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Sample records for dual inhibitory action

  1. Identification of a tsetse fly salivary protein with dual inhibitory action on human platelet aggregation.

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    Guy Caljon

    Full Text Available BACKGROUND: Tsetse flies (Glossina sp., the African trypanosome vectors, rely on anti-hemostatic compounds for efficient blood feeding. Despite their medical importance, very few salivary proteins have been characterized and functionally annotated. METHODOLOGY/PRINCIPAL FINDINGS: Here we report on the functional characterisation of a 5'nucleotidase-related (5'Nuc saliva protein of the tsetse fly Glossina morsitans morsitans. This protein is encoded by a 1668 bp cDNA corresponding at the genomic level with a single-copy 4 kb gene that is exclusively transcribed in the tsetse salivary gland tissue. The encoded 5'Nuc protein is a soluble 65 kDa glycosylated compound of tsetse saliva with a dual anti-hemostatic action that relies on its combined apyrase activity and fibrinogen receptor (GPIIb/IIIa antagonistic properties. Experimental evidence is based on the biochemical and functional characterization of recombinant protein and on the successful silencing of the 5'nuc translation in the salivary gland by RNA interference (RNAi. Refolding of a 5'Nuc/SUMO-fusion protein yielded an active apyrase enzyme with K(m and V(max values of 43+/-4 microM and 684+/-49 nmol Pi/min xmg for ATPase and 49+/-11 microM and 177+/-37 nmol Pi/min xmg for the ADPase activity. In addition, recombinant 5'Nuc was found to bind to GPIIb/IIIa with an apparent K(D of 92+/-25 nM. Consistent with these features, 5'Nuc potently inhibited ADP-induced thrombocyte aggregation and even caused disaggregation of ADP-triggered human platelets. The importance of 5'Nuc for the tsetse fly hematophagy was further illustrated by specific RNAi that reduced the anti-thrombotic activities in saliva by approximately 50% resulting in a disturbed blood feeding process. CONCLUSIONS/SIGNIFICANCE: These data show that this 5'nucleotidase-related apyrase exhibits GPIIb/IIIa antagonistic properties and represents a key thromboregulatory compound of tsetse fly saliva.

  2. Action potential initiation in neocortical inhibitory interneurons.

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    Tun Li

    2014-09-01

    Full Text Available Action potential (AP generation in inhibitory interneurons is critical for cortical excitation-inhibition balance and information processing. However, it remains unclear what determines AP initiation in different interneurons. We focused on two predominant interneuron types in neocortex: parvalbumin (PV- and somatostatin (SST-expressing neurons. Patch-clamp recording from mouse prefrontal cortical slices showed that axonal but not somatic Na+ channels exhibit different voltage-dependent properties. The minimal activation voltage of axonal channels in SST was substantially higher (∼7 mV than in PV cells, consistent with differences in AP thresholds. A more mixed distribution of high- and low-threshold channel subtypes at the axon initial segment (AIS of SST cells may lead to these differences. Surprisingly, NaV1.2 was found accumulated at AIS of SST but not PV cells; reducing NaV1.2-mediated currents in interneurons promoted recurrent network activity. Together, our results reveal the molecular identity of axonal Na+ channels in interneurons and their contribution to AP generation and regulation of network activity.

  3. First Order Actions for New Massive Dual Gravities

    CERN Document Server

    Bracho, Alexangel

    2013-01-01

    We present a first order formulation for the fourth order action of the new massive dual gravity in four dimensions. This proposal is easily generalized to arbitrary dimension. Also, we obtain the dual actions for massless and massive Curtright fields in D dimensions.

