQE). Methods: A cascaded systems analysis model describing the propagation of quanta through the imaging chain was developed. The model was validated in comparison to the physical performance of a silicon-strip PCD implemented on an experimental imaging bench. The signal response, MTF, and NPS were measured and compared to theory as a function of exposure conditions (70 kVp, 1–7 mA), detector threshold, and readout mode (i.e., the option for coincidence detection). The model sheds new light on the dependence of spatial resolution, charge sharing, and additive noise effects on threshold selection and was used to investigate the factors governing PCD performance, including the fundamental advantages and limitations of PCDs in comparison to energy-integrating detectors (EIDs) in the linear regime for which pulse pileup can be ignored. Results: The detector exhibited highly linear mean signal response across the system operating range and agreed well with theoretical prediction, as did the system MTF and NPS. The DQE analyzed as a function of kilovolt (peak), exposure, detector threshold, and readout mode revealed important considerations for system optimization. The model also demonstrated the important implications of false counts from both additive electronic noise and charge sharing and highlighted the system design and operational parameters that most affect detector performance in the presence of such factors: for example, increasing the detector threshold from 0 to 100 (arbitrary units of pulse height threshold roughly equivalent to 0.5 and 6 keV energy threshold, respectively), increased the f{sub 50} (spatial

  15. Genetic algorithm based separation cascade optimization

    International Nuclear Information System (INIS)

    Mahendra, A.K.; Sanyal, A.; Gouthaman, G.; Bera, T.K.

    2008-01-01

    The conventional separation cascade design procedure does not give an optimum design because of squaring-off, variation of flow rates and separation factor of the element with respect to stage location. Multi-component isotope separation further complicates the design procedure. Cascade design can be stated as a constrained multi-objective optimization. Cascade's expectation from the separating element is multi-objective i.e. overall separation factor, cut, optimum feed and separative power. Decision maker may aspire for more comprehensive multi-objective goals where optimization of cascade is coupled with the exploration of separating element optimization vector space. In real life there are many issues which make it important to understand the decision maker's perception of cost-quality-speed trade-off and consistency of preferences. Genetic algorithm (GA) is one such evolutionary technique that can be used for cascade design optimization. This paper addresses various issues involved in the GA based multi-objective optimization of the separation cascade. Reference point based optimization methodology with GA based Pareto optimality concept for separation cascade was found pragmatic and promising. This method should be explored, tested, examined and further developed for binary as well as multi-component separations. (author)

  16. Stability of a 500 km erbium-doped fiber amplifier cascade

    DEFF Research Database (Denmark)

    Lumholt, Ole; Bjarklev, Anders Overgaard; Povlsen, Jørn Hedegaard

    1992-01-01

    The stability of a cascade system of erbium-doped fiber amplifiers, due to pump and signal power variations, has been examined by use of a very accurate model. Even with an automatic gain control loop included, a fallout of a pump laser in the first inline amplifier is shown to produce a more than...

  17. Phase locking and spectral linewidth of a two-mode terahertz quantum cascade laser

    NARCIS (Netherlands)

    Baryshev, A.; Hovenier, J.N.; Adam, A.J.L.; Kašalynas, I.; Gao, J.R.; Klaassen, T.O.; Williams, B.S.; Kumar, S.; Hu, Q.; Reno, J.L.

    2006-01-01

    We have studied the phase locking and spectral linewidth of an ? 2.7?THz quantum cascade laser by mixing its two lateral lasing modes. The beat signal at about 8?GHz is compared with a microwave reference by applying conventional phase lock loop circuitry with feedback to the laser bias current.

  18. Phase locking and spectral linewidth of a two-mode terahertz quantum cascade laser

    NARCIS (Netherlands)

    Baryshev, A.; Hovenier, J. N.; Adam, A. J. L.; Kašalynas, I.; Gao, J. R.; Klaassen, T. O.; Williams, B. S.; Kumar, S.; Hu, Q.; Reno, J. L.

    2006-01-01

    We have studied the phase locking and spectral linewidth of an ˜2.7THz quantum cascade laser by mixing its two lateral lasing modes. The beat signal at about 8GHz is compared with a microwave reference by applying conventional phase lock loop circuitry with feedback to the laser bias current. Phase

  19. Aspects of the QCD cascade

    International Nuclear Information System (INIS)

    Olsson, Magnus.

    1993-02-01

    A model is proposed for the production of transverse jets from diffractively excited protons. We propose that transverse jets can be obtained from gluonic bremsstrahlung in a way similar to the emission in DIS. Qualitative agreement is obtained between the model and the uncorrected data published by the UA8 collaboration. Perturbative QCD in the MLLA approximation is applied to multiple jet production in e + e - -annihilation. We propose modified evolution equations for deriving the jet cross sections, defined in the 'k t ' or 'Durham' algorithm. The mean number of jets as a function of the jet resolution is studied, and analytical predictions are compared to the results of MC simulations. We also study a set of differential-difference equations for multiplicity distributions in e + e - -annihilations, supplemented with appropriate boundary conditions. These equations take into account nonsingular terms in the GLAP splitting functions as well as kinematical constraints related to recoil effects. The presence of retarded terms imply that the cascade develops more slowly and reduces the fluctuations. The solutions agree well with MC simulations and experimental data. (authors)

  20. Bursting behaviours in cascaded stimulated Brillouin scattering

    International Nuclear Information System (INIS)

    Liu Zhan-Jun; He Xian-Tu; Zheng Chun-Yang; Wang Yu-Gang

    2012-01-01

    Stimulated Brillouin scattering is studied by numerically solving the Vlasov—Maxwell system. A cascade of stimulated Brillouin scattering can occur when a linearly polarized laser pulse propagates in a plasma. It is found that a stimulated Brillouin scattering cascade can reduce the scattering and increase the transmission of light, as well as introduce a bursting behaviour in the evolution of the laser-plasma interaction. The bursting time in the reflectivity is found to be less than half the ion acoustic period. The ion temperature can affect the stimulated Brillouin scattering cascade, which can repeat several times at low ion temperatures and can be completely eliminated at high ion temperatures. For stimulated Brillouin scattering saturation, higher-harmonic generation and wave—wave interaction of the excited ion acoustic waves can restrict the amplitude of the latter. In addition, stimulated Brillouin scattering cascade can restrict the amplitude of the scattered light. (physics of gases, plasmas, and electric discharges)

  1. Defect accumulation under cascade damage conditions

    DEFF Research Database (Denmark)

    Trinkaus, H.; Singh, B.N.; Woo, C.H.

    1994-01-01

    in terms of this reaction kinetics taking into account cluster production, dissociation, migration and annihilation at extended sinks. Microstructural features which are characteristic of cascade damage and cannot be explained in terms of the conventional single defect reaction kinetics are emphasized......There is now ample evidence from both experimental and computer simulation studies that in displacement cascades not only intense recombination takes place but also efficient clustering of both self-interstitial atoms (SIAs) and vacancies. The size distributions of the two types of defects produced...... reactions kinetics associated with the specific features of cascade damage is described, with emphasis on asymmetries between SIA and vacancy type defects concerning their production, stability, mobility and interactions with other defects. Defect accumulation under cascade damage conditions is discussed...

  2. Cascade theory in isotopic separation processes

    International Nuclear Information System (INIS)

    Agostini, J.P.

    1994-06-01

    Three main areas are developed within the scope of this work: - the first one is devoted to fundamentals: separative power, value function, ideal cascade and square cascade. Applications to two main cases are carried out, namely: Study of binary isotopic mix, Study of processes with a small enrichment coefficient. - The second one is devoted to cascade coupling -high-flux coupling (more widely used and better known) as well as low-flux coupling are presented and compared to one another. - The third one is an outlook on problems linked to cascade transients. Those problem are somewhat intricate and their interest lies mainly into two areas: economics where the start-up time may have a large influence on the interests paid during the construction and start-up period, military productions where the start-up time has a direct bearing on the production schedule. (author). 50 figs. 3 annexes. 12 refs. 6 tabs

  3. τ polarization in SUSY cascade decays

    International Nuclear Information System (INIS)

    Choi, S.Y.; Hagiwara, K.; Kim, Y.G.

    2006-12-01

    τ leptons emitted in cascade decays of supersymmetric particles are polarized. The polarization may be exploited to determine spin and mixing properties of the neutralinos and stau particles involved. (orig.)

  4. MAP kinase cascades in Arabidopsis innate immunity

    DEFF Research Database (Denmark)

    Rasmussen, Magnus Wohlfahrt; Roux, Milena Edna; Petersen, Morten

    2012-01-01

    Plant mitogen-activated protein kinase (MAPK) cascades generally transduce extracellular stimuli into cellular responses. These stimuli include the perception of pathogen-associated molecular patterns (PAMPs) by host transmembrane pattern recognition receptors which trigger MAPK-dependent innate ...

  5. Cascade processes in kaonic and muonic atoms

    International Nuclear Information System (INIS)

    Faifman, M.P.; Men'shikov, L.I.

    2003-01-01

    Cascade processes in exotic (kaonic and muonic) hydrogen/deuterium have been studied with the quantum-classical Monte Carlo code (QCMC) developed for 'ab initio' - calculations. It has been shown that the majority of kaonic hydrogen atoms during cascade are accelerated to high energies E ∼ 100 eV, which leads to a much lower value for the calculated yields Y of x-rays than predicted by the 'standard cascade model'. The modified QCMC scheme has been applied to the study of the cascade in μp and μd muonic atoms. A comparison of the calculated yields for K-series x-rays with experimental data directly indicates that the molecular structure of the hydrogen target and new types of non-radiative transitions are essential for the light muonic atoms, while they are negligible for heavy (kaonic) atoms. These processes have been considered and estimates of their probabilities are presented. (author)

  6. Cascade Error Projection: A New Learning Algorithm

    Science.gov (United States)

    Duong, T. A.; Stubberud, A. R.; Daud, T.; Thakoor, A. P.

    1995-01-01

    A new neural network architecture and a hardware implementable learning algorithm is proposed. The algorithm, called cascade error projection (CEP), handles lack of precision and circuit noise better than existing algorithms.

  7. The capacity of the cascaded fading channel in the low power regime

    KAUST Repository

    Benkhelifa, Fatma

    2014-04-01

    In this paper, we present a simple way to compute the ergodic capacity of cascaded channels with perfect channel state information at both the transmitter and the receiver. We apply our generic results to the Rayleigh-double fading channel, and to the free-space optical channel in the presence of pointing errors and we express their low signal-to-noise ratio capacities. We mainly focus on the low signal-to-noise ratio range.

  8. Simulation of concentration spikes in cascades

    International Nuclear Information System (INIS)

    Wood, H.G.

    2006-01-01

    Research has been conducted to investigate the maximum possible enrichment that might be temporarily achieved in a facility that is producing enriched uranium for fuel for nuclear power reactors. The purpose is to provide information to evaluate if uranium enrichment facilities are producing 235 U enriched within declared limits appropriate for power reactors or if the facilities are actually producing more highly enriched uranium. The correlation between feed rate and separation factor in a gas centrifuge cascade shows that as flow decreases, the separation factor increases, thereby, creating small amounts of higher enriched uranium than would be found under optimum design operating conditions. The research uses a number of cascade enrichment programs to model the phenomenon and determine the maximum enrichment possible during the time transient of a gas centrifuge cascade. During cascade start-up, the flow through the centrifuges begins at lower than centrifuge design stage flow rates. Steady-state cascade models have been used to study the maximum 235 U concentrations that would be predicted in the cascade. These calculations should produce an upper bound of product concentrations expected during the transient phase of start-up. Due to the fact that there are different ways in which to start a cascade, several methods are used to determine the maximum enrichment during the time transient. Model cascades were created for gas centrifuges with several product to .feed assay separation factors. With this information, the models were defined and the equilibrium programs were used to determine the maximum enrichment level during the time transient. The calculations predict in a cascade with separation factor 1.254 designed to produce enriched uranium for the purpose of supplying reactor fuel, it would not be unreasonable to see some 235 U in the range of 12-15%. Higher assays produced during the start-up period might lead inspectors to believe the cascade is being

  9. Designing the Cascade inertial confinement fusion reactor

    International Nuclear Information System (INIS)

    Pitts, J.H.

    1987-01-01

    The primary goal in designing inertial confinement fusion (ICF) reactors is to produce electrical power as inexpensively as possible, with minimum activation and without compromising safety. This paper discusses a method for designing the Cascade rotating ceramic-granule-blanket reactor (Pitts, 1985) and its associated power plant (Pitts and Maya, 1985). Although focus is on the cascade reactor, the design method and issues presented are applicable to most other ICF reactors

  10. High energy evolution of soft gluon cascades

    International Nuclear Information System (INIS)

    Shuvaev, A.; Wallon, S.

    2006-01-01

    In this paper we derive an evolution equation for the gluon density in soft gluon cascades emitted from any colored source, in the leading logarithmic approximation of perturbative QCD. We show that this equation has the same form as the BFKL equation in the forward case. An explicit expression for the total cascade wavefunction involving an arbitrary number of soft gluons is obtained. Renormalization of the colored source wavefunction turns out to be responsible for the reggeization of the source. (orig.)

  11. High energy evolution of soft gluon cascades

    Energy Technology Data Exchange (ETDEWEB)

    Shuvaev, A. [St. Petersburg Nuclear Physics Institute, Gatchina, St. Petersburg district (Russian Federation); Wallon, S. [Universite Paris XI, Laboratoire de Physique Theorique, Orsay Cedex (France)

    2006-04-15

    In this paper we derive an evolution equation for the gluon density in soft gluon cascades emitted from any colored source, in the leading logarithmic approximation of perturbative QCD. We show that this equation has the same form as the BFKL equation in the forward case. An explicit expression for the total cascade wavefunction involving an arbitrary number of soft gluons is obtained. Renormalization of the colored source wavefunction turns out to be responsible for the reggeization of the source. (orig.)

  12. Cascade of links in complex networks

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Yeqian; Sun, Bihui [Department of Management Science, School of Government, Beijing Normal University, 100875 Beijing (China); Zeng, An, E-mail: anzeng@bnu.edu.cn [School of Systems Science, Beijing Normal University, 100875 Beijing (China)

    2017-01-30

    Cascading failure is an important process which has been widely used to model catastrophic events such as blackouts and financial crisis in real systems. However, so far most of the studies in the literature focus on the cascading process on nodes, leaving the possibility of link cascade overlooked. In many real cases, the catastrophic events are actually formed by the successive disappearance of links. Examples exist in the financial systems where the firms and banks (i.e. nodes) still exist but many financial trades (i.e. links) are gone during the crisis, and the air transportation systems where the airports (i.e. nodes) are still functional but many airlines (i.e. links) stop operating during bad weather. In this letter, we develop a link cascade model in complex networks. With this model, we find that both artificial and real networks tend to collapse even if a few links are initially attacked. However, the link cascading process can be effectively terminated by setting a few strong nodes in the network which do not respond to any link reduction. Finally, a simulated annealing algorithm is used to optimize the location of these strong nodes, which significantly improves the robustness of the networks against the link cascade. - Highlights: • We propose a link cascade model in complex networks. • Both artificial and real networks tend to collapse even if a few links are initially attacked. • The link cascading process can be effectively terminated by setting a few strong nodes. • A simulated annealing algorithm is used to optimize the location of these strong nodes.

  13. Cascade of links in complex networks

    International Nuclear Information System (INIS)

    Feng, Yeqian; Sun, Bihui; Zeng, An

    2017-01-01

    Cascading failure is an important process which has been widely used to model catastrophic events such as blackouts and financial crisis in real systems. However, so far most of the studies in the literature focus on the cascading process on nodes, leaving the possibility of link cascade overlooked. In many real cases, the catastrophic events are actually formed by the successive disappearance of links. Examples exist in the financial systems where the firms and banks (i.e. nodes) still exist but many financial trades (i.e. links) are gone during the crisis, and the air transportation systems where the airports (i.e. nodes) are still functional but many airlines (i.e. links) stop operating during bad weather. In this letter, we develop a link cascade model in complex networks. With this model, we find that both artificial and real networks tend to collapse even if a few links are initially attacked. However, the link cascading process can be effectively terminated by setting a few strong nodes in the network which do not respond to any link reduction. Finally, a simulated annealing algorithm is used to optimize the location of these strong nodes, which significantly improves the robustness of the networks against the link cascade. - Highlights: • We propose a link cascade model in complex networks. • Both artificial and real networks tend to collapse even if a few links are initially attacked. • The link cascading process can be effectively terminated by setting a few strong nodes. • A simulated annealing algorithm is used to optimize the location of these strong nodes.

  14. Quantum cascade lasers as metrological tools for space optics

    Science.gov (United States)

    Bartalini, S.; Borri, S.; Galli, I.; Mazzotti, D.; Cancio Pastor, P.; Giusfredi, G.; De Natale, P.

    2017-11-01

    A distributed-feedback quantum-cascade laser working in the 4.3÷4.4 mm range has been frequency stabilized to the Lamb-dip center of a CO2 ro-vibrational transition by means of first-derivative locking to the saturated absorption signal, and its absolute frequency counted with a kHz-level precision and an overall uncertainty of 75 kHz. This has been made possible by an optical link between the QCL and a near-IR Optical Frequency Comb Synthesizer, thanks to a non-linear sum-frequency generation process with a fiber-amplified Nd:YAG laser. The implementation of a new spectroscopic technique, known as polarization spectroscopy, provides an improved signal for the locking loop, and will lead to a narrower laser emission and a drastic improvement in the frequency stability, that in principle is limited only by the stability of the optical frequency comb synthesizer (few parts in 1013). These results confirm quantum cascade lasers as reliable sources not only for high-sensitivity, but also for highprecision measurements, ranking them as optimal laser sources for space applications.

  15. Defect production in simulated cascades: Cascade quenching and short-term annealing

    International Nuclear Information System (INIS)

    Heinisch, H.L.

    1983-01-01

    Defect production in displacement cascades in copper has been modeled using the MARLOWE code to generate cascades and the stochastic annealing code ALSOME to simulate cascade quenching and short-term annealing of isolated cascades. Quenching is accomplished by using exaggerated values for defect mobilities and for critical reaction distances in ALSOME for a very short time. The quenched cascades are then short-term annealed with normal parameter values. The quenching parameter values were empirically determined by comparison with results of resistivity measurements. Throughout the collisional, quenching and short-term annealing phases of cascade development, the high energy cascades continue to behave as a collection of independent lower energy lobes. For recoils above about 30 keV the total number of defects and the numbers of free defects scale with the damage energy. As the energy decreases from 30 keV, defect production varies with the changing nature of the cascade configuration, resulting in more defects per unit damage energy. The simulated annealing of a low fluence of interacting cascades revealed an interstitial shielding effect on depleted zones during Stage I recovery. (orig.)

  16. Free-space communication based on quantum cascade laser

    International Nuclear Information System (INIS)

    Liu Chuanwei; Zhai Shenqiang; Zhang Jinchuan; Zhou Yuhong; Jia Zhiwei; Liu Fengqi; Wang Zhanguo

    2015-01-01

    A free-space communication based on a mid-infrared quantum cascade laser (QCL) is presented. A room-temperature continuous-wave distributed-feedback (DFB) QCL combined with a mid-infrared detector comprise the basic unit of the communication system. Sinusoidal signals at a highest frequency of 40 MHz and modulated video signals with a carrier frequency of 30 MHz were successfully transmitted with this experimental setup. Our research has provided a proof-of-concept demonstration of space optical communication application with QCL. The highest operation frequency of our setup was determined by the circuit-limited modulation bandwidth. A high performance communication system can be obtained with improved modulation circuit system. (paper)

  17. Formalism of continual integrals for cascade processes with particle fusion

    International Nuclear Information System (INIS)

    Gedalin, Eh.V.

    1987-01-01

    Formalism of continuous integrals for description of cascade processes, in which besides cascade particle reproduction, their synthesis and coalescence take place, is used. Account of cascade particle coalescence leads to the fact that the development of some cascade branches cannot be independent and main equations of the cascade process become functional instead of integral. The method of continuous intagrals permits to construct in the closed form producing functionals for the cascade process and to obtain the rules of their calculation using diagrams. Analytical expressions in the form of continuous integrals for producing functionals describing cascade development are obtained

  18. Joint state and parameter estimation for a class of cascade systems: Application to a hemodynamic model

    KAUST Repository

    Zayane, Chadia

    2014-06-01

    In this paper, we address a special case of state and parameter estimation, where the system can be put on a cascade form allowing to estimate the state components and the set of unknown parameters separately. Inspired by the nonlinear Balloon hemodynamic model for functional Magnetic Resonance Imaging problem, we propose a hierarchical approach. The system is divided into two subsystems in cascade. The state and input are first estimated from a noisy measured signal using an adaptive observer. The obtained input is then used to estimate the parameters of a linear system using the modulating functions method. Some numerical results are presented to illustrate the efficiency of the proposed method.

  19. Short-range intercellular calcium signaling in bone

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye

    2005-01-01

    into biological effects in bone. Intercellular calcium waves are increases in intracellular calcium concentration in single cells, subsequently propagating to adjacent cells, and can be a possible mechanism for the coupling of bone formation to bone resorption. The aim of the present studies was to investigate...... whether bone cells are capable of communicating via intercellular calcium signals, and determine by which mechanisms the cells propagate the signals. First, we found that osteoblastic cells can propagate intercellular calcium transients upon mechanical stimulation, and that there are two principally...... different mechanisms for this propagation. One mechanism involves the secretion of a nucleotide, possibly ATP, acting in an autocrine action to purinergic P2Y2 receptors on the neighboring cells, leading to intracellular IP3 generation and subsequent release of calcium from intracellular stores. The other...

  20. [Myofibroblasts and afferent signalling in the urinary bladder. A concept].

    Science.gov (United States)

    Neuhaus, J; Scholler, U; Freick, K; Schwalenberg, T; Heinrich, M; Horn, L C; Stolzenburg, J U

    2008-09-01

    Afferent signal transduction in the urinary bladder is still not clearly understood. An increasing body of evidence supports the view of complex interactions between urothelium, suburothelial myofibroblasts, and sensory nerves. Bladder tissue from tumour patients was used in this study. Methods included confocal immunofluorescence, polymerase chain reaction, calcium imaging, and fluorescence recovery after photobleaching (FRAP).Myofibroblasts express muscarinic and purinergic receptors. They show constitutive spontaneous activity in calcium imaging, which completely depends on extracellular calcium. Stimulation with carbachol and ATP-evoked intracellular calcium transients also depend on extracellular calcium. The intensive coupling between the cells is significantly diminished by incubation with TGF-beta 1. Myofibroblasts form an important cellular element within the afferent signalling of the urinary bladder. They possess all features required to take part in the complex interactions with urothelial cells and sensory nerves. Modulation of their function by cytokines may provide a pathomechanism for bladder dysfunction.