  4. Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities

    Science.gov (United States)

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; Flockhart, David A.; Cushman, Mark

    2015-01-01

    Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer. PMID:25751283

  5. Dual inhibitory effect of Glycyrrhiza glabra (GutGard™) on COX and LOX products.

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    Chandrasekaran, C V; Deepak, H B; Thiyagarajan, P; Kathiresan, S; Sangli, Gopal Krishna; Deepak, M; Agarwal, Amit

    2011-02-15

    Glycyrrhiza glabra and its phytoconstituents have been known to possess widespread pharmacological properties as an anti-inflammatory, anti-viral, antitumour and hepatoprotective drug. In this study, we examined the inhibitory potential of extract of G. glabra (GutGard™) root and its phytoconstituents (glabridin, glycyrrhizin, and isoliquiritigenin) on both cyclooxygenase (COX) and lipoxygenase (LOX) products in order to understand the mechanism of its anti-inflammatory action. Inhibitory effect of GutGard™ and its phytoconstituents on lipopolysaccharide (LPS) induced prostaglandin E(2) (PGE(2)), calcimycin (A23187) induced thromboxane (TXB(2)), and leukotriene (LTB(4)) release was studied using murine macrophages (J774A.1) and human neutrophil (HL-60) cells. Results revealed that, G. glabra and glabridin significantly inhibited PGE(2), TXB(2) (COX) and LTB(4) (LOX), while, isoliquiritigenin exerted inhibitory effect only against COX products but failed to suppress LOX product. However, glycyrrhizin at the tested concentrations failed to exhibit inhibitory effect on both COX and LOX products. Here, we report for the first time that G. glabra (almost devoid of glycyrrhizin) exhibits anti-inflammatory property likely through the inhibition of PGE(2), TXB(2) and LTB(4) in mammalian cell assay system, which could be influenced in part by glabridin and isoliquiritigenin.

  6. Nanoformulated cell-penetrating survivin mutant and its dual actions

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    Sriramoju B

    2014-07-01

    Full Text Available Bhasker Sriramoju, Rupinder K Kanwar, Jagat R Kanwar Nanomedicine Laboratory of Immunology and Molecular Biomedical Research (NLIMBR, School of Medicine, Faculty of Health, Deakin University, Geelong, Australia Abstract: In this study, we investigated the differential actions of a dominant-negative survivin mutant (SurR9-C84A against cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons. In both the cases, the mutant protein displayed dual actions, where its effects were cytotoxic toward cancerous cells and proliferative toward the differentiated neurons. This can be explained by the fact that tumorous (undifferentiated SK-N-SH cells have a high endogenous survivin pool and upon treatment with mutant SuR9-C84A causes forceful survivin expression. These events significantly lowered the microtubule dynamics and stability, eventually leading to apoptosis. In the case of differentiated SK-N-SH neurons that express negligible levels of wild-type survivin, the mutant indistinguishably behaved in a wild-type fashion. It also favored cell-cycle progression, forming the chromosome-passenger complex, and stabilized the microtubule-organizing center. Therefore, mutant SurR9-C84A represents a novel therapeutic with its dual actions (cytotoxic toward tumor cells and protective and proliferative toward neuronal cells, and hence finds potential applications against a variety of neurological disorders. In this study, we also developed a novel poly(lactic-co-glycolic acid nanoparticulate formulation to surmount the hurdles associated with the delivery of SurR9-C84A, thus enhancing its effective therapeutic outcome. Keywords: survivin mutant, neurological disorders, protein therapeutics, inhibitor of apoptosis protein family, poly(lactic-co-glycolic acid

  7. Inhibitory action of docetaxel on the proliferation of HeLa and SiHa cells

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Objective To study the inhibitory action of docetaxel(DOC)on the proliferation of HeLa and SiHa cells.Methods Cell morphological changes were observed with inverted phase contrast microscope.MTT was adopted to test and calculate the cell inhibition ratio.Flow cytometry was used to detect cell cycle.Results DOC had an obvious concentration-dependent inhibitory effect on the proliferation of both HeLa and SiHa cells.The inhibition ratio of DOC on SiHa was significantly higher than that on HeLa(P<0.05).DOC blo...