  1. Method and apparatus for rapid adjustment of process gas inventory in gaseous diffusion cascades

    International Nuclear Information System (INIS)

    1980-01-01

    A method is specified for the operation of a gaseous diffusion cascade wherein electrically driven compressors circulate a process gas through a plurality of serially connected gaseous diffusion stages to establish first and second countercurrently flowing cascade streams of process gas, one of the streams being at a relatively low pressure and enriched in a component of the process gas and the other being at a higher pressure and depleted in the same, and wherein automatic control systems maintain the stage process gas pressures by positioning process gas flow control valve openings at values which are functions of the difference between reference-signal inputs to the systems, and signal inputs proportional to the process gas pressures in the gaseous diffusion stages associated with the systems, the cascade process gas inventory being altered, while the cascade is operating, by simultaneously directing into separate process-gas freezing zones a plurality of substreams derived from one of the first and second streams at different points along the lengths thereof to solidify approximately equal weights of process gas in the zone while reducing the reference-signal inputs to maintain the positions of the control valves substantially unchanged despite the removal of process gas inventory via the substreams. (author)

  2. Effects of Saw Palmetto Extract on Urodynamic Parameters, Bladder Muscarinic and Purinergic Receptors and Urinary Cytokines in Rats with Cyclophosphamide-Induced Cystitis.

    Science.gov (United States)

    Nasrin, Sweety; Masuda, Eiji; Kugaya, Haruna; Osano, Ayaka; Ito, Yoshihiko; Yamada, Shizuo

    2014-01-01

    To clarify the effect of saw palmetto extract (SPE), a phytotherapeutic agent, on urodynamic parameters, bladder muscarinic and purinergic receptors, and urinary cytokines in rats with cystitis induced by cyclophosphamide (CYP). Saw palmetto extract (60 mg/kg per day) was administered orally twice a day for 7 days to rats. The urodynamic parameters in CYP (150 mg/kg i.p.)-treated rats were monitored by a cystometric method under anesthesia. The muscarinic and purinergic receptors in the bladder and submaxillary gland were measured by radioreceptor assays using [N-methyl-(3) H] scopolamine chloride([(3) H]NMS) and αβ-methylene-ATP [2,8-(3) H] tetrasodium salt ([(3) H]αβ-MeATP), respectively. Urinary cytokines (interleukin-1β [IL-1β], IL-6 and L-17) were measured with enzyme linked immunosorbent assay kits. Micturition interval and micturition volume were significantly decreased and the frequency of micturition and basal pressure were significantly increased in the CYP-treated rats compared with sham-operated rats. Orally administered SPE significantly increased the micturition interval and micturition volume and decreased the frequency of micturition and basal pressure. The maximal number of sites (Bmax ) for the specific binding of [(3) H]NMS and [(3) H]αβ-MeATP was significantly decreased in the bladder. The decrease in receptors was attenuated by repeated treatment with SPE. An elevation in urinary cytokine (IL-1β and IL-17) levels were seen, and this increase was effectively suppressed by SPE treatment. Saw palmetto extract attenuates the alteration of urodynamic parameters, pharmacologically relevant receptors, and urinary cytokines in CYP-treated rats. Therefore, SPE may be a potential therapeutic agent for improving the clinical symptoms of cystitis. © 2013 Wiley Publishing Asia Pty Ltd.

  3. Defect production in simulated cascades: cascade quenching and short-term annealing

    International Nuclear Information System (INIS)

    Heinisch, H.L.

    1982-01-01

    Defect production in high energy displacement cascades has been modeled using the computer code MARLOWE to generate the cascades and the stochastic computer code ALSOME to simulate the cascade quenching and short-term annealing of isolated cascades. The quenching is accomplished by using ALSOME with exaggerated values for defect mobilities and critical reaction distanes for recombination and clustering, which are in effect until the number of defect pairs is equal to the value determined from resistivity experiments at 4K. Then normal mobilities and reaction distances are used during short-term annealing to a point representative of Stage III recovery. Effects of cascade interactions at low fluences are also being investigated. The quenching parameter values were empirically determined for 30 keV cascades. The results agree well with experimental information throughout the range from 1 keV to 100 keV. Even after quenching and short-term annealing the high energy cascades behave as a collection of lower energy subcascades and lobes. Cascades generated in a crystal having thermal displacements were found to be in better agreement with experiments after quenching and annealing than those generated in a non-thermal crystal

  4. Numerical routine for magnetic heat pump cascading

    DEFF Research Database (Denmark)

    Filonenko, Konstantin; Lei, Tian; Engelbrecht, Kurt

    Heat pumps use low-temperature heat absorbed from the energy source to create temperature gradient (TG) across the energy sink. Magnetic heat pumps (MHP) can perform this function through operating active magnetic regeneration (AMR) cycle. For building heating, TGs of up to a few K might...... and 3 K. Changing the number of MHPs, we optimized input parameters to achieve maximum heating powers. We have found that both maximum heating power and COP decrease together with number of heat pumps, but the TGs and the temperature span can be largely increased. References [1] M. Tahavori et al., “A...... be necessary, which is hardly achievable with a single MHP and such techniques as cascading are required. Series and parallel cascading increase the AMR span and heating power, respectively, but do not change TG. Therefore, the intermediate type of cascading was proposed with individual MHPs separately...

  5. Non-spill control squared cascade

    International Nuclear Information System (INIS)

    Kai, Tsunetoshi; Inoue, Yoshiya; Oya, Akio; Suemori, Nobuo.

    1974-01-01

    Object: To reduce a mixed loss thus enhancing separating efficiency by the provision of a simple arrangement wherein a reflux portion in a conventional spill control squared cascade is replaced by a special stage including centrifugal separators. Structure: Steps in the form of a square cascade, in which a plurality of centrifugal separators are connected by pipe lines, are accumulated in multistage fashion to form a squared cascade. Between the adjoining steps is disposed a special stage including a centrifugal separator which receives both lean flow from the upper step and rich flow from the lower step. The centrifugal separator in the special stage has its rich side connected to the upper step and its lean side connected to the lower step. Special stages are each disposed at the upper side of the uppermost step and at the lower side of the lowermost step. (Kamimura, M.)

  6. Sample Selection for Training Cascade Detectors.

    Science.gov (United States)

    Vállez, Noelia; Deniz, Oscar; Bueno, Gloria

    2015-01-01

    Automatic detection systems usually require large and representative training datasets in order to obtain good detection and false positive rates. Training datasets are such that the positive set has few samples and/or the negative set should represent anything except the object of interest. In this respect, the negative set typically contains orders of magnitude more images than the positive set. However, imbalanced training databases lead to biased classifiers. In this paper, we focus our attention on a negative sample selection method to properly balance the training data for cascade detectors. The method is based on the selection of the most informative false positive samples generated in one stage to feed the next stage. The results show that the proposed cascade detector with sample selection obtains on average better partial AUC and smaller standard deviation than the other compared cascade detectors.

  7. Sample Selection for Training Cascade Detectors.

    Directory of Open Access Journals (Sweden)

    Noelia Vállez

    Full Text Available Automatic detection systems usually require large and representative training datasets in order to obtain good detection and false positive rates. Training datasets are such that the positive set has few samples and/or the negative set should represent anything except the object of interest. In this respect, the negative set typically contains orders of magnitude more images than the positive set. However, imbalanced training databases lead to biased classifiers. In this paper, we focus our attention on a negative sample selection method to properly balance the training data for cascade detectors. The method is based on the selection of the most informative false positive samples generated in one stage to feed the next stage. The results show that the proposed cascade detector with sample selection obtains on average better partial AUC and smaller standard deviation than the other compared cascade detectors.

  8. Multilevel Inverter by Cascading Industrial VSI

    DEFF Research Database (Denmark)

    Teodorescu, Remus; Blaabjerg, Frede; Pedersen, John Kim

    2002-01-01

    In this paper the modularity concept applied to medium-voltage adjustable speed drives is addressed. First, the single-phase cascaded voltage-source inverter that uses series connection of IGBT H-bridge modules with isolated dc-buses is presented. Next, a novel three-phase cascaded voltage......-source inverter that uses three IGBT triphase inverter modules along with an output transformer to obtain a 3 p.u. multilevel output voltage is introduced. The system yields in high-quality multistep voltage with up to 4 levels and low dv/dt, balanced operation of the inverter modules, each supplying a third...... of the motor rated kVA. The concept of using cascaded inverters is further extended to a new modular motor-modular inverter system where the motor winding connections are reconnected into several three-phase groups, either six-lead or 12-lead connection according to the voltage level, each powered...

  9. Cascade enzymatic reactions for efficient carbon sequestration.

    Science.gov (United States)

    Xia, Shunxiang; Zhao, Xueyan; Frigo-Vaz, Benjamin; Zheng, Wenyun; Kim, Jungbae; Wang, Ping

    2015-04-01

    Thermochemical processes developed for carbon capture and storage (CCS) offer high carbon capture capacities, but are generally hampered by low energy efficiency. Reversible cascade enzyme reactions are examined in this work for energy-efficient carbon sequestration. By integrating the reactions of two key enzymes of RTCA cycle, isocitrate dehydrogenase and aconitase, we demonstrate that intensified carbon capture can be realized through such cascade enzymatic reactions. Experiments show that enhanced thermodynamic driving force for carbon conversion can be attained via pH control under ambient conditions, and that the cascade reactions have the potential to capture 0.5 mol carbon at pH 6 for each mole of substrate applied. Overall it manifests that the carbon capture capacity of biocatalytic reactions, in addition to be energy efficient, can also be ultimately intensified to approach those realized with chemical absorbents such as MEA. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Dissection of the insulin signaling pathway via quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Krüger, Marcus; Kratchmarova, Irina; Blagoev, Blagoy

    2008-01-01

    spectrum of the tyrosine phosphorylation cascade, we have defined the tyrosine-phosphoproteome of the insulin signaling pathway, using high resolution mass spectrometry in combination with phosphotyrosine immunoprecipitation and stable isotope labeling by amino acids in cell culture (SILAC......The insulin signaling pathway is of pivotal importance in metabolic diseases, such as diabetes, and in cellular processes, such as aging. Insulin activates a tyrosine phosphorylation cascade that branches to create a complex network affecting multiple biological processes. To understand the full...

  11. Cascade Processes in Muonic Hydrogen Atoms

    International Nuclear Information System (INIS)

    Faifman, M. P.; Men'Shikov, L. I.

    2001-01-01

    The QCMC scheme created earlier for cascade calculations in heavy hadronic atoms of hydrogen isotopes has been modified and applied to the study of cascade processes in the μp muonic hydrogen atoms. The distribution of μp atoms over kinetic energies has been obtained and the yields of K-series X-rays per one stopped muon have been calculated.Comparison with experimental data indicated directly that for muonic and pionic atoms new types of non-radiative transitions are essential, while they are negligible for heavy (kaonic, antiprotonic, etc.) atoms. These processes have been considered and their probabilities have been estimated.

  12. Interferometric modulation of quantum cascade interactions

    Science.gov (United States)

    Cusumano, Stefano; Mari, Andrea; Giovannetti, Vittorio

    2018-05-01

    We consider many-body quantum systems dissipatively coupled by a cascade network, i.e., a setup in which interactions are mediated by unidirectional environmental modes propagating through a linear optical interferometer. In particular we are interested in the possibility of inducing different effective interactions by properly engineering an external dissipative network of beam splitters and phase shifters. In this work we first derive the general structure of the master equation for a symmetric class of translation-invariant cascade networks. Then we show how, by tuning the parameters of the interferometer, one can exploit interference effects to tailor a large variety of many-body interactions.

  13. Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

    NARCIS (Netherlands)

    D. Hasan (Djo); P. Blankman (Paul); G.F. Nieman (Gary F.)

    2017-01-01

    textabstractSevere pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high

  14. Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis.

    Science.gov (United States)

    Sandefur, Conner I; Boucher, Richard C; Elston, Timothy C

    2017-08-29

    Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease. A systems-level description of airway surface liquid (ASL) homeostasis could accelerate development of such therapies. Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling. We trained our model from steady-state and time-dependent experimental measurements made using normal and cystic fibrosis (CF) cultured human airway epithelium. To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required. The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways.

  15. Signalling crosstalk in plants: emerging issues.

    Science.gov (United States)

    Taylor, Jane E; McAinsh, Martin R

    2004-01-01

    The Oxford English Dictionary defines crosstalk as 'unwanted transfer of signals between communication channels'. How does this definition relate to the way in which we view the organization and function of signalling pathways? Recent advances in the field of plant signalling have challenged the traditional view of a signalling transduction cascade as isolated linear pathways. Instead the picture emerging of the mechanisms by which plants transduce environmental signals is of the interaction between transduction chains. The manner in which these interactions occur (and indeed whether the transfer of these signals is 'unwanted' or beneficial) is currently the topic of intense research.

  16. On Generalized Fractional Differentiator Signals

    Directory of Open Access Journals (Sweden)

    Hamid A. Jalab

    2013-01-01

    Full Text Available By employing the generalized fractional differential operator, we introduce a system of fractional order derivative for a uniformly sampled polynomial signal. The calculation of the bring in signal depends on the additive combination of the weighted bring-in of N cascaded digital differentiators. The weights are imposed in a closed formula containing the Stirling numbers of the first kind. The approach taken in this work is to consider that signal function in terms of Newton series. The convergence of the system to a fractional time differentiator is discussed.

  17. Frequency modulation spectroscopy with a THz quantum-cascade laser.

    Science.gov (United States)

    Eichholz, R; Richter, H; Wienold, M; Schrottke, L; Hey, R; Grahn, H T; Hübers, H-W

    2013-12-30

    We report on a terahertz spectrometer for high-resolution molecular spectroscopy based on a quantum-cascade laser. High-frequency modulation (up to 50 MHz) of the laser driving current produces a simultaneous modulation of the frequency and amplitude of the laser output. The modulation generates sidebands, which are symmetrically positioned with respect to the laser carrier frequency. The molecular transition is probed by scanning the sidebands across it. In this way, the absorption and the dispersion caused by the molecular transition are measured. The signals are modeled by taking into account the simultaneous modulation of the frequency and amplitude of the laser emission. This allows for the determination of the strength of the frequency as well as amplitude modulation of the laser and of molecular parameters such as pressure broadening.

  18. Estimation of LOCA break size using cascaded Fuzzy neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Geon Pil; Yoo, Kwae Hwan; Back, Ju Hyun; Na, Man Gyun [Dept. of Nuclear Engineering, Chosun University, Gwangju (Korea, Republic of)

    2017-04-15

    Operators of nuclear power plants may not be equipped with sufficient information during a loss-of-coolant accident (LOCA), which can be fatal, or they may not have sufficient time to analyze the information they do have, even if this information is adequate. It is not easy to predict the progression of LOCAs in nuclear power plants. Therefore, accurate information on the LOCA break position and size should be provided to efficiently manage the accident. In this paper, the LOCA break size is predicted using a cascaded fuzzy neural network (CFNN) model. The input data of the CFNN model are the time-integrated values of each measurement signal for an initial short-time interval after a reactor scram. The training of the CFNN model is accomplished by a hybrid method combined with a genetic algorithm and a least squares method. As a result, LOCA break size is estimated exactly by the proposed CFNN model.

  19. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells.

    Science.gov (United States)

    Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R Douglas

    2004-02-01

    Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron-glia communication are not known. Recent research shows that adenosine is a neuron-glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2(A) adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

  20. Cascading effects of overfishing marine systems

    NARCIS (Netherlands)

    Scheffer, M.; Carpenter, S.; Young, de B.

    2005-01-01

    Profound indirect ecosystem effects of overfishing have been shown for coastal systems such as coral reefs and kelp forests. A new study from the ecosystem off the Canadian east coast now reveals that the elimination of large predatory fish can also cause marked cascading effects on the pelagic food

  1. Computer simulation of high energy displacement cascades

    International Nuclear Information System (INIS)

    Heinisch, H.L.

    1990-01-01

    A methodology developed for modeling many aspects of high energy displacement cascades with molecular level computer simulations is reviewed. The initial damage state is modeled in the binary collision approximation (using the MARLOWE computer code), and the subsequent disposition of the defects within a cascade is modeled with a Monte Carlo annealing simulation (the ALSOME code). There are few adjustable parameters, and none are set to physically unreasonable values. The basic configurations of the simulated high energy cascades in copper, i.e., the number, size and shape of damage regions, compare well with observations, as do the measured numbers of residual defects and the fractions of freely migrating defects. The success of these simulations is somewhat remarkable, given the relatively simple models of defects and their interactions that are employed. The reason for this success is that the behavior of the defects is very strongly influenced by their initial spatial distributions, which the binary collision approximation adequately models. The MARLOWE/ALSOME system, with input from molecular dynamics and experiments, provides a framework for investigating the influence of high energy cascades on microstructure evolution. (author)

  2. Energy Cascade in Fermi-Pasta Models

    Science.gov (United States)

    Ponno, A.; Bambusi, D.

    We show that, for long-wavelength initial conditions, the FPU dynamics is described, up to a certain time, by two KdV-like equations, which represent the resonant Hamiltonian normal form of the system. The energy cascade taking place in the system is then quantitatively characterized by arguments of dimensional analysis based on such equations.

  3. Molecular dynamics studies of displacement cascades

    International Nuclear Information System (INIS)

    Averback, R.S.; Hsieh, Horngming; Diaz de la Rubia, T.

    1990-02-01

    Molecular-dynamics simulations of cascades in Cu and Ni with primary-knock-on energies up to 5 keV and lattice temperatures in the range 0 K--700 K are described. Interatomic forces were represented by either the Gibson II (Cu) or Johnson-Erginsoy (Ni) potentials in most of this work, although some simulations using ''Embedded Atom Method'' potentials, e.g., for threshold events in Ni 3 Al, are also presented. The results indicate that the primary state of damage produced by displacement cascades is controlled by two phenomena, replacement collision sequences during the collisional phase of the cascade and local melting during the thermal spike. As expected, the collisional phase is rather similar in Cu and Ni, however, the thermal spike is of longer duration and has a more pronounced influence in Cu than Ni. When the ambient temperature of the lattice is increased, the melt zones are observed to both increase in size and cool more slowly. This has the effect of reducing defect production and enhancing atomic mixing and disordering. The implications of these results for defect production, cascade collapse, atomic disordering will be discussed. 34 refs., 7 figs., 2 tabs

  4. Impedance interactions in bidirectional cascaded converter

    DEFF Research Database (Denmark)

    Tian, Yanjun; Loh, Poh Chiang; Chen, Zhe

    2016-01-01

    A cascaded converter is built by connecting one elementary converter to another. Output impedance of one converter will therefore interact with input impedance of the other converter. This interaction will change when power flow reverses. To compare this difference, an investigation is performed...

  5. Forecasting Social Unrest Using Activity Cascades.

    Science.gov (United States)

    Cadena, Jose; Korkmaz, Gizem; Kuhlman, Chris J; Marathe, Achla; Ramakrishnan, Naren; Vullikanti, Anil

    2015-01-01

    Social unrest is endemic in many societies, and recent news has drawn attention to happenings in Latin America, the Middle East, and Eastern Europe. Civilian populations mobilize, sometimes spontaneously and sometimes in an organized manner, to raise awareness of key issues or to demand changes in governing or other organizational structures. It is of key interest to social scientists and policy makers to forecast civil unrest using indicators observed on media such as Twitter, news, and blogs. We present an event forecasting model using a notion of activity cascades in Twitter (proposed by Gonzalez-Bailon et al., 2011) to predict the occurrence of protests in three countries of Latin America: Brazil, Mexico, and Venezuela. The basic assumption is that the emergence of a suitably detected activity cascade is a precursor or a surrogate to a real protest event that will happen "on the ground." Our model supports the theoretical characterization of large cascades using spectral properties and uses properties of detected cascades to forecast events. Experimental results on many datasets, including the recent June 2013 protests in Brazil, demonstrate the effectiveness of our approach.

  6. Forecasting Social Unrest Using Activity Cascades.

    Directory of Open Access Journals (Sweden)

    Jose Cadena

    Full Text Available Social unrest is endemic in many societies, and recent news has drawn attention to happenings in Latin America, the Middle East, and Eastern Europe. Civilian populations mobilize, sometimes spontaneously and sometimes in an organized manner, to raise awareness of key issues or to demand changes in governing or other organizational structures. It is of key interest to social scientists and policy makers to forecast civil unrest using indicators observed on media such as Twitter, news, and blogs. We present an event forecasting model using a notion of activity cascades in Twitter (proposed by Gonzalez-Bailon et al., 2011 to predict the occurrence of protests in three countries of Latin America: Brazil, Mexico, and Venezuela. The basic assumption is that the emergence of a suitably detected activity cascade is a precursor or a surrogate to a real protest event that will happen "on the ground." Our model supports the theoretical characterization of large cascades using spectral properties and uses properties of detected cascades to forecast events. Experimental results on many datasets, including the recent June 2013 protests in Brazil, demonstrate the effectiveness of our approach.

  7. The Attention Cascade Model and Attentional Blink

    Science.gov (United States)

    Shih, Shui-I

    2008-01-01

    An attention cascade model is proposed to account for attentional blinks in rapid serial visual presentation (RSVP) of stimuli. Data were collected using single characters in a single RSVP stream at 10 Hz [Shih, S., & Reeves, A. (2007). "Attentional capture in rapid serial visual presentation." "Spatial Vision", 20(4), 301-315], and single words,…

  8. Cascaded FSO-VLC Communication System

    KAUST Repository

    Gupta, Akash; Sharma, Nikhil; Garg, Parul; Alouini, Mohamed-Slim

    2017-01-01

    The proposed cascaded free space optics (FSO)-visible light communication (VLC) system consists of multiple VLC access points which caters the end users connected via a decode and forward (DF) relay to the FSO backhaul link. The FSO link is assumed

  9. A simple method for potential flow simulation of cascades

    Indian Academy of Sciences (India)

    vortex panel method to simulate potential flow in cascades is presented. The cascade ... The fluid loading on the blades, such as the normal force and pitching moment, may ... of such discrete infinite array singularities along the blade surface.

  10. Cascade theory in isotopic separation processes; Theorie des cascades en separation isotopique

    Energy Technology Data Exchange (ETDEWEB)

    Agostini, J P

    1994-06-01

    Three main areas are developed within the scope of this work: - the first one is devoted to fundamentals: separative power, value function, ideal cascade and square cascade. Applications to two main cases are carried out, namely: Study of binary isotopic mix, Study of processes with a small enrichment coefficient. - The second one is devoted to cascade coupling -high-flux coupling (more widely used and better known) as well as low-flux coupling are presented and compared to one another. - The third one is an outlook on problems linked to cascade transients. Those problem are somewhat intricate and their interest lies mainly into two areas: economics where the start-up time may have a large influence on the interests paid during the construction and start-up period, military productions where the start-up time has a direct bearing on the production schedule. (author). 50 figs. 3 annexes. 12 refs. 6 tabs.