  8. Investigating a Potential Auxin-Related Mode of Hormetic/Inhibitory Action of the Phytotoxin Parthenin.

    Science.gov (United States)

    Belz, Regina G

    2016-01-01

    Parthenin is a metabolite of Parthenium hysterophorus and is believed to contribute to the weed's invasiveness via allelopathy. Despite the potential of parthenin to suppress competitors, low doses stimulate plant growth. This biphasic action was hypothesized to be auxin-like and, therefore, an auxin-related mode of parthenin action was investigated using two approaches: joint action experiments with Lactuca sativa, and dose-response experiments with auxin/antiauxin-resistant Arabidopsis thaliana genotypes. The joint action approach comprised binary mixtures of subinhibitory doses of the auxin 3-indoleacetic acid (IAA) mixed with parthenin or one of three reference compounds [indole-3-butyric acid (IBA), 2,3,5-triiodobenzoic acid (TIBA), 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB)]. The reference compounds significantly interacted with IAA at all doses, but parthenin interacted only at low doses indicating that parthenin hormesis may be auxin-related, in contrast to its inhibitory action. The genetic approach investigated the response of four auxin/antiauxin-resistant mutants and a wildtype to parthenin or two reference compounds (IAA, PCIB). The responses of mutant plants to the reference compounds confirmed previous reports, but differed from the responses observed for parthenin. Parthenin stimulated and inhibited all mutants independent of resistance. This provided no indication for an auxin-related action of parthenin. Therefore, the hypothesis of an auxin-related inhibitory action of parthenin was rejected in two independent experimental approaches, while the hypothesis of an auxin-related stimulatory effect could not be rejected.

  9. Compound dual radiation action theory for 252Cf brachytherapy.

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    Wang, C K; Zhang, X

    2004-01-01

    The existing dosimetry protocol that uses the concept of RBE for 252Cf brachytherapy contains large uncertainties. A new formula has been developed to correlate the biological effect (i.e. cell survival fraction) resulting from a mixed n + gamma radiation field with two physical quantities and two biological quantities. The formula is based on a pathway model evolved from that of the compound-dual-radiation-action (CDRA) theory, previously proposed by Rossi and Zaider. The new model employs the recently published data on radiation-induced DNA lesions. The new formula is capable of predicting quantitatively the synergistic effect caused by the interactions between neutron events and gamma ray events, and it is intended to be included into a new dosimetry protocol for future 252Cf brachytherapy.

  10. A dual inhibitory mechanism sufficient to maintain cell cycle restricted CENP-A assembly

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    Stankovic, Ana; Guo, Lucie Y.; Mata, João F.; Bodor, Dani L.; Cao, Xing-Jun; Bailey, Aaron O.; Shabanowitz, Jeffrey; Hunt, Donald F.; Garcia, Benjamin A.; Black, Ben E.; Jansen, Lars E.T

    2017-01-01

    Summary Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, mediating specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues, results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A. PMID:28017591

  11. The effect of somatostatin on release and insulinotropic action of gastric inhibitory polypeptide.

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    Pederson, R A; Dryburgh, J R; Brown, J C

    1975-12-01

    Studies were carried out in conscious dogs in which the effect of intravenous somatostatin on immunoreactive gastric inhibitory polypeptide (IR-GIP) release was investigated. In addition, the inhibitory action of somatostatin on the insulin response to pure porcine GIP was assessed. Intravenous administration of somatostatin resulted in a delayed IR-GIP and immunoreactive insulin (IRI) response to oral glucose. Somatostatin also delayed the IR-GIP response to the ingestion of fat. In both types of experiments, initial depression of IRI levels was followed by a sharp rise in IRI release. Intravenous infusion of somatostatin produced 80% inhibition of the IRI response to pure porcine GIP. It was concluded that somatostatin inhibits the physiological release of IR-GIP and the insulinotropic action of exogenous porcine GIP.

  12. Excitatory and inhibitory actions of isoflurane on the cholinergic ascending arousal system of the rat.

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    Dong, Hai-Long; Fukuda, Satoru; Murata, Eri; Higuchi, Takashi