  11. The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation.

    Science.gov (United States)

    Solini, Anna; Menini, Stefano; Rossi, Chiara; Ricci, Carlo; Santini, Eleonora; Blasetti Fantauzzi, Claudia; Iacobini, Carla; Pugliese, Giuseppe

    2013-11-01

    Renal disease associated with type 2 diabetes and the metabolic syndrome is characterized by a distinct inflammatory phenotype. The purinergic 2X7 receptor (P2X7 R) and the nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome have been separately shown to play a role in two models of non-metabolic chronic kidney disease. Moreover, the NLRP3 inflammasome has been implicated in chronic low-grade sterile inflammation characterizing metabolic disorders, though the mechanism(s) involved in inflammasome activation under these conditions are still unknown. We investigated the role of P2X7 R (through activation of the NLRP3 inflammasome) in renal inflammation and injury induced by a high-fat diet, an established model of the metabolic syndrome. On a high-fat diet, mice lacking P2X7 R developed attenuated renal functional and structural alterations as well as reduced inflammation, fibrosis, and oxidative/carbonyl stress, as compared with wild-type animals, in the absence of significant differences in metabolic parameters. This was associated with blunted up-regulation of the NLRP3 inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase 1, pro-interleukin (IL)-1β, and pro-IL-18, as well as reduced inflammasome activation, as evidenced by decreased formation of mature caspase 1, whereas mature IL-1β and IL-18 were not detected. Up-regulated expression of NLRP3 and pro-caspase 1, post-translational processing of pro-caspase-1, and release of IL-18 in response to lipopolysaccharide + 2'(3')-O-(4-benzoylbenzoyl)ATP were attenuated by P2X7 R silencing in cultured mouse podocytes. Protein and mRNA expression of P2X7 R, NLRP3, and ASC were also increased in kidneys from subjects with type 2 diabetes and the metabolic syndrome, showing histologically documented renal disease. These data provide evidence of a major role for the purinergic system, at

  12. Particle fluxes in atomic collision cascades

    International Nuclear Information System (INIS)

    Sckerl, B.W.; Sigmund, P.; Vicanek, M.

    1996-01-01

    The flux of recoil atoms in atomic collision cascades induced by an ion beam or another source of energetic particles in a material is known to approach isotropy at kinetic energies far below the beam energy. A variety of irradiation effects can be explained satisfactorily on the basis of an isotropic particle flux, but significant deviations from this simple behavior are known to exist. While numerous examples have been studied by numerical simulation of cascade processes, the systematics is, by and large, unknown. The present study aims at general scaling properties and estimates of the magnitude of moderate deviations from isotropy and their spatial dependence for a wide range of beam and material parameters. Anisotropies introduced by crystal structure are ignored. Although it is well established that cascade anisotropy is related to the momentum of beam particles, previous attempts to quantify this relation have failed. We have found that there are two leading correction terms to the isotropic particle flux, a well-known term centered around the beam direction as a symmetry axis and a new term proportional to the gradient of the deposited-energy density. As a general rule the two contributions are either both significant or both negligible. Specific situations in which the gradient term dominates are, however, of considerable interest in applications. The parameters which characterize the anisotropy of collision cascades also determine the deposition of momentum, but the connection is less straightforward than asserted hitherto. General principles are first illustrated on the specific case of elastic-collision cascades under self-bombardment which contains the essentials. Thereafter several generalizations are made, including atomic binding forces and inelasticity as well as allowance for multicomponent materials. Application areas in mixing and sputtering are outlined. (au) 58 refs

  13. Cascading Generative Adversarial Networks for Targeted

    KAUST Repository

    Hamdi, Abdullah

    2018-01-01

    Abundance of labelled data played a crucial role in the recent developments in computer vision, but that faces problems like scalability and transferability to the wild. One alternative approach is to utilize the data without labels, i.e. unsupervised learning, in learning valuable information and put it in use to tackle vision problems. Generative Adversarial Networks (GANs) have gained momentum for their ability to model image distributions in unsupervised manner. They learn to emulate the training set and that enables sampling from that domain and using the knowledge learned for useful applications. Several methods proposed enhancing GANs, including regularizing the loss with some feature matching. We seek to push GANs beyond the data in the training and try to explore unseen territory in the image manifold. We first propose a new regularizer for GAN based on K-Nearest Neighbor (K-NN) selective feature matching to a target set Y in high-level feature space, during the adversarial training of GAN on the base set X, and we call this novel model K-GAN. We show that minimizing the added term follows from cross-entropy minimization between the distributions of GAN and set Y. Then, we introduce a cascaded framework for GANs that try to address the task of imagining a new distribution that combines the base set X and target set Y by cascading sampling GANs with translation GANs, and we dub the cascade of such GANs as the Imaginative Adversarial Network (IAN). Several cascades are trained on a collected dataset Zoo-Faces and generated innovative samples are shown, including from K-GAN cascade. We conduct an objective and subjective evaluation for different IAN setups in the addressed task of generating innovative samples and we show the effect of regularizing GAN on different scores. We conclude with some useful applications for these IANs, like multi-domain manifold traversing.

  14. Cascading Generative Adversarial Networks for Targeted

    KAUST Repository

    Hamdi, Abdullah

    2018-04-09

    Abundance of labelled data played a crucial role in the recent developments in computer vision, but that faces problems like scalability and transferability to the wild. One alternative approach is to utilize the data without labels, i.e. unsupervised learning, in learning valuable information and put it in use to tackle vision problems. Generative Adversarial Networks (GANs) have gained momentum for their ability to model image distributions in unsupervised manner. They learn to emulate the training set and that enables sampling from that domain and using the knowledge learned for useful applications. Several methods proposed enhancing GANs, including regularizing the loss with some feature matching. We seek to push GANs beyond the data in the training and try to explore unseen territory in the image manifold. We first propose a new regularizer for GAN based on K-Nearest Neighbor (K-NN) selective feature matching to a target set Y in high-level feature space, during the adversarial training of GAN on the base set X, and we call this novel model K-GAN. We show that minimizing the added term follows from cross-entropy minimization between the distributions of GAN and set Y. Then, we introduce a cascaded framework for GANs that try to address the task of imagining a new distribution that combines the base set X and target set Y by cascading sampling GANs with translation GANs, and we dub the cascade of such GANs as the Imaginative Adversarial Network (IAN). Several cascades are trained on a collected dataset Zoo-Faces and generated innovative samples are shown, including from K-GAN cascade. We conduct an objective and subjective evaluation for different IAN setups in the addressed task of generating innovative samples and we show the effect of regularizing GAN on different scores. We conclude with some useful applications for these IANs, like multi-domain manifold traversing.

  15. Role of AC-cAMP-PKA Cascade in Antidepressant Action of Electroacupuncture Treatment in Rats

    Directory of Open Access Journals (Sweden)

    Jian-hua Liu

    2012-01-01

    Full Text Available Adenylyl cyclase (AC-cyclic adenosine monophosphate (cAMP-cAMP-dependent protein kinase A (PKA cascade is considered to be associated with the pathogenesis and treatment of depression. The present study was conducted to explore the role of the cAMP cascade in antidepressant action of electroacupuncture (EA treatment for chronic mild stress (CMS-induced depression model rats. The results showed that EA improved significantly behavior symptoms in depression and dysfunction of AC-cAMP-PKA signal transduction pathway induced by CMS, which was as effective as fluoxetine. Moreover, the antidepressant effects of EA rather than Fluoxetine were completely abolished by H89, a specific PKA inhibitor. Consequently, EA has a significant antidepressant treatment in CMS-induced depression model rats, and AC-cAMP-PKA signal transduction pathway is crucial for it.

  16. Sex differences in behavioral and PKA cascade responses to repeated cocaine administration.

    Science.gov (United States)

    Zhou, Luyi; Sun, Wei-Lun; Weierstall, Karen; Minerly, Ana Christina; Weiner, Jan; Jenab, Shirzad; Quinones-Jenab, Vanya

    2016-10-01

    Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point. Our results showed that females exhibited higher cocaine-induced behavioral responses and developed behavioral sensitization and tolerance faster than males. Whereas females developed behavioral sensitization to cocaine after 2 days and tolerance after 14 days, male rats developed sensitization after 5 days. In addition, cocaine induced a sexual dimorphic pattern in the progression of neuronal adaptations on the PKA cascade signaling in region (NAc vs. CPu) and time (days of cocaine administration)-dependent manners. In general, more PKA signaling cascade changes were found in the NAc of males on day 5 and in the CPu of females with repeated cocaine injection. In addition, in females, behavioral activities positively correlated with FosB levels in the NAc and CPu and negatively correlated with Cdk5 and p35 in the CPu, while no correlation was observed in males. Our studies suggest that repeated cocaine administration induced different patterns of behavioral and molecular responses in the PKA cascade in male and female rats.

  17. Gravity loading induces adenosine triphosphate release and phosphorylation of extracellular signal-regulated kinases in human periodontal ligament cells.

    Science.gov (United States)

    Ito, Mai; Arakawa, Toshiya; Okayama, Miki; Shitara, Akiko; Mizoguchi, Itaru; Takuma, Taishin

    2014-11-01

    The periodontal ligament (PDL) receives mechanical stress (MS) from dental occlusion or orthodontic tooth movement. Mechanical stress is thought to be a trigger for remodeling of the PDL and alveolar bone, although its signaling mechanism is still unclear. So we investigated the effect of MS on adenosine triphosphate (ATP) release and extracellular signal-regulated kinases (ERK) phosphorylation in PDL cells. Mechanical stress was applied to human PDL cells as centrifugation-mediated gravity loading. Apyrase, Ca(2+)-free medium and purinergic receptor agonists and antagonists were utilized to analyze the contribution of purinergic receptors to ERK phosphorylation. Gravity loading and ATP increased ERK phosphorylation by 5 and 2.5 times, respectively. Gravity loading induced ATP release from PDL cells by tenfold. Apyrase and suramin diminished ERK phosphorylation induced by both gravity loading and ATP. Under Ca(2+)-free conditions the phosphorylation by gravity loading was partially decreased, whereas ATP-induced phosphorylation was unaffected. Receptors P2Y4 and P2Y6 were prominently expressed in the PDL cells. Gravity loading induced ATP release and ERK phosphorylation in PDL fibroblasts, and ATP signaling via P2Y receptors was partially involved in this phosphorylation, which in turn would enhance gene expression for the remodeling of PDL tissue during orthodontic tooth movement. © 2013 Wiley Publishing Asia Pty Ltd.

  18. Quantum Cascade Lasers Modulation and Applications

    Science.gov (United States)

    Luzhansky, Edward

    The mid-wave IR (MWIR) spectral band, extending from 3 to 5 microns, is considered to be a low loss atmospheric window. There are several spectral sub-bands with relatively low atmospheric attenuation in this region making it popular for various commercial and military applications. Relatively low thermal and solar background emissions, effective penetration through the natural and anthropogenic obscurants and eye safety add to the long list of advantages of MWIR wavelengths. Quantum Cascade Lasers are compact semiconductor devices capable of operating in MWIR spectrum. They are based on inter-subband transitions in a multiple-quantum-well (QW) hetero-structure, designed by means of band-structure engineering. The inter-subband nature of the optical transition has several key advantages. First, the emission wavelength is primarily a function of the QW thickness. This characteristic allows choosing well-understood and reliable semiconductors for the generation of light in a wavelength range of interest. Second, a cascade process in which tens of photons are generated per injected electron. This cascading process is behind the intrinsic high-power capabilities of QCLs. This dissertation is focused on modulation properties of Quantum Cascade Lasers. Both amplitude and phase/frequency modulations were studied including modulation bandwidth, modulation efficiency and chirp linearity. Research was consisted of the two major parts. In the first part we describe the theory of frequency modulation (FM) response of Distributed Feedback Quantum Cascade Lasers (DFB QCL). It includes cascading effect on the QCL's maximum modulation frequency. The "gain levering" effect for the maximum FM response of the two section QCLs was studied as well. In the second part of research we concentrated on the Pulse Position Amplitude Modulation of a single section QCL. The low complexity, low size, weight and power Mid-Wavelength Infra-Red optical communications transceiver concept is

  19. Phase locking of 2.324 and 2.959 terahertz quantum cascade lasers using a Schottky diode harmonic mixer.

    Science.gov (United States)

    Danylov, Andriy; Erickson, Neal; Light, Alexander; Waldman, Jerry

    2015-11-01

    The 23rd and 31st harmonics of a microwave signal generated in a novel THz balanced Schottky diode mixer were used as a frequency stable reference source to phase lock solid-nitrogen-cooled 2.324 and 2.959 THz quantum cascade lasers. Hertz-level frequency stability was achieved, which was maintained for several hours.

  20. Purinergic modulation of adult guinea pig cardiomyocytes in long term cultures and co-cultures with extracardiac or intrinsic cardiac neurones.

    Science.gov (United States)

    Horackova, M; Huang, M H; Armour, J A

    1994-05-01

    To determine the capacity of ATP to modify cardiomyocytes directly or indirectly via peripheral autonomic neurones, the effects of various purinergic agents were studied on long term cultures of adult guinea pig ventricular myocytes and their co-cultures with extracardiac (stellate ganglion) or intrinsic cardiac neurones. Ventricular myocytes and cardiac neurones were enzymatically dissociated and plated together or alone (myocytes only). Myocyte cultures were used for experiments after three to six weeks. The electrical and contractile properties of cultured myocytes and myocyte-neuronal networks were investigated. The spontaneous beating frequency of ventricular myocytes co-cultured with stellate ganglion neurones increased by approximately 140% (p under control conditions, but when beta adrenergic receptors of tetrodotoxin sensitive neural responses were blocked, ATP induced greater augmentation (> 100%). In contrast, ATP induced much smaller effects in non-innervated myocyte cultures (approximately 26%, p UTP > MSATP > beta gamma ATP > alpha beta ATP. Adenosine (10(-4) M) attenuated the beating frequency of myocytes in both types of co-culture, while not significantly affecting non-innervated myocyte cultures. The experimental model used in this study showed that extrinsic and intrinsic cardiac neurones which possess P2 receptors can greatly enhance cardiac myocyte contractile rate when activated by ATP. Since adenosine reduced contractile rate in both types of co-cultures while not affecting non-innervated myocytes, it is concluded that some of these neurones possess P1 receptors.

  1. Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration*

    Science.gov (United States)

    Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B.; van der Hoorn, Frans A.

    2016-01-01

    The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. PMID:27226580

  2. Biophysically inspired rational design of structured chimeric substrates for DNAzyme cascade engineering.

    Directory of Open Access Journals (Sweden)

    Matthew R Lakin

    Full Text Available The development of large-scale molecular computational networks is a promising approach to implementing logical decision making at the nanoscale, analogous to cellular signaling and regulatory cascades. DNA strands with catalytic activity (DNAzymes are one means of systematically constructing molecular computation networks with inherent signal amplification. Linking multiple DNAzymes into a computational circuit requires the design of substrate molecules that allow a signal to be passed from one DNAzyme to another through programmed biochemical interactions. In this paper, we chronicle an iterative design process guided by biophysical and kinetic constraints on the desired reaction pathways and use the resulting substrate design to implement heterogeneous DNAzyme signaling cascades. A key aspect of our design process is the use of secondary structure in the substrate molecule to sequester a downstream effector sequence prior to cleavage by an upstream DNAzyme. Our goal was to develop a concrete substrate molecule design to achieve efficient signal propagation with maximal activation and minimal leakage. We have previously employed the resulting design to develop high-performance DNAzyme-based signaling systems with applications in pathogen detection and autonomous theranostics.

  3. Cascading failure in the wireless sensor scale-free networks

    Science.gov (United States)

    Liu, Hao-Ran; Dong, Ming-Ru; Yin, Rong-Rong; Han, Li

    2015-05-01

    In the practical wireless sensor networks (WSNs), the cascading failure caused by a failure node has serious impact on the network performance. In this paper, we deeply research the cascading failure of scale-free topology in WSNs. Firstly, a cascading failure model for scale-free topology in WSNs is studied. Through analyzing the influence of the node load on cascading failure, the critical load triggering large-scale cascading failure is obtained. Then based on the critical load, a control method for cascading failure is presented. In addition, the simulation experiments are performed to validate the effectiveness of the control method. The results show that the control method can effectively prevent cascading failure. Project supported by the Natural Science Foundation of Hebei Province, China (Grant No. F2014203239), the Autonomous Research Fund of Young Teacher in Yanshan University (Grant No. 14LGB017) and Yanshan University Doctoral Foundation, China (Grant No. B867).

  4. Invariant mass distributions in cascade decays

    CERN Document Server

    Miller, D J; Raklev, A R

    2006-01-01

    We derive analytical expressions for the shape of the invariant mass distributions of massless Standard Model endproducts in cascade decays involving massive New Physics (NP) particles, D -> Cc -> Bbc -> Aabc, where the final NP particle A in the cascade is unobserved and where two of the particles a, b, c may be indistinguishable. Knowledge of these expressions can improve the determination of NP parameters at the LHC. The shape formulas are composite, but contain nothing more complicated than logarithms of simple expressions. We study the effects of cuts, final state radiation and detector effects on the distributions through Monte Carlo simulations, using a supersymmetric model as an example. We also consider how one can deal with the width of NP particles and with combinatorics from the misidentification of final state particles. The possible mismeasurements of NP masses through `feet' in the distributions are discussed. Finally, we demonstrate how the effects of different spin configurations can be inclu...

  5. Invariant mass distributions in cascade decays

    International Nuclear Information System (INIS)

    Miller, David J.; Osland, Per; Raklev, Are R.

    2006-01-01

    We derive analytical expressions for the shape of the invariant mass distributions of massless Standard Model endproducts in cascade decays involving massive New Physics (NP) particles, D→Cc→Bbc→Aabc, where the final NP particle A in the cascade is unobserved and where two of the particles a, b, c may be indistinguishable. Knowledge of these expressions can improve the determination of NP parameters at the LHC. The shape formulas are composite, but contain nothing more complicated than logarithms of simple expressions. We study the effects of cuts, final state radiation and detector effects on the distributions through Monte Carlo simulations, using a supersymmetric model as an example. We also consider how one can deal with the width of NP particles and with combinatorics from the misidentification of final state particles. The possible mismeasurements of NP masses through 'feet' in the distributions are discussed. Finally, we demonstrate how the effects of different spin configurations can be included in the distributions

  6. Cascade-based attacks on complex networks

    Science.gov (United States)

    Motter, Adilson E.; Lai, Ying-Cheng

    2002-12-01

    We live in a modern world supported by large, complex networks. Examples range from financial markets to communication and transportation systems. In many realistic situations the flow of physical quantities in the network, as characterized by the loads on nodes, is important. We show that for such networks where loads can redistribute among the nodes, intentional attacks can lead to a cascade of overload failures, which can in turn cause the entire or a substantial part of the network to collapse. This is relevant for real-world networks that possess a highly heterogeneous distribution of loads, such as the Internet and power grids. We demonstrate that the heterogeneity of these networks makes them particularly vulnerable to attacks in that a large-scale cascade may be triggered by disabling a single key node. This brings obvious concerns on the security of such systems.

  7. Cascade Apartments: Deep Energy Multifamily Retrofit

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, A. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Mattheis, L. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Kunkle, R. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Howard, L. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Lubliner, M. [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2014-02-01

    In December of 2009-10, King County Housing Authority (KCHA) implemented energy retrofit improvements in the Cascade multifamily community, located in Kent, Washington (marine climate.)This research effort involved significant coordination from stakeholders KCHA, WA State Department of Commerce, utility Puget Sound Energy, and Cascade tenants. This report focuses on the following three primary BA research questions : 1. What are the modeled energy savings using DOE low income weatherization approved TREAT software? 2. How did the modeled energy savings compare with measured energy savings from aggregate utility billing analysis? 3. What is the Savings to Investment Ratio (SIR) of the retrofit package after considering utility window incentives and KCHA capitol improvement funding.

  8. MAP Kinase Cascades Regulate the Cold Response by Modulating ICE1 Protein Stability.

    Science.gov (United States)

    Zhao, Chunzhao; Wang, Pengcheng; Si, Tong; Hsu, Chuan-Chih; Wang, Lu; Zayed, Omar; Yu, Zheping; Zhu, Yingfang; Dong, Juan; Tao, W Andy; Zhu, Jian-Kang

    2017-12-04

    Mitogen-activated protein kinase cascades are important signaling modules that convert environmental stimuli into cellular responses. We show that MPK3, MPK4, and MPK6 are rapidly activated after cold treatment. The mpk3 and mpk6 mutants display increased expression of CBF genes and enhanced freezing tolerance, whereas constitutive activation of the MKK4/5-MPK3/6 cascade in plants causes reduced expression of CBF genes and hypersensitivity to freezing, suggesting that the MKK4/5-MPK3/6 cascade negatively regulates the cold response. MPK3 and MPK6 can phosphorylate ICE1, a basic-helix-loop-helix transcription factor that regulates the expression of CBF genes, and the phosphorylation promotes the degradation of ICE1. Interestingly, the MEKK1-MKK2-MPK4 pathway constitutively suppresses MPK3 and MPK6 activities and has a positive role in the cold response. Furthermore, the MAPKKK YDA and two calcium/calmodulin-regulated receptor-like kinases, CRLK1 and CRLK2, negatively modulate the cold activation of MPK3/6. Our results uncover important roles of MAPK cascades in the regulation of plant cold response. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Output Control Using Feedforward And Cascade Controllers

    Science.gov (United States)

    Seraji, Homayoun

    1990-01-01

    Report presents theoretical study of open-loop control elements in single-input, single-output linear system. Focus on output-control (servomechanism) problem, in which objective is to find control scheme that causes output to track certain command inputs and to reject certain disturbance inputs in steady state. Report closes with brief discussion of characteristics and relative merits of feedforward, cascade, and feedback controllers and combinations thereof.

  10. Modeling techniques for quantum cascade lasers

    Energy Technology Data Exchange (ETDEWEB)

    Jirauschek, Christian [Institute for Nanoelectronics, Technische Universität München, D-80333 Munich (Germany); Kubis, Tillmann [Network for Computational Nanotechnology, Purdue University, 207 S Martin Jischke Drive, West Lafayette, Indiana 47907 (United States)

    2014-03-15

    Quantum cascade lasers are unipolar semiconductor lasers covering a wide range of the infrared and terahertz spectrum. Lasing action is achieved by using optical intersubband transitions between quantized states in specifically designed multiple-quantum-well heterostructures. A systematic improvement of quantum cascade lasers with respect to operating temperature, efficiency, and spectral range requires detailed modeling of the underlying physical processes in these structures. Moreover, the quantum cascade laser constitutes a versatile model device for the development and improvement of simulation techniques in nano- and optoelectronics. This review provides a comprehensive survey and discussion of the modeling techniques used for the simulation of quantum cascade lasers. The main focus is on the modeling of carrier transport in the nanostructured gain medium, while the simulation of the optical cavity is covered at a more basic level. Specifically, the transfer matrix and finite difference methods for solving the one-dimensional Schrödinger equation and Schrödinger-Poisson system are discussed, providing the quantized states in the multiple-quantum-well active region. The modeling of the optical cavity is covered with a focus on basic waveguide resonator structures. Furthermore, various carrier transport simulation methods are discussed, ranging from basic empirical approaches to advanced self-consistent techniques. The methods include empirical rate equation and related Maxwell-Bloch equation approaches, self-consistent rate equation and ensemble Monte Carlo methods, as well as quantum transport approaches, in particular the density matrix and non-equilibrium Green's function formalism. The derived scattering rates and self-energies are generally valid for n-type devices based on one-dimensional quantum confinement, such as quantum well structures.

  11. Modeling techniques for quantum cascade lasers

    Science.gov (United States)

    Jirauschek, Christian; Kubis, Tillmann

    2014-03-01

    Quantum cascade lasers are unipolar semiconductor lasers covering a wide range of the infrared and terahertz spectrum. Lasing action is achieved by using optical intersubband transitions between quantized states in specifically designed multiple-quantum-well heterostructures. A systematic improvement of quantum cascade lasers with respect to operating temperature, efficiency, and spectral range requires detailed modeling of the underlying physical processes in these structures. Moreover, the quantum cascade laser constitutes a versatile model device for the development and improvement of simulation techniques in nano- and optoelectronics. This review provides a comprehensive survey and discussion of the modeling techniques used for the simulation of quantum cascade lasers. The main focus is on the modeling of carrier transport in the nanostructured gain medium, while the simulation of the optical cavity is covered at a more basic level. Specifically, the transfer matrix and finite difference methods for solving the one-dimensional Schrödinger equation and Schrödinger-Poisson system are discussed, providing the quantized states in the multiple-quantum-well active region. The modeling of the optical cavity is covered with a focus on basic waveguide resonator structures. Furthermore, various carrier transport simulation methods are discussed, ranging from basic empirical approaches to advanced self-consistent techniques. The methods include empirical rate equation and related Maxwell-Bloch equation approaches, self-consistent rate equation and ensemble Monte Carlo methods, as well as quantum transport approaches, in particular the density matrix and non-equilibrium Green's function formalism. The derived scattering rates and self-energies are generally valid for n-type devices based on one-dimensional quantum confinement, such as quantum well structures.

  12. How periodic are terahertz quantum cascade lasers?

    International Nuclear Information System (INIS)

    Kubis, T; Vogl, P

    2009-01-01

    We apply a novel non-equilibrium Green's function method for open quantum devices to analyze quantum cascade lasers. We find the carrier distribution in typical resonant phonon THz-QCLs to develop a periodicity that differs from the geometric periodicity of the QCL. We propose a design improvement that thermalizes electrons at threshold bias and thereby pins the electron density to the QCL periodicity.

  13. How periodic are terahertz quantum cascade lasers?

    Energy Technology Data Exchange (ETDEWEB)

    Kubis, T; Vogl, P, E-mail: tillmann.kubis@wsi.tum.d [Walter Schottky Institute, Technische Universitaet Muenchen, Am Coulombwall 3, 85748 Garching (Germany)

    2009-11-15

    We apply a novel non-equilibrium Green's function method for open quantum devices to analyze quantum cascade lasers. We find the carrier distribution in typical resonant phonon THz-QCLs to develop a periodicity that differs from the geometric periodicity of the QCL. We propose a design improvement that thermalizes electrons at threshold bias and thereby pins the electron density to the QCL periodicity.

  14. Cascade of circulations in fluid turbulence.

    Science.gov (United States)

    Eyink, Gregory L

    2006-12-01

    Kelvin's theorem on conservation of circulations is an essential ingredient of Taylor's theory of turbulent energy dissipation by the process of vortex-line stretching. In previous work, we have proposed a nonlinear mechanism for the breakdown of Kelvin's theorem in ideal turbulence at infinite Reynolds number. We develop here a detailed physical theory of this cascade of circulations. Our analysis is based upon an effective equation for large-scale coarse-grained velocity, which contains a turbulent-induced vortex force that can violate Kelvin's theorem. We show that singularities of sufficient strength, which are observed to exist in turbulent flow, can lead to nonvanishing dissipation of circulation for an arbitrarily small coarse-graining length in the effective equations. This result is an analog for circulation of Onsager's theorem on energy dissipation for singular Euler solutions. The physical mechanism of the breakdown of Kelvin's theorem is diffusion of lines of large-scale vorticity out of the advected loop. This phenomenon can be viewed as a classical analog of the Josephson-Anderson phase-slip phenomenon in superfluids due to quantized vortex lines. We show that the circulation cascade is local in scale and use this locality to develop concrete expressions for the turbulent vortex force by a multiscale gradient expansion. We discuss implications for Taylor's theory of turbulent dissipation and we point out some related cascade phenomena, in particular for magnetic flux in magnetohydrodynamic turbulence.

  15. Cascade laser applications: trends and challenges

    Science.gov (United States)

    d'Humières, B.; Margoto, Éric; Fazilleau, Yves

    2016-03-01

    When analyses need rapid measurements, cost effective monitoring and miniaturization, tunable semiconductor lasers can be very good sources. Indeed, applications like on-field environmental gas analysis or in-line industrial process control are becoming available thanks to the advantage of tunable semiconductor lasers. Advances in cascade lasers (CL) are revolutionizing Mid-IR spectroscopy with two alternatives: interband cascade lasers (ICL) in the 3-6μm spectrum and quantum cascade lasers (QCL), with more power from 3 to 300μm. The market is getting mature with strong players for driving applications like industry, environment, life science or transports. CL are not the only Mid-IR laser source. In fact, a strong competition is now taking place with other technologies like: OPO, VCSEL, Solid State lasers, Gas, SC Infrared or fiber lasers. In other words, CL have to conquer a share of the Mid-IR application market. Our study is a market analysis of CL technologies and their applications. It shows that improvements of components performance, along with the progress of infrared laser spectroscopy will drive the CL market growth. We compare CL technologies with other Mid-IR sources and estimate their share in each application market.

  16. Observer-based hyperchaos synchronization in cascaded discrete-time systems

    International Nuclear Information System (INIS)

    Grassi, Giuseppe

    2009-01-01

    This paper deals with the observer-based synchronization in a cascade connection of hyperchaotic discrete-time systems. The paper demonstrates that exact synchronization in finite time is achievable between pairs of drive-response systems using only a scalar synchronizing signal. This 'propagated synchronization' starts from the innermost drive-response system pair and propagates toward the outermost drive-system pair. Choosing the drive-system input to be an information signal (encrypted via an arbitrary encryption function) yields a potential application of this architecture in chaos-based communications.

  17. Three-beam double stimulated Raman scatterings: Cascading configuration

    Science.gov (United States)

    Rao, B. Jayachander; Cho, Minhaeng

    2018-03-01

    Two-beam stimulated Raman scattering (SRS) has been used in diverse label-free spectroscopy and imaging applications of live cells, biological tissues, and functional materials. Recently, we developed a theoretical framework for the three-beam double SRS processes that involve pump, Stokes, and depletion beams, where the pump-Stokes and pump-depletion SRS processes compete with each other. It was shown that the net Stokes gain signal can be suppressed by increasing the depletion beam intensity. The theoretical prediction has been experimentally confirmed recently. In the previous scheme for a selective suppression of one SRS by making it compete with another SRS, the two SRS processes occur in a parallel manner. However, there is another possibility of three-beam double SRS scheme that can be of use to suppress either Raman gain of the Stokes beam or Raman loss of the pump beam by depleting the Stokes photons with yet another SRS process induced by the pair of Stokes and another (second) Stokes beam. This three-beam double SRS process resembles a cascading energy transfer process from the pump beam to the first Stokes beam (SRS-1) and subsequently from the first Stokes beam to the second Stokes beam (SRS-2). Here, the two stimulated Raman gain-loss processes are associated with two different Raman-active vibrational modes of solute molecule. In the present theory, both the radiation and the molecules are treated quantum mechanically. We then show that the cascading-type three-beam double SRS can be described by coupled differential equations for the photon numbers of the pump and Stokes beams. From the approximate solutions as well as exact numerical calculation results for the coupled differential equations, a possibility of efficiently suppressing the stimulated Raman loss of the pump beam by increasing the second Stokes beam intensity is shown and discussed. To further prove a potential use of this scheme for developing a super-resolution SRS microscopy, we

  18. Strong anticipation: Multifractal cascade dynamics modulate scaling in synchronization behaviors

    International Nuclear Information System (INIS)

    Stephen, Damian G.; Dixon, James A.

    2011-01-01

    Research highlights: → We investigated anticipatory behaviors in response to chaotic metronomes. → We assessed multifractal structure in tap intervals and onset intervals. → Strength of multifractality in tap intervals appears to match that in onset intervals. - Abstract: Previous research on anticipatory behaviors has found that the fractal scaling of human behavior may attune to the fractal scaling of an unpredictable signal [Stephen DG, Stepp N, Dixon JA, Turvey MT. Strong anticipation: Sensitivity to long-range correlations in synchronization behavior. Physica A 2008;387:5271-8]. We propose to explain this attunement as a case of multifractal cascade dynamics [Schertzer D, Lovejoy S. Generalised scale invariance in turbulent phenomena. Physico-Chem Hydrodyn J 1985;6:623-5] in which perceptual-motor fluctuations are coordinated across multiple time scales. This account will serve to sharpen the contrast between strong and weak anticipation: whereas the former entails a sensitivity to the intermittent temporal structure of an unpredictable signal, the latter simply predicts sensitivity to an aggregate description of an unpredictable signal irrespective of actual sequence. We pursue this distinction through a reanalysis of Stephen et al.'s data by examining the relationship between the widths of singularity spectra for intertap interval time series and for each corresponding interonset interval time series. We find that the attunement of fractal scaling reported by Stephen et al. was not the trivial result of sensitivity to temporal structure in aggregate but reflected a subtle sensitivity to the coordination across multiple time scales of fluctuation in the unpredictable signal.

  19. Combinatorial and off-shell effects in new physics cascades

    Energy Technology Data Exchange (ETDEWEB)

    Wiesler, Daniel

    2012-12-15

    Up to now, the Standard Model of elementary particle physics is in very good agreement with most data. However, it has various shortcomings which motivate the presence of new physics at the TeV scale. The first major step following a potential discovery of new particles at the Large Hadron Collider (LHC) is the determination of their intrinsic properties, foremost masses and spins. Event topologies of new physics signals with a conserved parity motivated by precision data and the dark matter paradigm require for sophisticated measurement procedures, which have been developed in recent years. These techniques often rely on simplifying assumptions, albeit they need not necessarily be fulfilled. In this thesis we investigate the impact of combinatorial and off-shell effects on new physics cascades in three different contexts. A detailed understanding of these effects is essential for the topic of model parameter determination of new physics signatures at the LHC. First, we study the non-resonant contributions of a broad gluino on mass and spin measurements as a prime example for the importance of off-shell effects. A phenomenological scan over the gluino's width-to-mass ratio yields a severe smearing of invariant mass distributions and as a consequence thereof drastically shifted endpoint positions. Spin determinations, on the other hand, are barely affected and a model discrimination of the two prime candidates SUSY and UED is not at risk. In the second part, we assess the feasibility of the gluino dijet endpoint measurement in three fully inclusive scenarios at the LHC to investigate the impact of combinatorial and SUSY backgrounds on its precise determination. We develop a method to disentangle two major signal contributions and extract their associated edges with good accuracy. For this we use existent kinematic variables and propose new ones to overcome the former's deficiencies. The last part governs the issue of so-called 'fake combinatorics

  20. Divergent calcium signaling in RBCs from Tropidurus torquatus (Squamata – Tropiduridae strengthen classification in lizard evolution

    Directory of Open Access Journals (Sweden)

    Garcia Célia RS

    2007-08-01

    Full Text Available Abstract Background We have previously reported that a Teiid lizard red blood cells (RBCs such as Ameiva ameiva and Tupinambis merianae controls intracellular calcium levels by displaying multiple mechanisms. In these cells, calcium stores could be discharged not only by: thapsigargin, but also by the Na+/H+ ionophore monensin, K+/H+ ionophore nigericin and the H+ pump inhibitor bafilomycin as well as ionomycin. Moreover, these lizards possess a P2Y-type purinoceptors that mobilize Ca2+ from intracellular stores upon ATP addition. Results Here we report, that RBCs from the tropidurid lizard Tropidurus torquatus store Ca2+ in endoplasmic reticulum (ER pool but unlike in the referred Teiidae, these cells do not store calcium in monensin-nigericin sensitive pools. Moreover, mitochondria from T. torquatus RBCs accumulate Ca2+. Addition of ATP to a calcium-free medium does not increase the [Ca2+]c levels, however in a calcium medium we observe an increase in cytosolic calcium. This is an indication that purinergic receptors in these cells are P2X-like. Conclusion T. torquatus RBCs present different mechanisms from Teiid lizard red blood cells (RBCs, for controlling its intracellular calcium levels. At T. torquatus the ion is only stored at endoplasmic reticulum and mitochondria. Moreover activation of purinergic receptor, P2X type, was able to induce an influx of calcium from extracelullar medium. These studies contribute to the understanding of the evolution of calcium homeostasis and signaling in nucleated RBCs.

  1. Modeling of cascade and sub-cascade formation at high pka energies in irradiated fusion structural materials

    International Nuclear Information System (INIS)

    Ryazanov, A.; Metelkin, E.V.; Semenov, E.A.

    2007-01-01

    Full text of publication follows: A new theoretical model is developed for the investigations of cascade and sub-cascade formation in fusion structural materials under fast neutron irradiation at high primary knock atom (PKA) energies. Under 14 MeV neutron irradiation especially of light fusion structural materials such as Be, C, SiC materials PKA will have the energies up to 1 MeV. At such high energies it is very difficult to use the Monte Carlo or molecular dynamic simulations. The developed model is based on the analytical consideration of elastic collisions between displaced moving atoms into atomic cascades produced by a PKAs with the some kinetic energy obtained from fast neutrons. The Tomas-Fermy interaction potential is used for the describing of elastic collisions between moving atoms. The suggested model takes into account also the electronic losses for moving atoms between elastic collisions. The self consistent criterion for sub-cascade formation is suggested here which is based on the comparison of mean distance between two consequent PKA collisions and size of sub-cascade produced by PKA. The analytical relations for the most important characteristics of cascades and sub-cascade are determined including the average number of sub-cascades per one PKA in the dependence on PKA energy, the distance between sub-cascades and the average cascade and sub-cascade sizes as a function of PKA energy. The developed model allows determining the total numbers, distribution functions of cascades and sub-cascades in dependence on their sizes and generation rate of cascades and sub-cascades for different fusion neutron energy spectra. Based on the developed model the numerical calculations for main characteristics of cascades and sub-cascades in different fusion structural materials are performed using the neutron flux and PKA energy spectra for fusion reactors: ITER and DEMO. The main characteristics for cascade and sub-cascade formation are calculated here for the

  2. Wnt signaling: Ig-norrin the dogma.

    Science.gov (United States)

    Clevers, Hans

    2004-06-08

    Secreted Wnt proteins trigger the intracellular Wnt signaling cascade upon engagement of dedicated Frizzled-Lrp receptor complexes. Unexpectedly, a non-Wnt ligand for this receptor complex has now been discovered. This novel ligand, Norrin, is mutated in the hereditary ocular Norrie syndrome. Copyright 2004 Elsevier Ltd.

  3. Mathematical modelling of SERK mediated BR signalling

    NARCIS (Netherlands)

    Esse, van G.W.

    2013-01-01

    Being sessile by nature plants are continuously challenged by biotic and abiotic stress factors. At the cellular level, different stimuli are perceived and translated to the desired response. In order to achieve this, signal transduction cascades have to be interlinked. Complex networks

  4. New preemptive scheduling for OBS networks considering cascaded wavelength conversion

    Science.gov (United States)

    Gao, Xingbo; Bassiouni, Mostafa A.; Li, Guifang

    2009-05-01

    In this paper we introduce a new preemptive scheduling technique for next generation optical burst-switched networks considering the impact of cascaded wavelength conversions. It has been shown that when optical bursts are transmitted all optically from source to destination, each wavelength conversion performed along the lightpath may cause certain signal-to-noise deterioration. If the distortion of the signal quality becomes significant enough, the receiver would not be able to recover the original data. Accordingly, subject to this practical impediment, we improve a recently proposed fair channel scheduling algorithm to deal with the fairness problem and aim at burst loss reduction simultaneously in optical burst switching. In our scheme, the dynamic priority associated with each burst is based on a constraint threshold and the number of already conducted wavelength conversions among other factors for this burst. When contention occurs, a new arriving superior burst may preempt another scheduled one according to their priorities. Extensive simulation results have shown that the proposed scheme further improves fairness and achieves burst loss reduction as well.

  5. Ultrafast Ultrasound Imaging With Cascaded Dual-Polarity Waves.

    Science.gov (United States)

    Zhang, Yang; Guo, Yuexin; Lee, Wei-Ning

    2018-04-01

    Ultrafast ultrasound imaging using plane or diverging waves, instead of focused beams, has advanced greatly the development of novel ultrasound imaging methods for evaluating tissue functions beyond anatomical information. However, the sonographic signal-to-noise ratio (SNR) of ultrafast imaging remains limited due to the lack of transmission focusing, and thus insufficient acoustic energy delivery. We hereby propose a new ultrafast ultrasound imaging methodology with cascaded dual-polarity waves (CDWs), which consists of a pulse train with positive and negative polarities. A new coding scheme and a corresponding linear decoding process were thereby designed to obtain the recovered signals with increased amplitude, thus increasing the SNR without sacrificing the frame rate. The newly designed CDW ultrafast ultrasound imaging technique achieved higher quality B-mode images than coherent plane-wave compounding (CPWC) and multiplane wave (MW) imaging in a calibration phantom, ex vivo pork belly, and in vivo human back muscle. CDW imaging shows a significant improvement in the SNR (10.71 dB versus CPWC and 7.62 dB versus MW), penetration depth (36.94% versus CPWC and 35.14% versus MW), and contrast ratio in deep regions (5.97 dB versus CPWC and 5.05 dB versus MW) without compromising other image quality metrics, such as spatial resolution and frame rate. The enhanced image qualities and ultrafast frame rates offered by CDW imaging beget great potential for various novel imaging applications.

  6. Cascading Tesla Oscillating Flow Diode for Stirling Engine Gas Bearings

    Science.gov (United States)

    Dyson, Rodger

    2012-01-01

    Replacing the mechanical check-valve in a Stirling engine with a micromachined, non-moving-part flow diode eliminates moving parts and reduces the risk of microparticle clogging. At very small scales, helium gas has sufficient mass momentum that it can act as a flow controller in a similar way as a transistor can redirect electrical signals with a smaller bias signal. The innovation here forces helium gas to flow in predominantly one direction by offering a clear, straight-path microchannel in one direction of flow, but then through a sophisticated geometry, the reversed flow is forced through a tortuous path. This redirection is achieved by using microfluid channel flow to force the much larger main flow into this tortuous path. While microdiodes have been developed in the past, this innovation cascades Tesla diodes to create a much higher pressure in the gas bearing supply plenum. In addition, the special shape of the leaves captures loose particles that would otherwise clog the microchannel of the gas bearing pads.

  7. Superradiant cascade emissions in an atomic ensemble via four-wave mixing

    Energy Technology Data Exchange (ETDEWEB)

    Jen, H.H., E-mail: sappyjen@gmail.com

    2015-09-15

    We investigate superradiant cascade emissions from an atomic ensemble driven by two-color classical fields. The correlated pair of photons (signal and idler) is generated by adiabatically driving the system with large-detuned light fields via four-wave mixing. The signal photon from the upper transition of the diamond-type atomic levels is followed by the idler one which can be superradiant due to light-induced dipole–dipole interactions. We then calculate the cooperative Lamb shift (CLS) of the idler photon, which is a cumulative effect of interaction energy. We study its dependence on a cylindrical geometry, a conventional setup in cold atom experiments, and estimate the maximum CLS which can be significant and observable. Manipulating the CLS of cascade emissions enables frequency qubits that provide alternative robust elements in quantum network. - Highlights: • Superradiance from a cascade atomic transition. • Correlated photon pair generation via four-wave mixing. • Dynamical light–matter couplings in a phased symmetrical state. • Cooperative Lamb shift in a cylindrical atomic ensemble.

  8. Cascaded optical fiber link using the internet network for remote clocks comparison.

    Science.gov (United States)

    Chiodo, Nicola; Quintin, Nicolas; Stefani, Fabio; Wiotte, Fabrice; Camisard, Emilie; Chardonnet, Christian; Santarelli, Giorgio; Amy-Klein, Anne; Pottie, Paul-Eric; Lopez, Olivier

    2015-12-28

    We report a cascaded optical link of 1100 km for ultra-stable frequency distribution over an Internet fiber network. The link is composed of four spans for which the propagation noise is actively compensated. The robustness and the performance of the link are ensured by five fully automated optoelectronic stations, two of them at the link ends, and three deployed on the field and connecting the spans. This device coherently regenerates the optical signal with the heterodyne optical phase locking of a low-noise laser diode. Optical detection of the beat-note signals for the laser lock and the link noise compensation are obtained with stable and low-noise fibered optical interferometer. We show 3.5 days of continuous operation of the noise-compensated 4-span cascaded link leading to fractional frequency instability of 4x10(-16) at 1-s measurement time and 1x10(-19) at 2000 s. This cascaded link was extended to 1480-km with the same performance. This work is a significant step towards a sustainable wide area ultra-stable optical frequency distribution and comparison network at a very high level of performance.

  9. Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma.

    Science.gov (United States)

    Bunyavanich, S; Boyce, J A; Raby, B A; Weiss, S T

    2012-02-01

    Distinct receptors likely exist for leukotriene (LT)E(4), a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE(4)-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied. To test for association between variants in the P2Y12 gene (P2RY12) and lung function in human subjects with asthma, and to examine for gene-by-environment interaction with house dust mite exposure. Nineteen single nucleotide polymorphisms (SNPs) in P2RY12 were genotyped in 422 children with asthma and their parents (n = 1266). Using family based methods, we tested for associations between these SNPs and five lung function measures. We performed haplotype association analyses and tested for gene-by-environment interactions using house dust mite exposure. We used the false discovery rate to account for multiple comparisons. Five SNPs in P2RY12 were associated with multiple lung function measures (P-values 0.006–0.025). Haplotypes in P2RY12 were also associated with lung function (P-values 0.0055–0.046). House dust mite exposure modulated associations between P2RY12 and lung function, with minor allele homozygotes exposed to house dust mite demonstrating worse lung function than those unexposed (significant interaction P-values 0.0028–0.040). The P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by-environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.