    2006-01-01

    The cholinergic arousal systems are known to critically regulate the state of consciousness. The aim of this study was to determine the effect of isoflurane on the inhibitory or excitatory neurotransmitters efflux in important nuclei within the cholinergic arousal system using in vivo intracerebral microdialysis. The efflux of glutamate, gamma-aminobutyric acid (GABA), or acetylcholine in the posterior hypothalamus (PH), the basal forebrain (BF), and the somatosensory cortex (S1BF) of rats was detected using intracerebral microdialysis under an awake condition and at 0.5-2.0 minimum alveolar concentration (MAC) isoflurane anesthesia. The intrabasalis perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate on the cortical acetylcholine effluxes was also examined under both conditions. Isoflurane had no influence on the glutamate and GABA efflux in the PH, whereas in the BF, it dose-dependently increased glutamate efflux and decreased GABA efflux. A transient increase in glutamate efflux at 1.0 MAC and a decrease in GABA at 0.5-1.5 MAC were observed in the S1BF. Isoflurane dose-dependently decreased acetylcholine efflux in the S1BF. Perfusion of the BF with AMPA increased acetylcholine efflux in the S1BF with electroencephalographic activation during 0.75 MAC isoflurane anesthesia, suggesting an inhibitory action of isoflurane on AMPA receptors in the BF. However, N-methyl-D-aspartate had no effect on these parameters. Isoflurane induces both excitatory and inhibitory actions in the cholinergic arousal system. The predominant inhibitory action of isoflurane over its excitatory action at the BF would result in the decrease in the acetylcholine efflux in the S1BF.

  13. DUAL THEORY OF ACTION IONIZING RADIATION AND SPONTANEOUS CANCER

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    A. T. Gubin

    2015-01-01

    Full Text Available A mathematical model for radiogenic increasing of mortality was proposed, taking into account spontaneous background damages of the genetic material, that always occur in cells due to the influence of non-radiation internal and environmental factors. The model is based on the representation of indistinguishability between radiogenic andspontaneous cancers and on the postulates of the Kellerer-Rossi dual action theory. It was proposed that duringformation of premalignant damages dual interactions occur both between primary radiation damages, and betweenradiation and spontaneous primary damages (hybrid interactions. The role of the latter is particularly important at low levels exposure that corresponds to a linear dependence of cancer incidence on dose. Their significance is indicated by the following factor: at the adopted value of the nominal (radiation risk factor (0,05 Sv-1 and cancer mortality share among the population (0,15–0,2, the contribution of non-radiative carcinogenic factors for the total life is equivalent to radiation dose of 3–4 Sv or radiation at a constant dose rate of 40–50 mSv / year.The model assumes formation in DNA of both spaced apart (single damages with high probability of recovery, and nearby (double damages, which are more likely to interact, entering into the permanent state. Permanent damages being formed in certain portions of DNA can be inherited to daughter cells as premalignant defects. The relative role of spontaneous primary damages is greater the more single damages are formed as compared to double ones within the area of potential interaction.It was shown within this model that the presence of background cancer mortality for initial and finite population in the used by ICRP expression for interpopulation risk transfer has logical and biophysical justifications. Accounting of spontaneous primary damages and hybrid interactions enhances the capabilities for development of radiation risk models.

  14. Inhibitory action of sphingosine, sphinganine and dexamethasone on glucose uptake: Studies with hydrogen peroxide and phorbol ester

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    Murray, D.K.; Hill, M.E.; Nelson, D.H. (Univ. of Utah School of Medicine, Salt Lake City (USA))

    1990-01-01

    The mechanism of the inhibitory action of glucocorticoids on glucose uptake is incompletely understood. Treatment with corticosteriods of cells in which glucose uptake is stimulated at insulin postbinding and postreceptor sites may clarify the site of the steroid inhibitory action. Hydrogen peroxide, which has been shown to stimulate the insulin receptor tyrosine kinase, and phorbol myristate acetate (PMA) which stimulates protein kinase C were, therefore, used as stimulators of glucose transport in this study. These studies demonstrate that dexamethasone and the sphingoid bases, sphinganine and sphingosine, inhibit glucose uptake that has been stimulated at either the receptor kinase or protein kinase C level in both 3T3-L1 and 3T3-C2 cells. These data confirm glucocorticoid inhibitory action at a post binding level and support the suggestion that some corticosteriod inhibitory effects may be mediated by an action on sphingolipid metabolism.

  15. An investigation on the inhibitory action of benzazole derivatives as a consequence of sulfur atom induction

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    Moradi, Z.; Attar, M.M., E-mail: attar@aut.ac.ir

    2014-10-30

    Highlights: • The inhibitory behavior of three benzazole based molecules was studied. • Weight loss and EIS technique revealed a marked difference between three molecules’ potential inhibitory actions, although having the same adsorption isotherm. • AFM and contact angle measurements showed a decrease in roughness and hydrophillicity as a result of introducing sulfur which was related to better adsorption of the molecule and formation of more integrated inhibitor film. • The most constant results was obtained by HF method with 6-31G (d,p) basis set in water medium. - Abstract: The inhibitory action of three benzazole based molecules namely 2-methyl benzimidazole (2-MBI), 2-methyl benzothiazole (2-MBT) and 2-mercapto benzthiazole (2-SHBT) in 1 M HCl solution was studied by gravimetric analysis and electrochemical impedance spectroscopy (EIS). Results showed that the inhibitor adsorption on the iron surface was according to Langmuir adsorption isotherm for 2-MBI and 2-MBT and Flory Huggins Isotherm for 2-SHBT. Surface roughness obtained by Atomic Forced Microscopy (AFM) revealed that a good inhibitor decreases the surface roughness significantly which can be related to the formation of more integrated molecular film of inhibitor on steel surface. Based on contact angle (CA) measurements as the efficiency of the inhibitor molecules improve the hydrophobicity increases. These three molecules were chosen to see the effect of introducing sulfur atom into the structure the main effect of which would be on electronic parameters. To better understand this effect, the quantum chemical descriptors including: E{sub HOMO}, E{sub LUMO}, energy gap (ΔE), dipole moment (μ), hardness (η), softness (σ), electronegativity index (χ), fraction of electrons transferred (ΔN), that are most relevant to the potential action of a molecule as corrosion inhibitor, have been calculated in water and vacuum. Electronic parameters of these three inhibitors have been studied using

  16. Testosterone and the Male Skeleton: A Dual Mode of Action

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    Mieke Sinnesael

    2011-01-01

    Full Text Available Testosterone is an important hormone for both bone gain and maintenance in men. Hypogonadal men have accelerated bone turnover and increased fracture risk. In these men, administration of testosterone inhibits bone resorption and maintains bone mass. Testosterone, however, is converted into estradiol via aromatization in many tissues including male bone. The importance of estrogen receptor alpha activation as well of aromatization of androgens into estrogens was highlighted by a number of cases of men suffering from an inactivating mutation in the estrogen receptor alpha or in the aromatase enzyme. All these men typically had low bone mass, high bone turnover and open epiphyses. In line with these findings, cohort studies have confirmed that estradiol contributes to the maintenance of bone mass after reaching peak bone mass, with an association between estradiol and fractures in elderly men. Recent studies in knock-out mice have increased our understanding of the role of androgens and estrogens in different bone compartments. Estrogen receptor activation, but not androgen receptor activation, is involved in the regulation of male longitudinal appendicular skeletal growth in mice. Both the androgen and the estrogen receptor can independently mediate the cancellous bone-sparing effects of sex steroids in male mice. Selective KO studies of the androgen receptor in osteoblasts in male mice suggest that the osteoblast in the target cell for androgen receptor mediated maintenance of trabecular bone volume and coordination of bone matrix synthesis and mineralization. Taken together, both human and animal studies suggest that testosterone has a dual mode of action on different bone surfaces with involvement of both the androgen and estrogen receptor.

  17. Acting in solidarity : Testing an extended dual pathway model of collective action by bystander group members

    NARCIS (Netherlands)

    Saab, Rim; Tausch, Nicole; Spears, Russell; Cheung, Wing-Yee

    2015-01-01

    We examined predictors of collective action among bystander group members in solidarity with a disadvantaged group by extending the dual pathway model of collective action, which proposes one efficacy-based and one emotion-based path to collective action (Van Zomeren, Spears, Fischer, & Leach, 2004)

  18. [Inhibitory action of peruvoside and neriifolin on Na+, K(+)-ATPase].