  10. Deficiency of the Purinergic Receptor 2X7 Attenuates Nonalcoholic Steatohepatitis Induced by High-Fat Diet: Possible Role of the NLRP3 Inflammasome

    Directory of Open Access Journals (Sweden)

    Claudia Blasetti Fantauzzi

    2017-01-01

    Full Text Available Molecular mechanisms driving transition from simple steatosis to nonalcoholic steatohepatitis (NASH, a critical step in the progression of nonalcoholic fatty liver disease (NAFLD to cirrhosis, are poorly defined. This study aimed at investigating the role of the purinergic receptor 2X7 (PR2X7, through the NLRP3 inflammasome, in the development of NASH. To this end, mice knockout for the Pr2x7 gene (Pr2x7−/− and coeval wild-type (WT mice were fed a high-fat diet (HFD or normal-fat diet for 16 weeks. NAFLD grade and stage were lower in Pr2x7−/− than WT mice, and only 1/7 Pr2x7−/− animals showed evidence of NASH, as compared with 4/7 WT mice. Molecular markers of inflammation, oxidative stress, and fibrosis were markedly increased in WT-HFD mice, whereas no or significantly reduced increments were detected in Pr2x7−/− animals, which showed also decreased modulation of genes of lipid metabolism. Deletion of Pr2x7 gene was associated with blunted or abolished activation of NLRP3 inflammasome and expression of its components, which were induced in liver sinusoidal endothelial cells challenged with appropriate stimuli. These data show that Pr2x7 gene deletion protects mice from HFD-induced NASH, possibly through blunted activation of NLRP3 inflammasome, suggesting that PR2X7 and NLRP3 may represent novel therapeutic targets.

  11. Search for neutrino-induced cascade events in the icecube detector

    Energy Technology Data Exchange (ETDEWEB)

    Panknin, Sebastian

    2011-09-15

    This thesis presents results of a search for a diffuse flux of high energetic neutrinos from extra-terrestrial origin. Such a flux is predicted by several models of sources of cosmic ray particles. In a neutrino detector, such as IceCube, there are mainly two signatures available for detection of neutrinos: The track-like light signal of a neutrino induced muon and the spherical light pattern of a neutrino induced particle shower, called cascades in this context. The search is based on the measurement of neutrino induced cascades within the IceCube neutrino detector. The data were taken in 2008/2009 with a total uptime of 367 days. At that time the detector was still under construction and had just reached half of its final size. A search for a neutrino flux using cascades is sensitive to all neutrino flavors. A cascade develops within few meters, in contrast to the muon track of several kilometers length. Therefore a good energy reconstruction is possible. With such a reconstruction the astrophysical neutrino flux can be statistically distinguished from the background of atmospheric neutrinos. In the simulation of cascades so far it was not included, that in hadronic cascades muons are produced. This can influence the shape of the cascade, to a less spherical one. Therefore the effect was parameterized in this thesis and included in the simulation. Further cuts on the event topology and reconstructed energy were developed, in order to reduce the background of atmospheric muons and atmospheric neutrinos. Four events from the measured data pass these cuts. Taking the high systematic uncertainties into account, this result is in agreement with the expected background of 0.72{+-}0.28{+-}{sup 1.54}{sub 0.49} events. For an assumed flavor ratio of {nu}{sub e}:{nu}{sub {mu}}:{nu}{sub {tau}}=1:1:1 the upper limit for the all flavor neutrino flux is 9.5.10{sup -8}E{sup -2} GeVs{sup -1}sr{sup -1}cm{sup -2}.

  12. Search for neutrino-induced cascade events in the icecube detector

    International Nuclear Information System (INIS)

    Panknin, Sebastian

    2011-01-01

    This thesis presents results of a search for a diffuse flux of high energetic neutrinos from extra-terrestrial origin. Such a flux is predicted by several models of sources of cosmic ray particles. In a neutrino detector, such as IceCube, there are mainly two signatures available for detection of neutrinos: The track-like light signal of a neutrino induced muon and the spherical light pattern of a neutrino induced particle shower, called cascades in this context. The search is based on the measurement of neutrino induced cascades within the IceCube neutrino detector. The data were taken in 2008/2009 with a total uptime of 367 days. At that time the detector was still under construction and had just reached half of its final size. A search for a neutrino flux using cascades is sensitive to all neutrino flavors. A cascade develops within few meters, in contrast to the muon track of several kilometers length. Therefore a good energy reconstruction is possible. With such a reconstruction the astrophysical neutrino flux can be statistically distinguished from the background of atmospheric neutrinos. In the simulation of cascades so far it was not included, that in hadronic cascades muons are produced. This can influence the shape of the cascade, to a less spherical one. Therefore the effect was parameterized in this thesis and included in the simulation. Further cuts on the event topology and reconstructed energy were developed, in order to reduce the background of atmospheric muons and atmospheric neutrinos. Four events from the measured data pass these cuts. Taking the high systematic uncertainties into account, this result is in agreement with the expected background of 0.72±0.28± 1.54 0.49 events. For an assumed flavor ratio of ν e :ν μ :ν τ =1:1:1 the upper limit for the all flavor neutrino flux is 9.5.10 -8 E -2 GeVs -1 sr -1 cm -2 .

  13. Mitogen-activated protein kinase signaling in plants

    DEFF Research Database (Denmark)

    Rodriguez, Maria Cristina Suarez; Petersen, Morten; Mundy, John

    2010-01-01

    crossinhibition, feedback control, and scaffolding. Plant MAPK cascades regulate numerous processes, including stress and hormonal responses, innate immunity, and developmental programs. Genetic analyses have uncovered several predominant MAPK components shared by several of these processes including...... of substrate proteins, whose altered activities mediate a wide array of responses, including changes in gene expression. Cascades may share kinase components, but their signaling specificity is maintained by spaciotemporal constraints and dynamic protein-protein interactions and by mechanisms that include...

  14. Phase Locking of a 2.7 THz Quantum Cascade Laser to a Microwave Reference

    Science.gov (United States)

    Khosropanah, P.; Baryshev, A.; Zhang, W.; Jellema, W.; Hovenier, J. N.; Gao, J. R.; Klapwijk, T. M.; Paveliev, D. G.; Williams, B. S.; Hu, Q.; hide

    2009-01-01

    We demonstrate the phase locking of a 2.7 THz metal-metal waveguide quantum cascade laser (QCL) to an external microwave signal. The reference is the 15th harmonic, generated by a semiconductor superlattice nonlinear device, of a signal at 182 GHz, which itself is generated by a multiplier chain (x 12) from a microwave synthesizer at approx. 15 GHz. Both laser and reference radiations are coupled into a bolometer mixer, resulting in a beat signal, which is fed into a phase-lock loop. The spectral analysis of the beat signal confirms that the QCL is phase locked. This result opens the possibility to extend heterodyne interferometers into the far-infrared range.

  15. Heat cascading regenerative sorption heat pump

    Science.gov (United States)

    Jones, Jack A. (Inventor)

    1995-01-01

    A simple heat cascading regenerative sorption heat pump process with rejected or waste heat from a higher temperature chemisorption circuit (HTCC) powering a lower temperature physisorption circuit (LTPC) which provides a 30% total improvement over simple regenerative physisorption compression heat pumps when ammonia is both the chemisorbate and physisorbate, and a total improvement of 50% or more for LTPC having two pressure stages. The HTCC contains ammonia and a chemisorbent therefor contained in a plurality of canisters, a condenser-evaporator-radiator system, and a heater, operatively connected together. The LTPC contains ammonia and a physisorbent therefor contained in a plurality of compressors, a condenser-evaporator-radiator system, operatively connected together. A closed heat transfer circuit (CHTC) is provided which contains a flowing heat transfer liquid (FHTL) in thermal communication with each canister and each compressor for cascading heat from the HTCC to the LTPC. Heat is regenerated within the LTPC by transferring heat from one compressor to another. In one embodiment the regeneration is performed by another CHTC containing another FHTL in thermal communication with each compressor. In another embodiment the HTCC powers a lower temperature ammonia water absorption circuit (LTAWAC) which contains a generator-absorber system containing the absorbent, and a condenser-evaporator-radiator system, operatively connected together. The absorbent is water or an absorbent aqueous solution. A CHTC is provided which contains a FHTL in thermal communication with the generator for cascading heat from the HTCC to the LTAWAC. Heat is regenerated within the LTAWAC by transferring heat from the generator to the absorber. The chemical composition of the chemisorbent is different than the chemical composition of the physisorbent, and the absorbent. The chemical composition of the FHTL is different than the chemisorbent, the physisorbent, the absorbent, and ammonia.

  16. Cascade plant control by timer method

    International Nuclear Information System (INIS)

    Kiguchi, Takashi; Inoue, Kotaro; Kawai, Toshio; Senoo, Makoto.

    1970-01-01

    The present invention relates to a method of controlling uranium flow rate through a cascaded centrifuge plant for the purpose of enriching uranium 235. Such a cascade includes multiple gas separation stage each of which consists of a plurality of centrifuges. The product gas usually includes a large amount of He gas, and a cold trap is used to eliminate the He from UF 6 . The cold trap is operated periodically in such a way that the mixed gas of He and UF 6 is cooled to solidify only UF 6 and then warmed to obtain UF 6 by gasification. In order to operate the plant continuously, parallel multiple cold traps are operated alternatively. The operating conditions in such a complex cascade system are difficult to alter by conventional control methods. The present invention provides a rapid method of controlling the system when a certain percentage of the centrifuges in one stage malfunction. The control system consists of timers which are provided one for each cold trap to control the operational period of the trap. For example, if 20% of the centrifuges in a particular stage malfunction, the timer period of the cold traps attached to the normally operating centrifuge within the stage is maintained, and the period of all the other centrifuges are changed to 10/8 times that of the initial value. In this way the flow volume through all centrifuges except that in the particular stage is reduced to 80% of the initial value and the operation of the system can be continued with reduced efficiency. (Masui, R.)

  17. Cascaded two-photon spectroscopy of Yb atoms with a transportable effusive atomic beam apparatus

    Energy Technology Data Exchange (ETDEWEB)

    Song, Minsoo; Yoon, Tai Hyun [Department of Physics, Korea University, Anam-dong, Seongbuk-gu, Seoul 136-713 (Korea, Republic of)

    2013-02-15

    We present a transportable effusive atomic beam apparatus for cascaded two-photon spectroscopy of the dipole-forbidden transition (6s{sup 2} {sup 1}S{sub 0}{r_reversible} 6s7s {sup 1}S{sub 0}) of Yb atoms. An ohmic-heating effusive oven is designed to have a reservoir volume of 1.6 cm{sup 3} and a high degree of atomic beam collimation angle of 30 mrad. The new atomic beam apparatus allows us to detect the spontaneously cascaded two-photons from the 6s7s{sup 1}S{sub 0} state via the intercombination 6s6p{sup 3}P{sub 1} state with a high signal-to-noise ratio even at the temperature of 340 Degree-Sign C. This is made possible in our apparatus because of the enhanced atomic beam flux and superior detection solid angle.

  18. Cascaded two-photon spectroscopy of Yb atoms with a transportable effusive atomic beam apparatus

    International Nuclear Information System (INIS)

    Song, Minsoo; Yoon, Tai Hyun

    2013-01-01

    We present a transportable effusive atomic beam apparatus for cascaded two-photon spectroscopy of the dipole-forbidden transition (6s 2 1 S 0 ↔ 6s7s 1 S 0 ) of Yb atoms. An ohmic-heating effusive oven is designed to have a reservoir volume of 1.6 cm 3 and a high degree of atomic beam collimation angle of 30 mrad. The new atomic beam apparatus allows us to detect the spontaneously cascaded two-photons from the 6s7s 1 S 0 state via the intercombination 6s6p 3 P 1 state with a high signal-to-noise ratio even at the temperature of 340 °C. This is made possible in our apparatus because of the enhanced atomic beam flux and superior detection solid angle.

  19. Biomaterial delivery of morphogens to mimic the natural healing cascade in bone.

    Science.gov (United States)

    Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

    2012-09-01

    Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Energy cascading in large district heating systems

    International Nuclear Information System (INIS)

    Mayer, F.W.

    1978-01-01

    District heat transfer is the most economical utilization of the waste heat of power plants. Optimum utilization and heat transfer over large distances are possible because of a new energy distribution system, the ''energy cascading system,'' in which heat is transferred to several consumer regions at different temperature ranges. It is made more profitable by the use of heat pumps. The optimum flow-line temperature is 368 0 K, and the optimum return-line temperature is 288 0 K, resulting in an approximately 50% reduction of electric power loss at the power plant

  1. The identification of a cascade hypernucleus

    CERN Document Server

    Mondal, A S; Husain, A; Kasim, M M

    1979-01-01

    In a systematic search for rare hypernuclear species in nuclear emulsion exposed to 3.0 GeV/c K/sup -/-mesons at the CERN PS, an event with three connecting stars has been observed. The two secondary stars are most probably due to the decay of a cascade hypernucleus according to the following channel: /sub Xi //sup -13/-C to /sub Lambda //sup 8 /Be+/sub Lambda //sup 5/He+Q. The binding energy of the Xi - hypernucleus is B/sub Xi /-(/sub Xi //sup 13/-C)=(18.1+or-3.2) MeV. (11 refs).

  2. Cascaded recompression closed brayton cycle system

    Energy Technology Data Exchange (ETDEWEB)

    Pasch, James J.

    2018-01-02

    The present disclosure is directed to a cascaded recompression closed Brayton cycle (CRCBC) system and method of operation thereof, where the CRCBC system includes a compressor for compressing the system fluid, a separator for generating fluid feed streams for each of the system's turbines, and separate segments of a heater that heat the fluid feed streams to different feed temperatures for the system's turbines. Fluid exiting each turbine is used to preheat the fluid to the turbine. In an embodiment, the amount of heat extracted is determined by operational costs.

  3. Tracking Control for Switched Cascade Nonlinear Systems

    Directory of Open Access Journals (Sweden)

    Xiaoxiao Dong

    2015-01-01

    Full Text Available The issue of H∞ output tracking for switched cascade nonlinear systems is discussed in this paper, where not all the linear parts of subsystems are stabilizable. The conditions of the solvability for the issue are given by virtue of the structural characteristics of the systems and the average dwell time method, in which the total activation time for stabilizable subsystems is longer than that for the unstabilizable subsystems. At last, a simulation example is used to demonstrate the validity and advantages of the proposed approach.

  4. Cascaded Quadratic Soliton Compression in Waveguide Structures

    DEFF Research Database (Denmark)

    Guo, Hairun

    between the Kerr nonlinear effects and the dispersive effects in the medium. A Kerr-like nonlinearity is produced through the cascaded phase mismatched quadratic process, e.g. the second harmonic generation process, which can be flexibly tuned in both the sign and the amplitude, making possible a strong......-phase-matching technology is not necessarily needed. In large-RI-changed waveguides, CQSC is extended to the mid-infrared range to generate single-cycle pulses with purely nonlinear interactions, since an all-normal dispersion profile could be achieved within the guidance band. We believe that CQSC in quadratic waveguides...

  5. Quadrotor trajectory tracking using PID cascade control

    Science.gov (United States)

    Idres, M.; Mustapha, O.; Okasha, M.

    2017-12-01

    Quadrotors have been applied to collect information for traffic, weather monitoring, surveillance and aerial photography. In order to accomplish their mission, quadrotors have to follow specific trajectories. This paper presents proportional-integral-derivative (PID) cascade control of a quadrotor for path tracking problem when velocity and acceleration are small. It is based on near hover controller for small attitude angles. The integral of time-weighted absolute error (ITAE) criterion is used to determine the PID gains as a function of quadrotor modeling parameters. The controller is evaluated in three-dimensional environment in Simulink. Overall, the tracking performance is found to be excellent for small velocity condition.

  6. Atom localization with double-cascade configuration

    International Nuclear Information System (INIS)

    Gordeev, Maksim Yu; Rozhdestvensky, Yuri V; Efremova, Ekaterina A

    2016-01-01

    We investigate the one-dimensional (1D) and two-dimensional (2D) atom localization of a four-level system in a double-cascade configuration. We demonstrate the possibility of 1D localization in the field of a standing wave, 2D localization in the field of two standing waves and 2D localization only in the field of running waves by using different configurations of driven waves on transitions. In addition, for each configuration we reached a high-precision atom localization in one of the states at scales much smaller than the wavelength of the incident optical radiation. (paper)

  7. Cascaded recompression closed brayton cycle system

    Science.gov (United States)

    Pasch, James J.

    2018-01-02

    The present disclosure is directed to a cascaded recompression closed Brayton cycle (CRCBC) system and method of operation thereof, where the CRCBC system includes a compressor for compressing the system fluid, a separator for generating fluid feed streams for each of the system's turbines, and separate segments of a heater that heat the fluid feed streams to different feed temperatures for the system's turbines. Fluid exiting each turbine is used to preheat the fluid to the turbine. In an embodiment, the amount of heat extracted is determined by operational costs.

  8. Influence of non-binary effects on intranuclear cascade method

    International Nuclear Information System (INIS)

    Gomes, E.H.C.

    1985-01-01

    The importance of non binary process effects in the intranuclear cascade method is analysed. It is shown that, in the higher density steps, the non binary collisions lead to baryon density distribution and rapidity differents from the one obtained using the usual intranuclear cascade method (limited to purely binary collisions). The validity of the applications of binary intranuclear cascade method to the simulation of the thermal equilibrium, nuclear transparency and particle production, is discussed. (M.C.K.) [pt

  9. Sugar signalling and gene expression in relation to carbohydrate ...

    Indian Academy of Sciences (India)

    Sucrose is required for plant growth and development. The sugar status of plant cells is sensed by sensor proteins. The signal generated by signal transduction cascades, which could involve mitogen-activated protein kinases, protein phosphatases, Ca2+ and calmodulins, results in appropriate gene expression. A variety of ...

  10. The comparison of extraction of energy in two-cascade and one-cascade targets

    Energy Technology Data Exchange (ETDEWEB)

    Dolgoleva, G. V., E-mail: dolgg@list.ru [National Research Tomsk State University, 36, Lenin Ave., 634050, Tomsk (Russian Federation); Ponomarev, I. V., E-mail: wingof17@mail.ru [Moscow State University, Department of Mechanics and Mathematics, 1, Vorobyovy Gory, Moscow,119961 (Russian Federation)

    2016-01-15

    The paper is devoted to numerical designing of cylindrical microtargets on the basis of shock-free compression. When designing microtargets for the controlled thermonuclear fusion, the core tasks are to select geometry and make-up of layers, and the law of energy embedding as well, which allow receiving of “burning” of deuterium- tritium mix, that is, the existence of thermonuclear reactions of working area. Yet, the energy yield as a result of thermonuclear reactions has to be more than the embedded energy (the coefficient of amplification is more than a unit). So, an important issue is the value of the embedded energy. The purpose of the present paper is to study the extraction of energy by working DT area in one-cascade and two-cascade targets. A bigger extraction of energy will contribute to a better burning of DT mix and a bigger energy yield as a result of thermonuclear reactions. The comparison of analytical results to numerical calculations is carried out. The received results show advantages of a two-cascade target compared to a one-cascade one.

  11. Computer simulation of electronic excitation in atomic collision cascades

    International Nuclear Information System (INIS)

    Duvenbeck, A.

    2007-01-01

    The impact of an keV atomic particle onto a solid surface initiates a complex sequence of collisions among target atoms in a near-surface region. The temporal and spatial evolution of this atomic collision cascade leads to the emission of particles from the surface - a process usually called sputtering. In modern surface analysis the so called SIMS technology uses the flux of sputtered particles as a source of information on the microscopical stoichiometric structure in the proximity of the bombarded surface spots. By laterally varying the bombarding spot on the surface, the entire target can be scanned and chemically analyzed. However, the particle detection, which bases upon deflection in electric fields, is limited to those species that leave the surface in an ionized state. Due to the fact that the ionized fraction of the total flux of sputtered atoms often only amounts to a few percent or even less, the detection is often hampered by rather low signals. Moreover, it is well known, that the ionization probability of emitted particles does not only depend on the elementary species, but also on the local environment from which a particle leaves the surface. Therefore, the measured signals for different sputtered species do not necessarily represent the stoichiometric composition of the sample. In the literature, this phenomenon is known as the Matrix Effect in SIMS. In order to circumvent this principal shortcoming of SIMS, the present thesis develops an alternative computer simulation concept, which treats the electronic energy losses of all moving atoms as excitation sources feeding energy into the electronic sub-system of the solid. The particle kinetics determining the excitation sources are delivered by classical molecular dynamics. The excitation energy calculations are combined with a diffusive transport model to describe the spread of excitation energy from the initial point of generation. Calculation results yield a space- and time-resolved excitation

  12. Computer simulation of electronic excitation in atomic collision cascades

    Energy Technology Data Exchange (ETDEWEB)

    Duvenbeck, A.

    2007-04-05

    The impact of an keV atomic particle onto a solid surface initiates a complex sequence of collisions among target atoms in a near-surface region. The temporal and spatial evolution of this atomic collision cascade leads to the emission of particles from the surface - a process usually called sputtering. In modern surface analysis the so called SIMS technology uses the flux of sputtered particles as a source of information on the microscopical stoichiometric structure in the proximity of the bombarded surface spots. By laterally varying the bombarding spot on the surface, the entire target can be scanned and chemically analyzed. However, the particle detection, which bases upon deflection in electric fields, is limited to those species that leave the surface in an ionized state. Due to the fact that the ionized fraction of the total flux of sputtered atoms often only amounts to a few percent or even less, the detection is often hampered by rather low signals. Moreover, it is well known, that the ionization probability of emitted particles does not only depend on the elementary species, but also on the local environment from which a particle leaves the surface. Therefore, the measured signals for different sputtered species do not necessarily represent the stoichiometric composition of the sample. In the literature, this phenomenon is known as the Matrix Effect in SIMS. In order to circumvent this principal shortcoming of SIMS, the present thesis develops an alternative computer simulation concept, which treats the electronic energy losses of all moving atoms as excitation sources feeding energy into the electronic sub-system of the solid. The particle kinetics determining the excitation sources are delivered by classical molecular dynamics. The excitation energy calculations are combined with a diffusive transport model to describe the spread of excitation energy from the initial point of generation. Calculation results yield a space- and time-resolved excitation

  13. Optimization of the cascade with gas centrifuges for uranium enrichment

    International Nuclear Information System (INIS)

    Ozaki, N.; Harada, I.

    1976-01-01

    Computer programs to optimize the step and tapered-step cascades with gas centrifuges are developed. The 'Complex Method', one of the direct search method, is employed to find the optimum of the nonlinear function of several variables within a constrained region. The separation characteristics of the optimized step and tapered-step cascades are discussed in comparison with that of the ideal cascade. The local optima of the cascade profile, the convergence of the object function, and the stopping criterion for the optimization trial are also discussed. (author)

  14. All passive architecture for high efficiency cascaded Raman conversion

    Science.gov (United States)

    Balaswamy, V.; Arun, S.; Chayran, G.; Supradeepa, V. R.

    2018-02-01

    Cascaded Raman fiber lasers have offered a convenient method to obtain scalable, high-power sources at various wavelength regions inaccessible with rare-earth doped fiber lasers. A limitation previously was the reduced efficiency of these lasers. Recently, new architectures have been proposed to enhance efficiency, but this came at the cost of enhanced complexity, requiring an additional low-power, cascaded Raman laser. In this work, we overcome this with a new, all-passive architecture for high-efficiency cascaded Raman conversion. We demonstrate our architecture with a fifth-order cascaded Raman converter from 1117nm to 1480nm with output power of ~64W and efficiency of 60%.