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    Ye, Y X; Yang, X R

    1990-11-01

    Effects of peruvoside and neriifolin, main components of neriperside, a tevetoside extracted from Thevitia neriifolia Juss, on Na+, K(+)-ATPase activities and on [3H] ouabain binding to the Na+, K(+)-ATPase isolated from hearts of guinea pigs, dogs and cats and kidneys of guinea pigs and cats were compared with digoxin and ouabain. It was found that peruvoside and neriifolin inhibited Na+, K(+)-ATPase activities and they showed a strong competitive inhibition on [3H] ouabain binding to the enzymes isolated from various tissues. A marked species difference existed as great as that of digitalis. The mechanism of action of these 2 drugs may be similar to that of digitalis. Their inhibitory effects on the enzyme activity were stronger than their positive inotropic effects, while both actions of digitalis were parallel quantitatively. There may be some differences in the modulation of the intracellular Ca2+ between neripersides and digitalis.

  19. Evaluation of anti-diabetic and alpha glucosidase inhibitory action of anthraquinones from Rheum emodi.

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    Arvindekar, Aditya; More, Tanaji; Payghan, Pavan V; Laddha, Kirti; Ghoshal, Nanda; Arvindekar, Akalpita

    2015-08-01

    Rheum emodi is used as a culinary plant across the world and finds an eminent role in the Ayurvedic and traditional Chinese systems of medicine. The plant is known to principally contain 1,8-dihydroxyanthraquinones (DHAQs) like rhein, aloe emodin, emodin, chrysophanol and physcion that possess diverse pharmacological and therapeutic actions. The present work deals with developing a platform technology for isolation of these DHAQs and evaluating their anti-diabetic potential. Herein, we report the anti-hyperglycemic activity and alpha glucosidase (AG) inhibitory actions of five isolated DHAQs from R. emodi. All the five isolated DHAQs showed good anti-hyperglycemic activity with aloe emodin exhibiting maximum lowering of blood glucose in an oral glucose tolerance test. However, on evaluation of the AG inhibitory potential of the DHAQs only emodin exhibited potent intestinal AG inhibition (93 ± 2.16%) with an IC50 notably lower than acarbose. Subsequent kinetic studies indicated a mixed type of inhibition for emodin. In vivo studies using oral maltose load showed almost total inhibition for emodin when compared to acarbose. Molecular docking studies revealed the presence of an allosteric topographically distinct 'quinone binding site' and showed that interaction with Ser 74 occurs exclusively with emodin, which is vital for AG inhibition. The net benefit from the glucose lowering effect and mixed type inhibition by emodin would enable the administration of a small dosage that is safe and non-toxic in the case of prolonged use in treating diabetes.

  20. Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse.

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    Fei, Guijun; Raehal, Kirsten; Liu, Sumei; Qu, Mei-Hua; Sun, Xiaohong; Wang, Guo-Du; Wang, Xi-Yu; Xia, Yun; Schmid, Cullen L; Bohn, Laura M; Wood, Jackie D

    2010-07-01

    Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. Measurements of fecal wet weight were used to obtain information on morphine-lubiprostone interactions in conscious mice. Morphine decreased basal Isc, with an IC(50) of 96.1 nM. The action of dimethylphenylpiperazinium (DMPP), a nicotinic receptor agonist that stimulates neurogenic Isc, was suppressed by morphine. Lubiprostone applied after pretreatment with morphine reversed morphine suppression of both basal Isc and DMPP-evoked chloride secretion. Electrical field stimulation (EFS) of submucosal neurons evoked biphasic increases in Isc. Morphine abolished the first phase and marginally suppressed the second phase. Lubiprostone reversed, in concentration-dependent manner, the action of morphine on the first and second phases of the EFS-evoked responses. Subcutaneous lubiprostone increased fecal wet weight and numbers of pellets expelled. Morphine significantly reduced fecal wet weight and number of pellets. Injection of lubiprostone, 30-min after morphine, reversed morphine-induced suppression of fecal wet weight. We conclude that inhibitory action of morphine on chloride secretion reflects suppression of excitability of cholinergic secretomotor neurons in the enteric nervous system. Lubiprostone, which does not directly affect enteric neurons, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium.

  1. Inhibitory actions of Anti-Müllerian Hormone (AMH) on ovarian primordial follicle assembly.

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    Nilsson, Eric E; Schindler, Ryan; Savenkova, Marina I; Skinner, Michael K

    2011-01-01

    The current study was designed to investigate the actions of Anti-Müllerian Hormone (AMH) on primordial follicle assembly. Ovarian primordial follicles develop from the breakdown of oocyte nests during fetal development for the human and immediately after birth in rodents. AMH was found to inhibit primordial follicle assembly and decrease the initial primordial follicle pool size in a rat ovarian organ culture. The AMH expression was found to be primarily in the stromal tissue of the ovaries at this period of development, suggesting a stromal-epithelial cell interaction for primordial follicle assembly. AMH was found to promote alterations in the ovarian transcriptome during primordial follicle assembly with over 200 genes with altered expression. A gene network was identified suggesting a potential central role for the Fgf2/Nudt6 antisense transcript in the follicle assembly process. A number of signal transduction pathways are regulated by AMH actions on the ovarian transcriptome, in particular the transforming growth factor-beta (TGFß) signaling process. AMH is the first hormone/protein shown to have an inhibitory action on primordial follicle assembly. Due to the critical role of the primordial follicle pool size for female reproduction, elucidation of factors, such as AMH, that regulate the assembly process will provide insights into potential therapeutics to manipulate the pool size and female reproduction.

  2. Inhibitory actions of Anti-Mullerian Hormone (AMH on ovarian primordial follicle assembly.

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    Eric E Nilsson

    Full Text Available The current study was designed to investigate the actions of Anti-Müllerian Hormone (AMH on primordial follicle assembly. Ovarian primordial follicles develop from the breakdown of oocyte nests during fetal development for the human and immediately after birth in rodents. AMH was found to inhibit primordial follicle assembly and decrease the initial primordial follicle pool size in a rat ovarian organ culture. The AMH expression was found to be primarily in the stromal tissue of the ovaries at this period of development, suggesting a stromal-epithelial cell interaction for primordial follicle assembly. AMH was found to promote alterations in the ovarian transcriptome during primordial follicle assembly with over 200 genes with altered expression. A gene network was identified suggesting a potential central role for the Fgf2/Nudt6 antisense transcript in the follicle assembly process. A number of signal transduction pathways are regulated by AMH actions on the ovarian transcriptome, in particular the transforming growth factor-beta (TGFß signaling process. AMH is the first hormone/protein shown to have an inhibitory action on primordial follicle assembly. Due to the critical role of the primordial follicle pool size for female reproduction, elucidation of factors, such as AMH, that regulate the assembly process will provide insights into potential therapeutics to manipulate the pool size and female reproduction.

  3. Inhibitory action of halothane on rat masculine sexual behavior and sperm motility.

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    Oropeza-Hernández, Luis F; Quintanilla-Vega, Betzabet; Albores, Arnulfo; Fernández-Guasti, Alonso

    2002-07-01

    Adult male rats were exposed to inhale halothane in the following regime: 15 ppm/4 h/5 days/week/9 weeks. Sexual behavior observations and sperm motility test were made before halothane exposure (0 days) and at 15, 30, 45 and 60 days of exposure. Fifteen days after halothane exposure, this anesthetic inhibited the proportion of animals displaying ejaculation. In those animals ejaculating, halothane produced an inhibition of masculine sexual behavior reflected as an increase in the intromission latency, number of mounts and postejaculatory interval. At 30 days after exposure, only an increase in the intromission latency was observed. At 45 and 60 days, the inhibitory effect of halothane on sexual behavior disappeared. Similarly, at 15 and 30 days, but not at 45 or 60 days of halothane exposure, a reduced sperm motility was observed. Such transient effects of halothane suggest the development of tolerance to the inhibitory actions of this anesthetic on sexual behavior and sperm motility. These halothane effects are in line with an inhibition of masculine sexual behavior after stimulation of the GABAergic system.

  4. Dual Axis Radiographic Hydrodynamic Test Facility mitigation action plan. Annual report for 1998

    Energy Technology Data Exchange (ETDEWEB)

    Haagenstad, T.