  15. Gas separation performance of tapered cascade with membrane

    International Nuclear Information System (INIS)

    Ohno, Masayoshi; Morisue, Tetsuo; Ozaki, Osamu; Miyauchi, Terukatsu.

    1978-01-01

    Membrane gas separation cascades are analyzed at steady state. The method of calculating the flow rate and concentration profiles in the cascade are examined, using formulas expressing the various membrane separation cell characteristics. The method adopted is applicable to relatively high concentrations and separation factors. Considerations are further given on the steady state performance of four theoretical forms of cascade: (a) with common value of cut for all stages, (b) with symmetric separation cells, (c) with no mixing at the junction at each stage, and (d) ideal cascade. The analysis showed that, with membrane cells, the ideal cascade would have a pressure ratio varying from stage to stage. The symmetric separation cascade would provide a separation performance lower than the ideal cascade on account of the mixing at the junctions of streams possessing different concentrations, whereas the cut and separation factor of the no-mixing cascade requiring minimum membrane area exhibits zig-zag curves when plotted against stage number. Both these circumstances contribute to the lower separation performance obtained with these two forms as compared with the ideal cascade, and results in larger total membrane area; but these semi-ideal forms retain the advantage of easy practical treatment with their pressure ratio common to all stages. (auth.)

  16. Statins and ATP regulate nuclear pAkt via the P2X7 purinergic receptor in epithelial cells

    International Nuclear Information System (INIS)

    Mistafa, Oras; Hoegberg, Johan; Stenius, Ulla

    2008-01-01

    Many studies have documented P2X7 receptor functions in cells of mesenchymal origin. P2X7 is also expressed in epithelial cells and its role in these cells remains largely unknown. Our data indicate that P2X7 regulate nuclear pAkt in epithelial cells. We show that low concentration of atorvastatin, a drug inhibiting HMG-CoA reductase and cholesterol metabolism, or the natural agonist extracellular ATP rapidly decreased the level of insulin-induced phosphorylated Akt in the nucleus. This effect was seen within minutes and was inhibited by P2X7 inhibitors. Experiments employing P2X7 siRNA and HEK293 cells heterologously expressing P2X7 and in vivo experiments further supported an involvement of P2X7. These data indicate that extracellular ATP and statins via the P2X7 receptor modulate insulin-induced Akt signaling in epithelial cells

  17. Statins and ATP regulate nuclear pAkt via the P2X7 purinergic receptor in epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Mistafa, Oras; Hoegberg, Johan [Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177 Stockholm (Sweden); Stenius, Ulla [Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177 Stockholm (Sweden)

    2008-01-04

    Many studies have documented P2X7 receptor functions in cells of mesenchymal origin. P2X7 is also expressed in epithelial cells and its role in these cells remains largely unknown. Our data indicate that P2X7 regulate nuclear pAkt in epithelial cells. We show that low concentration of atorvastatin, a drug inhibiting HMG-CoA reductase and cholesterol metabolism, or the natural agonist extracellular ATP rapidly decreased the level of insulin-induced phosphorylated Akt in the nucleus. This effect was seen within minutes and was inhibited by P2X7 inhibitors. Experiments employing P2X7 siRNA and HEK293 cells heterologously expressing P2X7 and in vivo experiments further supported an involvement of P2X7. These data indicate that extracellular ATP and statins via the P2X7 receptor modulate insulin-induced Akt signaling in epithelial cells.

  18. A novel electrochemical sensor for lead ion based on cascade DNA and quantum dots amplification

    International Nuclear Information System (INIS)

    Tang, Shurong; Lu, Wei; Gu, Fang; Tong, Ping; Yan, Zhiming; Zhang, Lan

    2014-01-01

    A new enzyme-free and ultrasensitive electrochemical Pb 2+ biosensor was developed. By coupling the DNA-assisted cascade of hybridization reaction with the quantum dots (QDs) for signal amplification, a detection limit as low as 6.1 pM can be obtained for Pb 2+ . In this study, the “8-17” DNAzyme was used for specific recognition of Pb 2+ . In the presence of Pb 2+ , the DNAzyme was activated and cleaved the substrate strand. And then, the hybridization between the linker probe and signal probe was initiated, which resulted in formation of a long cascade DNA structure as well as assemble of numerous QDs at last. By the use of magnetic beads, the free signal probe can be easily removed by external magnetic field. After acid lysis, a great amount of redox cations can be released from the QDs and eventually result in significantly amplified electrochemical signals. This method is highly sensitive, selective and simple without the participation of any protein based enzyme (nuclease), thereby holds great potential for real sample analysis

  19. Cascading walks model for human mobility patterns.

    Science.gov (United States)

    Han, Xiao-Pu; Wang, Xiang-Wen; Yan, Xiao-Yong; Wang, Bing-Hong

    2015-01-01

    Uncovering the mechanism behind the scaling laws and series of anomalies in human trajectories is of fundamental significance in understanding many spatio-temporal phenomena. Recently, several models, e.g. the explorations-returns model (Song et al., 2010) and the radiation model for intercity travels (Simini et al., 2012), have been proposed to study the origin of these anomalies and the prediction of human movements. However, an agent-based model that could reproduce most of empirical observations without priori is still lacking. In this paper, considering the empirical findings on the correlations of move-lengths and staying time in human trips, we propose a simple model which is mainly based on the cascading processes to capture the human mobility patterns. In this model, each long-range movement activates series of shorter movements that are organized by the law of localized explorations and preferential returns in prescribed region. Based on the numerical simulations and analytical studies, we show more than five statistical characters that are well consistent with the empirical observations, including several types of scaling anomalies and the ultraslow diffusion properties, implying the cascading processes associated with the localized exploration and preferential returns are indeed a key in the understanding of human mobility activities. Moreover, the model shows both of the diverse individual mobility and aggregated scaling displacements, bridging the micro and macro patterns in human mobility. In summary, our model successfully explains most of empirical findings and provides deeper understandings on the emergence of human mobility patterns.

  20. The cascad spent fuel dry storage facility

    International Nuclear Information System (INIS)

    Guay, P.; Bonnet, C.

    1991-01-01

    France has a wide variety of experimental spent fuels different from LWR spent fuel discharged from commercial reactors. Reprocessing such fuels would thus require the development and construction of special facilities. The French Atomic Energy Commission (CEA) has consequently opted for long-term interim storage of these spent fuels over a period of 50 years. Comparative studies of different storage concepts have been conducted on the basis of safety (mainly containment barriers and cooling), economic, modular design and operating flexibility criteria. These studies have shown that dry storage in a concrete vault cooled by natural convection is the best solution. A research and development program including theoretical investigations and mock-up tests confirmed the feasibility of cooling by natural convection and the validity of design rules applied for fuel storage. A facility called CASCAD was built at the CEA's Cadarache Nuclear Research Center, where it has been operational since mid-1990. This paper describes the CASCAD facility and indicates how its concept can be applied to storage of LWR fuel assemblies

  1. Turbulent cascades in foreign exchange markets

    Science.gov (United States)

    Ghashghaie, S.; Breymann, W.; Peinke, J.; Talkner, P.; Dodge, Y.

    1996-06-01

    THE availability of high-frequency data for financial markets has made it possible to study market dynamics on timescales of less than a day1. For foreign exchange (FX) rates Müller et al.2 have shown that there is a net flow of information from long to short timescales: the behaviour of long-term traders (who watch the markets only from time to time) influences the behaviour of short-term traders (who watch the markets continuously). Motivated by this hierarchical feature, we have studied FX market dynamics in more detail, and report here an analogy between these dynamics and hydrodynamic turbulence3-8. Specifically, the relationship between the probability density of FX price changes (δx) and the time delay (δt) (Fig. la) is much the same as the relationship between the probability density of the velocity differences (δv) of two points in a turbulent flow and their spatial separation δr (Fig. 1b). Guided by this similarity we claim that there is an information cascade in FX market dynamics that corresponds to the energy cascade in hydrodynamic turbulence. On the basis of this analogy we can now rationalize the statistics of FX price differences at different time delays, which is important for, for example, option pricing. The analogy also provides a conceptual framework for understanding the short-term dynamics of speculative markets.

  2. Cascade Distiller System Performance Testing Interim Results

    Science.gov (United States)

    Callahan, Michael R.; Pensinger, Stuart; Sargusingh, Miriam J.

    2014-01-01

    The Cascade Distillation System (CDS) is a rotary distillation system with potential for greater reliability and lower energy costs than existing distillation systems. Based upon the results of the 2009 distillation comparison test (DCT) and recommendations of the expert panel, the Advanced Exploration Systems (AES) Water Recovery Project (WRP) project advanced the technology by increasing reliability of the system through redesign of bearing assemblies and improved rotor dynamics. In addition, the project improved the CDS power efficiency by optimizing the thermoelectric heat pump (TeHP) and heat exchanger design. Testing at the NASA-JSC Advanced Exploration System Water Laboratory (AES Water Lab) using a prototype Cascade Distillation Subsystem (CDS) wastewater processor (Honeywell d International, Torrance, Calif.) with test support equipment and control system developed by Johnson Space Center was performed to evaluate performance of the system with the upgrades as compared to previous system performance. The system was challenged with Solution 1 from the NASA Exploration Life Support (ELS) distillation comparison testing performed in 2009. Solution 1 consisted of a mixed stream containing human-generated urine and humidity condensate. A secondary objective of this testing is to evaluate the performance of the CDS as compared to the state of the art Distillation Assembly (DA) used in the ISS Urine Processor Assembly (UPA). This was done by challenging the system with ISS analog waste streams. This paper details the results of the AES WRP CDS performance testing.

  3. Quaternary Magmatism in the Cascades - Geologic Perspectives

    Science.gov (United States)

    Hildreth, Wes

    2007-01-01

    Foreward The Cascade magmatic arc is a belt of Quaternary volcanoes that extends 1,250 km from Lassen Peak in northern California to Meager Mountain in Canada, above the subduction zone where the Juan de Fuca Plate plunges beneath the North American Plate. This Professional Paper presents a synthesis of the entire volcanic arc, addressing all 2,300 known Quaternary volcanoes, not just the 30 or so visually prominent peaks that comprise the volcanic skyline. Study of Cascade volcanoes goes back to the geological explorers of the late 19th century and the seminal investigations of Howel Williams in the 1920s and 1930s. However, major progress and application of modern scientific methods and instrumentation began only in the 1970s with the advent of systematic geological, geophysical, and geochemical studies of the entire arc. Initial stimulus from the USGS Geothermal Research Program was enhanced by the USGS Volcano Hazards Program following the 1980 eruption of Mount St. Helens. Together, these two USGS Programs have provided more than three decades of stable funding, staffing, and analytical support. This Professional Paper summarizes the resultant USGS data sets and integrates them with the parallel contributions of other investigators. The product is based upon an all-encompassing and definitive geological database, including chemical and isotopic analyses to characterize the rocks and geochronology to provide the critical time constraints. Until now, this massive amount of data has not been summarized, and a systematic and uniform interpretation firmly grounded in geological fact has been lacking. Herein lies the primary utility of this Cascade volume. It not only will be the mandatory starting point for new workers, but also will provide essential geological context to broaden the perspectives of current investigators of specific Cascade volcanoes. Wes Hildreth's insightful understanding of volcanic processes and his uncompromising scientific integrity make him

  4. Modeling of cascade and sub-cascade formation at high PKA energies in irradiated fusion structural materials

    International Nuclear Information System (INIS)

    Ryazanov, A.I.; Metelkin, E.V.; Semenov, E.V.

    2009-01-01

    A new theoretical model is developed for the investigations of cascade and sub-cascade formation in fusion structural materials under fast neutron irradiation at high primary knock-on atom energies. Light fusion structural materials: such as Be, C and SiC under 14 MeV neutron irradiation in fusion reactor will have the primary knock-on atoms with the energies up to 1 MeV. It is very difficult to use at such high energies the Monte-Carlo or molecular dynamic simulations [H.L. Heinisch, B.N. Singh, Philos. Mag. A67 (1993) 407; H.L. Heinisch, B.N. Singh, J. Nucl. Mater. 251 (1997) 77]. The developed model is based on the analytical consideration of elastic collisions between displaced moving atoms produced by primary knock-on atoms with some kinetic energies obtained from fast neutrons and crystal lattice atoms. The Thomas-Fermi interaction potential is used here for the description of these elastic atomic collisions. The suggested model takes into account also the electronic losses for moving atoms between elastic collisions. The self-consistent criterion for sub-cascade formation is suggested here which is based on the comparison of mean distance of primary knock-on atoms between consequent collisions of them with the target atoms and a size of sub-cascade produced by moving secondary knock-on atoms produced in such collisions. The analytical relations for the most important characteristics of cascades and sub-cascades are determined including the average number of sub-cascades per one primary knock-on atom in the dependence on its energy, the distance between sub-cascades and the average cascade and sub-cascade sizes. The developed model allows determining the total numbers, distribution functions of cascades and sub-cascades in dependence on their sizes and generation rate of cascades and sub-cascades for the different fusion neutron energy spectra. On the basis of this developed model the numerical calculations for main characteristics of cascades and sub-cascades

  5. Processing of cell-surface signalling anti-sigma factors prior to signal recognition is aconserved autoproteolytic mechanism that produces two functional domains.

    NARCIS (Netherlands)

    Bastiaansen, K.C.J.T.; Otero-Asman, J.R.; Luirink, J.; Bitter, W.; Llamas, M.A.

    2015-01-01

    Cell-surface signalling (CSS) enables Gram-negative bacteria to transduce an environmental signal into a cytosolic response. This regulatory cascade involves an outer membrane receptor that transmits the signal to an anti-sigma factor in the cytoplasmic membrane, allowing the activation of an

  6. Quantum cascade laser-based photoacoustic sulfuryl fluoride sensing

    Science.gov (United States)

    Minini, Kariza Mayra Silva; Bueno, Sâmylla Cristina Espécie; da Silva, Marcelo Gomes; Sthel, Marcelo Silva; Vargas, Helion; Angster, Judit; Miklós, András

    2017-02-01

    Although sulfuryl fluoride (SO2F2) is an efficient fumigant that does not react with the surface of indoor materials and does not reduce the stratospheric ozone shield, there are some concerns about its use. It is a toxic gas that attacks the central nervous system, and its global warming potential (GWP) value is 4780 for 100 years' time. Therefore, it is a clear necessity of implementing detection methods for tracing such a molecule. In this work a sensitive photoacoustic setup was built to detect SO2F2 at concentrations of parts per billion by volume (ppbv). The symmetric S-O stretching mode was excited by a continuous-wave quantum cascade laser with radiation wavenumber ranging from 1275.7 to 1269.3 cm-1. The photoacoustic signal was generated by modulating the laser wavenumber at the first longitudinal mode of the photoacoustic cell with amplitude depth of 5 × 10-3 cm-1. The detection of a minimum SO2F2 concentration of 20 ppbv was achieved.

  7. Estimation of Minimum DNBR Using Cascaded Fuzzy Neural Networks

    International Nuclear Information System (INIS)

    Kim, Dong Yeong; Yoo, Kwae Hwan; Na, Man Gyun

    2015-01-01

    This phenomenon of boiling crisis is called a departure from nucleate boiling (DNB). The DNB phenomena can influence the fuel cladding and fuel pellets. The DNB ratio (DNBR) is defined as the ratio of the expected DNB heat flux to the actual fuel rod heat flux. Since it is very important to monitor and predict the minimum DNBR in a reactor core to prevent the boiling crisis and clad melting, a number of researches have been conducted to predict DNBR values. The aim of this study is to estimate the minimum DNBR in a reactor core using the measured signals of the reactor coolant system (RCS) by applying cascaded fuzzy neural networks (CFNN) according to operating conditions. Reactor core monitoring and protection systems require minimum DNBR prediction. The CFNN can be used to optimize the minimum DNBR value through the process of adding fuzzy neural networks (FNN) repeatedly. The proposed algorithm is trained by using the data set prepared for training (development data) and verified by using another data set different (independent) from the development data. The developed CFNN models were applied to the first fuel cycle of OPR1000. The RMS errors are 0.23% and 0.12% for the positive and negative ASI, respectively

  8. The critical care cascade: a systems approach.

    Science.gov (United States)

    Ghosh, Rishi; Pepe, Paul

    2009-08-01

    To emphasize the evolving body of evidence that supports the need for a more seamless and interconnected continuum of patient care for a growing compendium of critical care conditions, starting in the prehospital and emergency department (ED) phases of management and continuing through ICU and rehabilitation services. The care of critically ill and injured patients has become increasingly complex. It now has been demonstrated that, for a number of such critical care conditions, optimal management not only relies heavily on the talents of highly coordinated, multidisciplinary teams, but it also may require shared responsibilities across a continuum of longitudinal care involving numerous specialties and departments. This continuum usually needs to begin in the prehospital and ED settings with management extending through specialized in-hospital diagnostic and interventional suites to traditional ICU and rehabilitation programs. In recent years, examples of these conditions have included the development of systems of care for trauma, cardiac arrest, myocardial infarction, stroke, sepsis syndromes, toxicology and other critical illnesses. Although the widespread implementation of such multidisciplinary, multispecialty critical care cascades of care has been achieved most commonly in trauma care, current healthcare delivery systems generally tend to employ compartmentalized organization for the majority of other critical care patients. Accordingly, optimal systematic care often breaks down in the management of these complex patients due to barriers such as lack of interoperable communication between teams, disjointed transfers between services, unnecessary time-consuming, re-evaluations and transitional pauses in time-dependent circumstances, deficiencies in cross-disciplinary education and quality assurance loops, and significant variability in patient care practices. Such barriers can lead to adverse outcomes in this fragile patient population. This article discusses

  9. Eruptive history of South Sister, Oregon Cascades

    Science.gov (United States)

    Fierstein, J.; Hildreth, W.; Calvert, A.T.

    2011-01-01

    South Sister is southernmost and highest of the Three Sisters, three geologically dissimilar stratovolcanoes that together form a spectacular 20km reach along the Cascade crest in Oregon. North Sister is a monotonously mafic edifice as old as middle Pleistocene, Middle Sister a basalt-andesite-dacite cone built between 48 and 14ka, and South Sister is a basalt-free edifice that alternated rhyolitic and intermediate modes from 50ka to 2ka (largely contemporaneous with Middle Sister). Detailed mapping, 330 chemical analyses, and 42 radioisotopic ages show that the oldest exposed South Sister lavas were initially rhyolitic ~50ka. By ~37ka, rhyolitic lava flows and domes (72-74% SiO2) began alternating with radially emplaced dacite (63-68% SiO2) and andesite (59-63% SiO2) lava flows. Construction of a broad cone of silicic andesite-dacite (61-64% SiO2) culminated ~30ka in a dominantly explosive sequence that began with crater-forming andesitic eruptions that left fragmental deposits at least 200m thick. This was followed at ~27ka by growth of a steeply dipping summit cone of agglutinate-dominated andesite (56-60.5% SiO2) and formation of a summit crater ~800m wide. This crater was soon filled and overtopped by a thick dacite lava flow and then by >150m of dacitic pyroclastic ejecta. Small-volume dacite lavas (63-67% SiO2) locally cap the pyroclastic pile. A final sheet of mafic agglutinate (54-56% SiO2) - the most mafic product of South Sister - erupted from and drapes the small (300-m-wide) present-day summit crater, ending a summit-building sequence that lasted until ~22ka. A 20kyr-long-hiatus was broken by rhyolite eruptions that produced (1) the Rock Mesa coulee, tephra, and satellite domelets (73.5% SiO2) and (2) the Devils Chain of ~20 domes and short coulees (72.3-72.8% SiO2) from N-S vent alignments on South Sister's flanks. The compositional reversal from mafic summit agglutinate to recent rhyolites epitomizes the frequently changing compositional modes of the

  10. Energy cascading in the beat-wave accelerator

    International Nuclear Information System (INIS)

    McKinstrie, C.J.; Batha, S.H.

    1987-01-01

    A review is given of energy cascading in the beat-wave accelerator. The properties of the electromagnetic cascade and the corresponding plasma-wave evolution are well understood within the framework of an approximate analytic model. Based on this model, idealized laser-plasma coupling efficiencies of the order of 10% do not seem unreasonable. 28 refs

  11. Time development of cascades by the binary collision approximation code

    International Nuclear Information System (INIS)

    Fukumura, A.; Ishino, S.; Sekimura, N.

    1991-01-01

    To link a molecular dynamic calculation to binary collision approximation codes to explore high energy cascade damage, time between consecutive collisions is introduced into the binary collision MARLOWE code. Calculated results for gold by the modified code show formation of sub-cascades and their spatial and time overlapping, which can affect formation of defect clusters. (orig.)

  12. Cascades for hydrogen isotope separation using metal hydrides

    International Nuclear Information System (INIS)

    Hill, F.B.; Grzetic, V.

    1982-01-01

    Designs are presented for continuous countercurrent hydrogen isotope separation cascades based on the use of metal hydrides. The cascades are made up of pressure swing adsorption (PSA) or temperature swing adsorption (TSA) stages. The designs were evolved from consideration of previously conducted studies of the separation performance of four types of PSA and TSA processes

  13. A simple model of global cascades on random networks

    Science.gov (United States)

    Watts, Duncan J.

    2002-04-01

    The origin of large but rare cascades that are triggered by small initial shocks is a phenomenon that manifests itself as diversely as cultural fads, collective action, the diffusion of norms and innovations, and cascading failures in infrastructure and organizational networks. This paper presents a possible explanation of this phenomenon in terms of a sparse, random network of interacting agents whose decisions are determined by the actions of their neighbors according to a simple threshold rule. Two regimes are identified in which the network is susceptible to very large cascadesherein called global cascadesthat occur very rarely. When cascade propagation is limited by the connectivity of the network, a power law distribution of cascade sizes is observed, analogous to the cluster size distribution in standard percolation theory and avalanches in self-organized criticality. But when the network is highly connected, cascade propagation is limited instead by the local stability of the nodes themselves, and the size distribution of cascades is bimodal, implying a more extreme kind of instability that is correspondingly harder to anticipate. In the first regime, where the distribution of network neighbors is highly skewed, it is found that the most connected nodes are far more likely than average nodes to trigger cascades, but not in the second regime. Finally, it is shown that heterogeneity plays an ambiguous role in determining a system's stability: increasingly heterogeneous thresholds make the system more vulnerable to global cascades; but an increasingly heterogeneous degree distribution makes it less vulnerable.

  14. Cascade in muonic and pionic atoms with Z = 1

    International Nuclear Information System (INIS)

    Markushin, V.E.

    1999-01-01

    Recent theoretical and experimental studies of the exotic atoms with Z = 1 are reviewed. An interplay between the atomic internal and external degrees of freedom is essential for a good description of the atomic cascade. The perspective of ab initio cascade calculations is outlined

  15. Intermittent Flow Regimes in a Transonic Fan Airfoil Cascade

    Directory of Open Access Journals (Sweden)

    J. Lepicovsky

    2004-01-01

    velocity.To date, this flow behavior has only been observed in a linear transonic cascade. Further research is necessary to confirm this phenomenon occurs in actual transonic fans and is not the by-product of an endwall restricted linear cascade.

  16. A cascaded online uninterruptible power supply using reduced semiconductor

    DEFF Research Database (Denmark)

    Zhang, Lei; Loh, Poh Chiang; Gao, Feng

    2011-01-01

    A cascaded online uninterruptible power supply (UPS) is proposed here that uses 25% lesser semiconductor, as compared to its traditional H-bridge cascaded precedence. Unlike other component-saving configurations where compromises are unavoidable, almost no performance degradations and constraints...

  17. Cascades for hydrogen isotope separation using metal hydrides

    Energy Technology Data Exchange (ETDEWEB)

    Hill, F B; Grzetic, V [Brookhaven National Lab., Upton, NY (USA)

    1983-02-01

    Designs are presented for continuous countercurrent hydrogen isotope separation cascades based on the use of metal hydrides. The cascades are made up of pressure swing adsorption (PSA) or temperature swing adsorption (TSA) stages. The designs were evolved from consideration of previously conducted studies of the separation performance of four types of PSA and TSA processes.

  18. Participant intimacy: A cluster analysis of the intranuclear cascade

    International Nuclear Information System (INIS)

    Cugnon, J.; Knoll, J.; Randrup, J.

    1981-01-01

    The intranuclear cascade for relativistic nuclear collisions is analyzed in terms of clusters consisting of groups of nucleons which are dynamically linked to each other by violent interactions. The formation cross sections for the different cluster types as well as their intrinsic dynamics are studied and compared with the predictions of the linear cascade model ( rows-on-rows ). (orig.)

  19. Climate Change and Baleen Whale Trophic Cascades in Greenland

    Science.gov (United States)

    2009-09-30

    DISTRIBUTION STATEMENT A: Approved for public release; distribution is unlimited. Climate Change and Baleen Whale Trophic Cascades in Greenland...SUBTITLE Climate Change And Baleen Whale Trophic Cascades In Greenland 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S

  20. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease.

    Science.gov (United States)

    Warden, Scott M; Andreoli, Christopher M; Mukai, Shizuo

    2007-01-01

    The Wnt signaling pathway is highly conserved among species and has an important role in many cell biological processes throughout the body. This signaling cascade is involved in regulating ocular growth and development, and recent findings indicate that this is particularly true in the retina. Mutations involving different aspects of the Wnt signaling pathway are being linked to several diseases of retinal development. The aim of this article is to first review the Wnt signaling pathway. We will then describe two conditions, familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND), which have been shown to be caused in part by defects in the Wnt signaling cascade.

  1. Quantification of the glycogen cascade system: the ultrasensitive responses of liver glycogen synthase and muscle phosphorylase are due to distinctive regulatory designs

    Directory of Open Access Journals (Sweden)

    Venkatesh KV

    2005-05-01

    Full Text Available Abstract Background Signaling pathways include intricate networks of reversible covalent modification cycles. Such multicyclic enzyme cascades amplify the input stimulus, cause integration of multiple signals and exhibit sensitive output responses. Regulation of glycogen synthase and phosphorylase by reversible covalent modification cycles exemplifies signal transduction by enzyme cascades. Although this system for regulating glycogen synthesis and breakdown appears similar in all tissues, subtle differences have been identified. For example, phosphatase-1, a dephosphorylating enzyme of the system, is regulated quite differently in muscle and liver. Do these small differences in regulatory architecture affect the overall performance of the glycogen cascade in a specific tissue? We address this question by analyzing the regulatory structure of the glycogen cascade system in liver and muscle cells at steady state. Results The glycogen cascade system in liver and muscle cells was analyzed at steady state and the results were compared with literature data. We found that the cascade system exhibits highly sensitive switch-like responses to changes in cyclic AMP concentration and the outputs are surprisingly different in the two tissues. In muscle, glycogen phosphorylase is more sensitive than glycogen synthase to cyclic AMP, while the opposite is observed in liver. Furthermore, when the liver undergoes a transition from starved to fed-state, the futile cycle of simultaneous glycogen synthesis and degradation switches to reciprocal regulation. Under such a transition, different proportions of active glycogen synthase and phosphorylase can coexist due to the varying inhibition of glycogen-synthase phosphatase by active phosphorylase. Conclusion The highly sensitive responses of glycogen synthase in liver and phosphorylase in muscle to primary stimuli can be attributed to distinctive regulatory designs in the glycogen cascade system. The different

  2. Ion-irradiation studies of cascade damage in metals

    International Nuclear Information System (INIS)

    Averback, R.S.

    1982-03-01

    Ion-irradiation studies of the fundamental aspects of cascade damage in metals are reviewed. The emphasis of these studies has been the determination of the primary state of damage (i.e. the arrangement of atoms in the cascade region prior to thermal migration of defects). Progress has been made towards understanding the damage function (i.e. the number of Frenkel pairs produced as a function of primary recoil atom energy), the spatial configuration of vacancies and interstitials in the cascade and the cascade-induced mixing of atoms. It is concluded for these studies that the agitation of the lattice in the vicinity of energetic displacement cascades stimulates the defect motion and that such thermal spike motion induces recombination and clustering of Frenkel defects. 9 figures

  3. Geothermal segmentation of the Cascade Range in the USA

    Science.gov (United States)

    Guffanti, Marianne; Muffler, L.J.; Mariner, R.H.; Sherrod, D.R.; Smith, James G.; Blackwell, D.D.; Weaver, C.S.

    1990-01-01

    Characteristics of the crustal thermal regime of the Quaternary Cascades vary systematically along the range. Spatially congruent changes in volcanic vent distribution, volcanic extrusion rate, hydrothermal discharge rate, and regional conductive heat flow define 5 geothermal segments. These segments are, from north to south: (1) the Washington Cascades north of Mount Rainier, (2) the Cascades from Mount Rainier to Mount Hood, (3) the Oregon Cascades from south of Mount Hood to the California border, (4) northernmost California, including Mount Shasta and Medicine Lake volcano, and (5) the Lassen region of northern California. This segmentation indicates that geothermal resource potential is not uniform in the Cascade Range. Potential varies from high in parts of Oregon to low in Washington north of Mount Rainier.

  4. Cascaded Amplitude Modulations in Sound Texture Perception

    DEFF Research Database (Denmark)

    McWalter, Richard Ian; Dau, Torsten

    2017-01-01

    . In this study, we investigated the perception of sound textures that contain rhythmic structure, specifically second-order amplitude modulations that arise from the interaction of different modulation rates, previously described as "beating" in the envelope-frequency domain. We developed an auditory texture...... model that utilizes a cascade of modulation filterbanks that capture the structure of simple rhythmic patterns. The model was examined in a series of psychophysical listening experiments using synthetic sound textures-stimuli generated using time-averaged statistics measured from real-world textures....... In a texture identification task, our results indicated that second-order amplitude modulation sensitivity enhanced recognition. Next, we examined the contribution of the second-order modulation analysis in a preference task, where the proposed auditory texture model was preferred over a range of model...

  5. RG cascades in hyperbolic quiver gauge theories

    International Nuclear Information System (INIS)

    Ahl Laamara, R.; Ait Ben Haddou, M.; Belhaj, A.; Drissi, L.B.; Saidi, E.H.

    2004-01-01

    In this paper, we provide a general classification of supersymmatric QFT4s into three basic sets: ordinary, affine and indefinite classes. The last class, which has not been enough explored in literature, is shown to share most of properties of ordinary and affine super-QFT4s. This includes, amongst others, its embedding in type II string on local Calabi-Yau threefolds. We give realizations of these supersymmetric QFT4s as D-brane world volume gauge theories. A special interest is devoted to hyperbolic subset for its peculiar features and for the role it plays in type IIB background with non-zero axion. We also study RG flows and duality cascades in case of hyperbolic quiver theories. Comments regarding the full indefinite sector are made

  6. Congestion and cascades in payment systems

    Science.gov (United States)

    Beyeler, Walter E.; Glass, Robert J.; Bech, Morten L.; Soramäki, Kimmo

    2007-10-01

    We develop a parsimonious model of the interbank payment system. The model incorporates an endogenous instruction arrival process, a scale-free topology of payments between banks, a fixed total liquidity which limits banks’ capacity to process arriving instructions, and a global market that distributes liquidity. We find that at low liquidity the system becomes congested and payment settlement loses correlation with payment instruction arrival, becoming coupled across the network. The onset of congestion is evidently related to the relative values of three characteristic times: the time for banks’ net position to return to 0, the time for a bank to exhaust its liquidity endowment, and the liquidity market relaxation time. In the congested regime settlement takes place in cascades having a characteristic length scale. A global liquidity market substantially attenuates congestion, requiring only a small fraction of the payment-induced liquidity flow to achieve strong beneficial effects.

  7. Prolate yrast cascade in 183Tl

    International Nuclear Information System (INIS)

    Reviol, W.; Carpenter, M. P.; Janssens, R. V. F.; Jenkins, D.; Toth, K. S.; Bingham, C. R.; Riedinger, L. L.; Weintraub, W.; Cizewski, J. A.; Lauritsen, T.

    2000-01-01

    The yrast sequence in 183 Tl has been studied for the first time in recoil-mass selected γ-ray spectroscopic measurements. A rotational-like cascade of seven transitions is established down to the band head with probable spin and parity (13/2 + ). Unlike in the adjacent odd-mass Tl nuclei, prompt γ decay from the yrast band to a lower lying weakly deformed (oblate) structure is not observed. These features are consistent with the predicted drop of the prolate band head in 183 Tl compared to 185 Tl. The implications for the prolate energy minimum in odd-mass Tl nuclei at the neutron i 13/2 midshell (N=103) are discussed. (c) 2000 The American Physical Society

  8. Hadron cascade by the method of characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Tsui, K.H.; Portella, H.M.; Navia, C.E.; Shigueoka, H. [Universidade Federal Fluminense, Niteroi, RJ (Brazil). Inst. de Fisica]. E-mails: tsui@if.uff.br; hmport@if.uff.br; gficnoj@if.uff.br; hisa@if.uff.br; Oliveira, L.C.S. de [Centro Brasileiro de Pesquisas Fisicas (CBPF), Rio de Janeiro, RJ (Brazil)]. E-mail: oliveira@cbpf.br

    2005-02-01

    Hadron diffusion equations with energy-dependent interaction mean free paths and inelasticities are solved using the Mellin transform. Instead of using operators on the finite difference terms, the Mellin transformed equations are Taylor expanded into a first order partial differential equation in atmospheric depth t and in the transform parameter s. Then, these equations are solved by the method of residues. For the case of a regularized power law primary spectrum these hadron fluxes are given by simple residues and one, never before mentioned, essential singularities. A comparison of our solutions with the nucleon flux measured at sea level and with the hadron fluxes measured at t = 840 g/cm{sup 2} and at sea level are made. The agreement between them is in general very good, greater than 90%. In order to check the accuracy of our calculations, a comparison between our solution and the simulated nucleon cascades is also made. (author)

  9. Cascaded face alignment via intimacy definition feature

    Science.gov (United States)

    Li, Hailiang; Lam, Kin-Man; Chiu, Man-Yau; Wu, Kangheng; Lei, Zhibin

    2017-09-01

    Recent years have witnessed the emerging popularity of regression-based face aligners, which directly learn mappings between facial appearance and shape-increment manifolds. We propose a random-forest based, cascaded regression model for face alignment by using a locally lightweight feature, namely intimacy definition feature. This feature is more discriminative than the pose-indexed feature, more efficient than the histogram of oriented gradients feature and the scale-invariant feature transform feature, and more compact than the local binary feature (LBF). Experimental validation of our algorithm shows that our approach achieves state-of-the-art performance when testing on some challenging datasets. Compared with the LBF-based algorithm, our method achieves about twice the speed, 20% improvement in terms of alignment accuracy and saves an order of magnitude on memory requirement.

  10. Cascade generation in Al laser induced plasma

    Science.gov (United States)

    Nagli, Lev; Gaft, Michael; Raichlin, Yosef; Gornushkin, Igor

    2018-05-01

    We found cascade IR generation in Al laser induced plasma. This generation includes doublet transitions 3s 25s 2S1/2 → 3s24p 2P1/2,3/2 → 3s24s 2S1/2; corresponding to strong lines at 2110 and 2117 nm, and much weaker lines at 1312-1315 nm. The 3s25s2S 1/2 starting IR generation level is directly pumped from the 3s23p 2P3/2 ground level. The starting level for UV generation at 396.2 nm (transitions 3s24s 2S1/2 → 4p 2P3/2) is populated due to the fast collisional processes in the plasma plume. These differences led to different time and special dependences on the lasing in the IR and UV spectral range within the aluminum laser induced plasma.

  11. Signal Words

    Science.gov (United States)

    SIGNAL WORDS TOPIC FACT SHEET NPIC fact sheets are designed to answer questions that are commonly asked by the ... making decisions about pesticide use. What are Signal Words? Signal words are found on pesticide product labels, ...

  12. Cascaded multiplexed optical link on a telecommunication network for frequency dissemination.

    Science.gov (United States)

    Lopez, Olivier; Haboucha, Adil; Kéfélian, Fabien; Jiang, Haifeng; Chanteau, Bruno; Roncin, Vincent; Chardonnet, Christian; Amy-Klein, Anne; Santarelli, Giorgio

    2010-08-02

    We demonstrate a cascaded optical link for ultrastable frequency dissemination comprised of two compensated links of 150 km and a repeater station. Each link includes 114 km of Internet fiber simultaneously carrying data traffic through a dense wavelength division multiplexing technology, and passes through two routing centers of the telecommunication network. The optical reference signal is inserted in and extracted from the communication network using bidirectional optical add-drop multiplexers. The repeater station operates autonomously ensuring noise compensation on the two links and the ultra-stable signal optical regeneration. The compensated link shows a fractional frequency instability of 3 x 10(-15) at one second measurement time and 5 x 10(-20) at 20 hours. This work paves the way to a wide dissemination of ultra-stable optical clock signals between distant laboratories via the Internet network.

  13. GPR17: Molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors

    Directory of Open Access Journals (Sweden)

    Ranghino Graziella

    2008-06-01

    Full Text Available Abstract Background GPR17 is a G-protein-coupled receptor located at intermediate phylogenetic position between two distinct receptor families: the P2Y and CysLT receptors for extracellular nucleotides and cysteinyl-LTs, respectively. We previously showed that GPR17 can indeed respond to both classes of endogenous ligands and to synthetic compounds active at the above receptor families, thus representing the first fully characterized non-peptide "hybrid" GPCR. In a rat brain focal ischemia model, the selective in vivo knock down of GPR17 by anti-sense technology or P2Y/CysLT antagonists reduced progression of ischemic damage, thus highlighting GPR17 as a novel therapeutic target for stroke. Elucidation of the structure of GPR17 and of ligand binding mechanisms are the necessary steps to obtain selective and potent drugs for this new potential target. On this basis, a 3-D molecular model of GPR17 embedded in a solvated phospholipid bilayer and refined by molecular dynamics simulations has been the first aim of this study. To explore the binding mode of the "purinergic" component of the receptor, the endogenous agonist UDP and two P2Y receptor antagonists demonstrated to be active on GPR17 (MRS2179 and cangrelor were then modeled on the receptor. Results Molecular dynamics simulations suggest that GPR17 nucleotide binding pocket is similar to that described for the other P2Y receptors, although only one of the three basic residues that have been typically involved in ligand recognition is conserved (Arg255. The binding pocket is enclosed between the helical bundle and covered at the top by EL2. Driving interactions are H-bonds and salt bridges between the 6.55 and 6.52 residues and the phosphate moieties of the ligands. An "accessory" binding site in a region formed by the EL2, EL3 and the Nt was also found. Conclusion Nucleotide binding to GPR17 occurs on the same receptor regions identified for already known P2Y receptors. Agonist

  14. Comparison of P2 purinergic receptors of aortic endothelial cells with those of adrenal medulla: evidence for heterogeneity of receptor subtype and of inositol phosphate response.

    Science.gov (United States)

    Allsup, D J; Boarder, M R

    1990-07-01

    Vascular endothelial cells from different parts of the circulation are known to show different functional responses, presumably corresponding to physiological roles. Previous studies have shown that ATP acts on P2 purinergic receptors of endothelial cells of major blood vessels, stimulating the formation of inositol phosphates. Here we have compared the action of ATP and congeners acting on endothelial cells of bovine thoracic aorta with cells derived from the microvasculature of bovine adrenal medulla. With measurement of total inositol phosphates, cells from the aorta showed a rank order of agonist potency of 2-methylthio-ATP greater than adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) greater than ADP greater than ATP greater than beta, gamma-imido-ATP greater than beta, gamma-methylene-ATP, consistent with action at receptors of the P2Y subtype. However, with adrenal cells the rank order of potency was ATP gamma S greater than ATP greater than beta, gamma-imido-ATP greater than ADP greater than beta, gamma-methylene-ATP = 2-methylthio-ATP. This profile is not consistent with either P2X or P2Y receptors. When the nature of this inositol phosphate response was analyzed with anion exchange chromatography, it was found that the aortic cells showed an inositol trisphosphate stimulation that peaked within a few seconds and rapidly declined, whereas the response of the adrenal medulla cells continued to rise through 5 min. Analysis of isomers of inositol phosphates revealed a different pattern of metabolism between the two cell types, which may account for the different time course of response. With adrenal cells, ATP at low micromolar concentrations caused a dose-dependent increase in levels of cyclic AMP and had a greater than additive effect on cyclic AMP levels when combined with submaximal stimulation by prostaglandin E2. These results suggest the presence of a P2Y receptor on aortic endothelial cells, with an 'atypical' purinocepter, i.e., neither P2X nor P2Y

  15. Effect of experimental diabetes on cholinergic, purinergic and peptidergic motor responses of the isolated rat bladder to electrical field stimulation or capsaicin.

    Science.gov (United States)

    Benkó, Rita; Lázár, Zsófia; Pórszász, Róbert; Somogyi, George T; Barthó, Loránd

    2003-09-30

    An attempt has been made to pharmacologically isolate cholinergic, P(2) purinoceptor-mediated and peptidergic (capsaicin-sensitive, tachykinin-mediated) contraction of the guanethidine-treated rat bladder detrusor preparation, in vitro. The effect of experimental diabetes was assessed on these types of contraction. Responses were evoked by electrical field stimulation (single shocks or 1 Hz for 30 s or 10 Hz for 40 s). Single shocks and 1-Hz stimulation were applied in the presence of (a). atropine (1 microM) or (b). P(2) purinoceptor antagonists (50 microM pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) [PPADS] plus 100 microM suramin. Long-term electrical field stimulation (10 Hz for 40 s) (c). was applied with both atropine and the P(2) purinoceptor antagonists present in the organ bath. The effects of capsaicin (d). and ATP (e). were also studied. Three groups of experimental animals were used: streptozotocin-treated (50 mg.kg(-1) i.p., 8 weeks before the experiment), parallel solvent-treated and untreated rats. (a). Responses to electrical field stimulation in the presence of atropine were reduced by half by PPADS plus suramin, but were resistant to capsaicin tachyphylaxis. They were enhanced in preparations taken from diabetic rats. (b). Contractions to electrical field stimulation in the presence of PPADS plus suramin were reduced by 2/3 by atropine, but were left unchanged by capsaicin or diabetes. (c). Contractions to long-term stimulation had a quick and a sustained phase. Especially the latter was inhibited by capsaicin tachypyhlaxis; it was also strongly reduced in preparations taken from diabetic rats. (d). Contractions to capsaicin (30 nM and 1 microM) were resistant to tetrodotoxin, strongly reduced by a combination of tachykinin NK(1) and NK(2) receptor antagonists, and slightly reduced in preparations from diabetic animals. Capsaicin (1 microM) had no acute inhibitory action on cholinergic or purinergic responses, nor did it cause relaxation

  16. Double closed-loop cascade control for lower limb exoskeleton with elastic actuation.

    Science.gov (United States)

    Zhu, Yanhe; Zheng, Tianjiao; Jin, Hongzhe; Yang, Jixing; Zhao, Jie

    2015-01-01

    Unlike traditional rigid actuators, the significant features of Series Elastic Actuator (SEA) are stable torque control, lower output impedance, impact resistance and energy storage. Recently, SEA has been applied in many exoskeletons. In such applications, a key issue is how to realize the human-exoskeleton movement coordination. In this paper, double closed-loop cascade control for lower limb exoskeleton with SEA is proposed. This control method consists of inner SEA torque loop and outer contact force loop. Utilizing the SEA torque control with a motor velocity loop, actuation performances of SEA are analyzed. An integrated exoskeleton control system is designed, in which joint angles are calculated by internal encoders and resolvers and contact forces are gathered by external pressure sensors. The double closed-loop cascade control model is established based on the feedback signals of internal and external sensor. Movement experiments are accomplished in our prototype of lower limb exoskeleton. Preliminary results indicate the exoskeleton movements with pilot can be realized stably by utilizing this double closed-loop cascade control method. Feasibility of the SEA in our exoskeleton robot and effectiveness of the control method are verified.

  17. System design description for the CPDF Cascade Control Room: SDD-7

    International Nuclear Information System (INIS)

    1980-05-01

    The Cascade Control Room (CCR) is the nerve center of the Centrifuge Plant Demonstration Facility (CPDF). The components within the CCR monitor and control those variables necessary for the safe and efficient operation of the cascade during normal and emergency operation. The CCR interfaces with all the process systems and most of the support systems, receiving and transmitting data signals at frequent intervals during all phases of cascade operation. The main component in the CCR is the control room computer (CRC), which serves as the primary interface between the CCR and the process and support systems. The other components in the CCR are: (1) instrumentation cabinets; (2) operator control panel; (3) mass spectrometer - tails (MST); (4) mass spectrometer - product (MSP); (5) product light gas analyzer (PLGA); and (6) the operator. CCR instrumentation provides audible and visual alarms of abnormal events detected by process and utilities instrumentation or by the CRC. Records of alarms and process and utility variables are continuously generated in the CCR. Operator control functions are performed through the CRC or at the various instrument cabinets. Analysis of the current operating status of the plant is aided by the CRC and CCR instrumentation. 14 figs., 2 tabs

  18. Simulated annealing of displacement cascades in FCC metals. 1. Beeler cascades

    International Nuclear Information System (INIS)

    Doran, D.G.; Burnett, R.A.

    1974-09-01

    An important source of damage to structural materials in fast reactors is the displacement of atoms from normal lattice sites. A high energy neutron may impart sufficient energy to an atom to initiate a displacement cascade consisting of a localized high density of hundreds of interstitials and vacancies. These defects subsequently interact to form clusters and to reduce their density by mutual annihilation. This short term annealing of an isolated cascade has been simulated at high and low temperatures using a correlated random walk model. The cascade representations used were developed by Beeler and the point defect properties were based on the model of γ-iron by Johnson. Low temperature anneals, characterized by no vacancy migration and a 104 site annihilation region (AR), resulted in 49 defect pairs at 20 keV and 11 pairs at 5 keV. High temperature anneals, characterized by both interstitial and vacancy migration and a 32 site AR, resulted in 68 pairs at 20 keV and 18 pairs at 5 keV when no cluster dissociation was permitted; most of the vacancies were in immobile clusters. These high temperature values dropped to 40 and 14 upon dissolution of the vacancy clusters. Parameter studies showed that, at a given temperature, the large AR resulted in about one-half as many defects as the small AR. Cluster size distributions and examples of spatial configurations are included. (U.S.)

  19. Optical feedback in dfb quantum cascade laser for mid-infrared cavity ring-down spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Terabayashi, Ryohei, E-mail: terabayashi.ryouhei@h.mbox.nagoya-u.ac.jp; Sonnenschein, Volker, E-mail: volker@nagoya-u.jp; Tomita, Hideki, E-mail: tomita@nagoya-u.jp; Hayashi, Noriyoshi, E-mail: hayashi.noriyoshi@h.mbox.nagoya-u.ac.jp; Kato, Shusuke, E-mail: katou.shuusuke@f.mbox.nagoya-u.ac.jp; Jin, Lei, E-mail: kin@nuee.nagoya-u.ac.jp; Yamanaka, Masahito, E-mail: yamanaka@nuee.nagoya-u.ac.jp; Nishizawa, Norihiko, E-mail: nishizawa@nuee.nagoya-u.ac.jp [Nagoya University, Department of Quantum Engineering, Graduate School of Engineering (Japan); Sato, Atsushi, E-mail: atsushi.sato@sekisui.com; Nozawa, Kohei, E-mail: kohei.nozawa@sekisui.com; Hashizume, Kenta, E-mail: kenta.hashizume@sekisui.com; Oh-hara, Toshinari, E-mail: toshinari.ohara@sekisui.com [Sekisui Medical Co., Ltd., Drug Development Solutions Center (Japan); Iguchi, Tetsuo, E-mail: t-iguchi@nucl.nagoya-u.ac.jp [Nagoya University, Department of Quantum Engineering, Graduate School of Engineering (Japan)

    2017-11-15

    A simple external optical feedback system has been applied to a distributed feedback quantum cascade laser (DFB QCL) for cavity ring-down spectroscopy (CRDS) and a clear effect of feedback was observed. A long external feedback path length of up to 4m can decrease the QCL linewidth to around 50kHz, which is of the order of the transmission linewidth of our high finesse ring-down cavity. The power spectral density of the transmission signal from high finesse cavity reveals that the noise at frequencies above 20kHz is reduced dramatically.

  20. Analytical Structuring of Periodic and Regular Cascading Solutions in Self-Pulsing Lasers

    Directory of Open Access Journals (Sweden)

    Belkacem Meziane

    2008-01-01

    Full Text Available A newly proposed strong harmonic-expansion method is applied to the laser-Lorenz equations to analytically construct a few typical solutions, including the first few expansions of the well-known period-doubling cascade that characterizes the system in its self-pulsing regime of operation. These solutions are shown to evolve in accordance with the driving frequency of the permanent solution that we recently reported to illustrate the system. The procedure amounts to analytically construct the signal Fourier transform by applying an iterative algorithm that reconstitutes the first few terms of its development.

  1. A 8X Oversampling Ratio, 14bit, 5-MSamples/s Cascade 3-1 Sigma-delta Modulator

    Directory of Open Access Journals (Sweden)

    Y. Yin

    2005-01-01

    Full Text Available A 14-b, 5-MHz output-rate cascaded 3-1 sigma-delta analog-to-digital converters (ADC has been developed for broadband communication applications, and a novel 4th-order noise-shaping is obtained by using the proposed architecture. At a low oversampling ratio (OSR of 8, the ADC achieves 91.5dB signal-to-quantization ratio (SQNR, in contrast to 71.8dB of traditional 2-1-1 cascaded sigma-delta ADC in 2.5-MHz bandwidth and over 80dB signal-to-noise and distortion (SINAD even under assumptions of awful circuit non-idealities and opamp non-linearity. The proposed architecture can potentially operates at much more high frequencies with scaled IC technology, to expand the analog-to-digital conversion rate for high-resolution applications.

  2. Wnt Signaling in Kidney Development and Disease.

    Science.gov (United States)

    Wang, Yongping; Zhou, Chengji J; Liu, Youhua

    2018-01-01

    Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Deregulation of Interferon Signaling in Malignant Cells

    Directory of Open Access Journals (Sweden)

    Leonidas C. Platanias

    2010-02-01

    Full Text Available Interferons (IFNs are a family of cytokines with potent antiproliferative, antiviral, and immunomodulatory properties. Much has been learned about IFNs and IFN-activated signaling cascades over the last 50 years. Due to their potent antitumor effects in vitro and in vivo, recombinant IFNs have been used extensively over the years, alone or in combination with other drugs, for the treatment of various malignancies. This review summarizes the current knowledge on IFN signaling components and pathways that are deregulated in human malignancies. The relevance of deregulation of IFN signaling pathways in defective innate immune surveillance and tumorigenesis are discussed.

  4. All-optical network coding for DPSK signals

    DEFF Research Database (Denmark)

    An, Yi; Da Ros, Francesco; Peucheret, Christophe

    2013-01-01

    All-optical network coding for path protection is experimentally demonstrated using four-wave mixing in SOAs for10 Gbit/s NRZ-DPSK signals with error free performance. The total power penalty after two cascaded XOR stage is only 2 dB.......All-optical network coding for path protection is experimentally demonstrated using four-wave mixing in SOAs for10 Gbit/s NRZ-DPSK signals with error free performance. The total power penalty after two cascaded XOR stage is only 2 dB....

  5. Energy and carbon balances of wood cascade chains

    Energy Technology Data Exchange (ETDEWEB)

    Sathre, Roger; Gustavsson, Leif [Ecotechnology, Mid Sweden University, SE-831 25 OEstersund (Sweden)

    2006-07-15

    In this study we analyze the energy and carbon balances of various cascade chains for recovered wood lumber. Post-recovery options include reuse as lumber, reprocessing as particleboard, pulping to form paper products, and burning for energy recovery. We compare energy and carbon balances of chains of cascaded products to the balances of products obtained from virgin wood fiber or from non-wood material. We describe and quantify several mechanisms through which cascading can affect the energy and carbon balances: direct cascade effects due to different properties and logistics of virgin and recovered materials, substitution effects due to the reduced demand for non-wood materials when wood is cascaded, and land use effects due to alternative possible land uses when less timber harvest is needed because of wood cascading. In some analyses we assume the forest is a limiting resource, and in others we include a fixed amount of forest land from which biomass can be harvested for use as material or biofuel. Energy and carbon balances take into account manufacturing processes, recovery and transportation energy, material recovery losses, and forest processes. We find that land use effects have the greatest impact on energy and carbon balances, followed by substitution effects, while direct cascade effects are relatively minor. (author)

  6. A thermal modelling of displacement cascades in uranium dioxide

    Energy Technology Data Exchange (ETDEWEB)

    Martin, G., E-mail: guillaume.martin@cea.fr [CEA – DEN/DEC/SESC/LLCC, Bât. 352, 13108 Saint-Paul-Lez-Durance Cedex (France); Garcia, P.; Sabathier, C. [CEA – DEN/DEC/SESC/LLCC, Bât. 352, 13108 Saint-Paul-Lez-Durance Cedex (France); Devynck, F.; Krack, M. [Laboratory for Reactor Physics and Systems Behaviour, Paul Scherrer Institute, CH-5232 Villigen PSI (Switzerland); Maillard, S. [CEA – DEN/DEC/SESC/LLCC, Bât. 352, 13108 Saint-Paul-Lez-Durance Cedex (France)

    2014-05-01

    The space and time dependent temperature distribution was studied in uranium dioxide during displacement cascades simulated by classical molecular dynamics (MD). The energy for each simulated radiation event ranged between 0.2 keV and 20 keV in cells at initial temperatures of 700 K or 1400 K. Spheres into which atomic velocities were rescaled (thermal spikes) have also been simulated by MD to simulate the thermal excitation induced by displacement cascades. Equipartition of energy was shown to occur in displacement cascades, half of the kinetic energy of the primary knock-on atom being converted after a few tenths of picoseconds into potential energy. The kinetic and potential parts of the system energy are however subjected to little variations during dedicated thermal spike simulations. This is probably due to the velocity rescaling process, which impacts a large number of atoms in this case and would drive the system away from a dynamical equilibrium. This result makes questionable MD simulations of thermal spikes carried out up to now (early 2014). The thermal history of cascades was compared to the heat equation solution of a punctual thermal excitation in UO{sub 2}. The maximum volume brought to a temperature above the melting temperature during the simulated cascade events is well reproduced by this simple model. This volume eventually constitutes a relevant estimate of the volume affected by a displacement cascade in UO{sub 2}. This definition of the cascade volume could also make sense in other materials, like iron.

  7. Cascade fuzzy control for gas engine driven heat pump

    International Nuclear Information System (INIS)

    Li Shuze; Zhang Wugao; Zhang Rongrong; Lv Dexu; Huang Zhen

    2005-01-01

    In addition to absorption chillers, today's gas cooling technology includes gas engine driven heat pump systems (GEHP) in a range of capacities and temperature capacities suitable for most commercial air conditioning and refrigeration applications. Much is expected from GEHPs as a product that would help satisfy the air conditioning system demand from medium and small sized buildings, restrict electric power demand peaks in summer and save energy in general. This article describes a kind of control strategy for a GEHP, a cascade fuzzy control. GEHPs have large and varying time constants and their dynamic modeling cannot be easily achieved. A cascade control strategy is effective for systems that have large time constants and disturbances, and a fuzzy control strategy is fit for a system that lacks an accurate model. This cascade fuzzy control structure brings together the best merits of fuzzy control and cascade control structures. The performance of the cascade fuzzy control is compared to that of a cascade PI (proportional and integral) control strategy, and it is shown by example that the cascade fuzzy control strategy gives a better performance, reduced reaction time and smaller overshoot temperature

  8. Phase locking of a 3.4 THz third-order distributed feedback quantum cascade laser using a room-temperature superlattice harmonic mixer

    NARCIS (Netherlands)

    Hayton, D. J.; Khudchencko, A.; Pavelyev, D. G.; Hovenier, J. N.; Baryshev, A.; Gao, J. R.; Kao, T. Y.; Hu, Q.; Reno, J. L.; Vaks, V.

    2013-01-01

    We report on the phase locking of a 3.4 THz third-order distributed feedback quantum cascade laser (QCL) using a room temperature GaAs/AlAs superlattice diode as both a frequency multiplier and an internal harmonic mixer. A signal-to-noise level of 60 dB is observed in the intermediate frequency

  9. Phase locking of a 3.4 THz third-order distributed feedback quantum cascade laser using a room-temperature superlattice harmonic mixer

    NARCIS (Netherlands)

    Hayton, D.J.; Khudchenko, A.; Pavelyev, D.G.; Hovenier, J.N.; Baryshev, A.; Gao, J.R.; Kao, T.Y.; Hu, Q.; Reno, J.L.; Vaks, V.

    2013-01-01

    We report on the phase locking of a 3.4 THz third-order distributed feedback quantum cascade laser (QCL) using a room temperature GaAs/AlAs superlattice diode as both a frequency multiplier and an internal harmonic mixer. A signal-to-noise level of 60?dB is observed in the intermediate frequency

  10. Tunable All-Optical Wavelength Conversion Based on Cascaded SHG/DFG in a Ti:PPLN Waveguide Using a Single CW Control Laser

    DEFF Research Database (Denmark)

    Hu, Hao; Nouroozi, Rahman; Wang, Wenrui

    2012-01-01

    Tunable all-optical wavelength conversion (AOWC) of a 40-Gb/s RZ-OOK data signal based on cascaded second-harmonic generation (SHG) and difference-frequency generation (DFG) in a Ti:PPLN waveguide is demonstrated. Error-free performances with negligible power penalty are achieved for the wavelength...

  11. Cascade multiplicity inside deuteron in Π d high energy collisions

    International Nuclear Information System (INIS)

    Kisielewska, D.

    1983-01-01

    Multiplicity distribution of double scattering events is analysed using the additive quark model including the cascading effect. The mean multiplicity of particles produced in the process of cascading estimated for Π d experiments at 100, 205 and 360 GeV/c is equal to 1.15 ± .31. This value does not depend on the momentum of the incident pion. Some indications are found that the probability of cascading depends on multiplicity of the collision with the first nucleon and is smaller for low multiplicities. (author)

  12. Criticality safety study of shutdown diffusion cascade coolers

    International Nuclear Information System (INIS)

    Paschal, L.S.; Basoglu, B.; Bentley, C.L.; Dunn, M.E.

    1996-01-01

    Gaseous diffusion plants use cascade coolers in the production of highly enriched uranium (HEU) to remove heat from the enriched stream of UF 6 . The cascade coolers operate like shell and tube heat exchangers with the UF 6 on the shell side and Freon on the tube side. Recirculating cooling water (RCW) in condensers is used to cool the Freon. A criticality safety analysis was previously performed for cascade coolers during normal operation. The purpose of this paper is to evaluate several different hypothetical accidents regarding RCW ingress into the cooler to determine whether criticality safety concerns exist

  13. Increasing sensitivity of MOS dosemeters in cascade connection

    International Nuclear Information System (INIS)

    Vychytil, F.; Cechak, T.; Gerndt, J.; Petr, I.

    1978-01-01

    The possibilities of increasing the sensitivity of MOS transistors in their cascade connection were studied theoretically and experimentally. The measurements confirmed the presumption that the instability of cascade-connected MOS transistors increased with the square of the number of transistors in the system. This allows systems to be formed with different sensitivity to ionizing radiation by encasing 10 to 10 4 transistors connected in cascade, which is technologically feasible. The procedure is also acceptable from the point of view of cost. (Z.M.)

  14. Revised tephra volumes for Cascade Range volcanoes

    Science.gov (United States)

    Nathenson, Manuel

    2017-01-01

    Isopach maps from tephra eruptions from Mount St. Helens were reported in Carey et al. (1995) and for tephra eruptions from Glacier Peak in Gardner et al. (1998). For exponential thinning, the isopach data only define a single slope on a log thickness versus square root of area plot. Carey et al. (1995) proposed a model that was used to estimate a second slope, and volumes were presented in both studies using this model. A study by Sulpizio (2005) for estimating the second slope and square root of area where the lines intersect involves a systematic analysis of many eruptions to provide correlation equations. The purpose of this paper is to recalculate the volumes of Cascades eruptions and compare results from the two methods. In order to gain some perspective on the methods for estimating the second slope, we use data for thickness versus distance beyond the last isopach that are available for some of the larger eruptions in the Cascades. The thickness versus square root of area method is extended to thickness versus distance by developing an approximate relation between the two assuming elliptical isopachs with the source at one of the foci. Based on the comparisons made between the Carey et al. (1995) and Sulpizio (2005) methods, it is felt that the later method provides a better estimate of the second slope. For Mount St. Helens, the estimates of total volume using the Sulpizio (2005) method are generally smaller than those using the Carey et al. (1995) method. For the volume estimates of Carey et al. (1995), the volume of the May 18, 1980, eruption of Mount St. Helens is smaller than six of the eight previous eruptions. With the new volumes using the Sulpizio (2005) method, the 1980 eruption is smaller in volume than the upper end of the range for only three of the layers (Wn, Ye, and Yn) and is the same size as layer We. Thus the 1980 eruption becomes representative of the mid-range of volumes rather than being in the lower range.

  15. GEFs: Dual regulation of Rac1 signaling.

    Science.gov (United States)

    Marei, Hadir; Malliri, Angeliki

    2017-04-03

    GEFs play a critical role in regulating Rac1 signaling. They serve as signaling nodes converting upstream signals into downstream Rac1-driven cellular responses. Through associating with membrane-bound Rac1, GEFs facilitate the exchange of GDP for GTP, thereby activating Rac1. As a result, Rac1 undergoes conformational changes that mediate its interaction with downstream effectors, linking Rac1 to a multitude of physiological and pathological processes. Interestingly, there are at least 20 GEFs involved in Rac1 activation, suggesting a more complex role of GEFs in regulating Rac1 signaling apart from promoting the exchange of GDP for GTP. Indeed, accumulating evidence implicates GEFs in directing the specificity of Rac1-driven signaling cascades, although the underlying mechanisms were poorly defined. Recently, through conducting a comparative study, we highlighted the role of 2 Rac-specific GEFs, Tiam1 and P-Rex1, in dictating the biological outcome downstream of Rac1. Importantly, further proteomic analysis uncovered a GEF activity-independent function for both GEFs in modulating the Rac1 interactome, which results in the stimulation of GEF-specific signaling cascades. Here, we provide an overview of our recent findings and discuss the role of GEFs as master regulators of Rac1 signaling with a particular focus on GEF-mediated modulation of cell migration following Rac1 activation.

  16. Mode structure of a quantum cascade laser

    Science.gov (United States)

    Bogdanov, A. A.; Suris, R. A.

    2011-03-01

    We analyze the mode structure of a quantum cascade laser (QCL) cavity considering the surface plasmon-polariton modes and familiar modes of hollow resonator jointly, within a single model. We present a comprehensive mode structure analysis of the laser cavity, varying its geometric parameters and free electron concentration inside cavity layers within a wide range. Our analysis covers, in particular, the cases of metal-insulator-metal and insulator-metal-insulator waveguides. We discuss the phenomenon of negative dispersion for eigenmodes in detail and explain the nature of this phenomenon. We specify a waveguide parameters domain in which negative dispersion exists. The mode structure of QCL cavity is considered in the case of the anisotropic electrical properties of the waveguide materials. We show that anisotropy of the waveguide core results in propagation of Langmuir modes that are degenerated in the case of the isotropic core. Comparative analysis of optical losses due to free carrier absorption is presented for different modes within the frequency range from terahertz to ultraviolet frequencies.

  17. MCDF calculations of Auger cascade processes

    Science.gov (United States)

    Beerwerth, Randolf; Fritzsche, Stephan

    2017-10-01

    We model the multiple ionization of near-neutral core-excited atoms where a cascade of Auger processes leads to the emission of several electrons. We utilize the multiconfiguration Dirac-Fock (MCDF) method to generate approximate wave functions for all fine-structure levels and to account for all decays between them. This approach allows to compute electron spectra, the population of final-states and ion yields, that are accessible in many experiments. Furthermore, our approach is based on the configuration interaction method. A careful treatment of correlation between electronic configurations enables one to model three-electron processes such as an Auger decay that is accompanied by an additional shake-up transition. Here, this model is applied to the triple ionization of atomic cadmium, where we show that the decay of inner-shell 4p holes to triply-charged final states is purely due to the shake-up transition of valence 5s electrons. Contribution to the Topical Issue "Atomic and Molecular Data and their Applications", edited by Gordon W.F. Drake, Jung-Sik Yoon, Daiji Kato, Grzegorz Karwasz.

  18. Feeding supermassive black holes by collisional cascades

    Science.gov (United States)

    Faber, Christian; Dehnen, Walter

    2018-05-01

    The processes driving gas accretion on to supermassive black holes (SMBHs) are still poorly understood. Angular momentum conservation prevents gas within ˜10 pc of the black hole from reaching radii ˜10-3 pc where viscous accretion becomes efficient. Here we present simulations of the collapse of a clumpy shell of swept-up isothermal gas, which is assumed to have formed as a result of feedback from a previous episode of AGN activity. The gas falls towards the SMBH forming clumps and streams, which intersect, collide, and often form a disc. These collisions promote partial cancellations of angular momenta, resulting in further infall and more collisions. This continued collisional cascade generates a tail of gas with sufficiently small angular momenta and provides a viable route for gas inflow to sub-parsec scales. The efficiency of this process hardly depends on details, such as gas temperature, initial virial ratio and power spectrum of the gas distribution, as long as it is not strongly rotating. Adding star formation to this picture might explain the near-simultaneous formation of the S-stars (from tidally disrupted binaries formed in plunging gas streams) and the sub-parsec young stellar disc around Sgr A⋆.

  19. Depression: An Immuno-Inflammatory Cascade

    Directory of Open Access Journals (Sweden)

    Vivek Sharma

    2016-06-01

    Full Text Available Major depressive disorder also known as clinical depression, unipolar depression or depression is associated with significant morbidity, mortality, high suicidal tendencies and deaths. Preclinical and clinical studies suggest that psychiatric illnesses like MDD, are associated with inflammatory processes. While it is unlikely that major depressive disorder is a primary and lsquo;inflammatory' disorder, there is now evidence to suggest that inflammation play a subtle role in the pathophysiology of major depressive disorder. The inflammation in depression cascade pin points to the origin from immune hyperactivity and thus a new theory that explains role of immune system mediated inflammation has been accepted and researched upon. widely. This theory states that depression is accompanied by altered immune function and activation of the inflammatory response system. This theory is strengthened form the fact that the current therapeutic options which mainly target neurotransmitters, are not effective in many patients and these patients has been found to be associated with elevated levels of inflammatory mediators specifically cytokines. It is reported more recently that other risk factors for depression, including psychosocial stress, psychological trauma, sleep disturbance and pain, also increases inflammatory processes. Thus the intervention in the immune system originated from inflammatory cytokines seems a therapeutically viable option in the field of depression research. [Archives Medical Review Journal 2016; 25(2.000: 223-240

  20. Dissipation range turbulent cascades in plasmas

    International Nuclear Information System (INIS)

    Terry, P. W.; Almagri, A. F.; Forest, C. B.; Nornberg, M. D.; Rahbarnia, K.; Sarff, J. S.; Fiksel, G.; Hatch, D. R.; Jenko, F.; Prager, S. C.; Ren, Y.

    2012-01-01

    Dissipation range cascades in plasma turbulence are described and spectra are formulated from the scaled attenuation in wavenumber space of the spectral energy transfer rate. This yields spectra characterized by the product of a power law and exponential fall-off, applicable to all scales. Spectral indices of the power law and exponential fall-off depend on the scaling of the dissipation, the strength of the nonlinearity, and nonlocal effects when dissipation rates of multiple fluctuation fields are different. The theory is used to derive spectra for MHD turbulence with magnetic Prandtl number greater than unity, extending previous work. The theory is also applied to generic plasma turbulence by considering the spectrum from damping with arbitrary wavenumber scaling. The latter is relevant to ion temperature gradient turbulence modeled by gyrokinetics. The spectrum in this case has an exponential component that becomes weaker at small scale, giving a power law asymptotically. Results from the theory are compared to three very different types of turbulence. These include the magnetic plasma turbulence of the Madison Symmetric Torus, the MHD turbulence of liquid metal in the Madison Dynamo Experiment, and gyrokinetic simulation of ion temperature gradient turbulence.