    1999-01-15

    This Mitigation Action Plan Annual Report (MAPAR) has been prepared as part of implementing the Dual Axis Radiographic Hydrodynamic Test Facility (DARHT) Mitigation Action Plan (MAP) to protect workers, soils, water, and biotic and cultural resources in and around the facility.

  5. [Inhibitory action of divalent copper compounds on cumene hydroperoxide oxidative demethylation of N,N-dimethylaniline by cytochrome P-450].

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    Kurchenko, V P; Usanov, S A; Metelitsa, D I

    1980-07-01

    The inhibitory action of divalent copper compounds on hydroperoxide-dependent oxidative demethylation of N,N-demethylaniline involving rabbit liver microsomes and highly purified cytochrome P-450 has been studied. CuCl2 is a non-competitive inhibitor, whereas copper tyrosine and lysine complexes are characterized by a mixed type inhibition. The inhibitory action of copper complexes is based on a decrease of cumene hydroperoxide concentration. The reaction results in formation of RO and RO2 radicals destroying cytochrome P-450 CuCl2 (0,001 M) also destroys cytochrome P-450 in the absence of cumene hydroperoxide; the destruction process is characterized by two phases with different rate constants. The nature of the inhibitory action of CuCl2 on N,N-demethylaniline oxidation by hydroperoxides is discussed.

  6. Central and peripheral components of the inhibitory actions of 5-HTP on ethanol consumption in the rat.

    Science.gov (United States)

    Zabik, J E; Sprague, J E; Binkerd, K

    1994-03-01

    When administered under a backward conditioning paradigm, 5-HTP administration resulted in a decrease in ethanol intake followed by a persistently decreased ethanol consumption. A central component to this inhibitory effect was suggested by the inability of xylamidine to significantly reduce the initial inhibitory effect of 5-HTP. The persistent rejection was prevented by xylamidine. Methysergide reduced the initial as well as the persistent effects of 5-HTP. In studies utilizing a forward conditioning paradigm, 5-HTP and lithium were each effective in developing CTAs to ethanol and saccharin. Only the ethanol-5-HTP pairing showed a persistent aversion. A peripheral component to the actions of 5-HTP was suggested by xylamidine blocking the CTAs induced by 5-HTP. Xylamidine also prevented the persistent ethanol avoidance induced by 5-HTP, but was ineffective in antagonizing lithium-induced CTAs. These results suggest central as well as peripheral components associated with the inhibitory effects of 5-HTP on ethanol consumption. Central actions appear to mediate the initial inhibitory effects while peripheral actions appear to be associated with persistent avoidance of ethanol following 5-HTP treatment.

  7. [1+1 or 2x1? Another form of dual antidepressive mechanism of action].

    Science.gov (United States)

    Lakatos, László; Rihmer, Zoltán

    2005-09-01

    The primary aim of this review is to summarize the result of clinical trials comparing tricyclic antidepressants with first generation SSRIs, dual action (serotonergic and noradrenergic) agents like venlafaxine or mirtazapine with SSRIs and escitalopram with other SSRIs and venlafaxine. The review analyzes the relationship between the clinical efficacy and tolerability data and the mode of action. The clinical data suggest that multiple mode of action can substantially improve efficacy, however the relative risk of side-effects also increases if a drug affects multiple neurotransmitters. A new opportunity of development is the molecule of escitalopram introduced to the market some years ago. Its unique dual action on serotonergic transmission offers improved efficacy without compromising the favourable side-effect profile due to selectivity. Based on clinical trials escitalopram shows improved efficacy, faster onset of action and higher remission rates compared to first generation SSRIs. Remission rates with escitalopram are at least as high as with venlafaxine and escitalopram shows faster onset of action, earlier sustained remission and better tolerability. The good clinical efficacy data of escitalopram may be explained by its unique dual serotonergic effect on serotonin transporter protein.

  8. Dual action of antimuscarinic agents on the intestinal smooth muscle

    Directory of Open Access Journals (Sweden)

    Acharya SRK

    1979-01-01

    Full Text Available Propantheline, oxyphenonium, isoproponaide, epidosine, adiphe-nine and atropine were studied for their effect on the superfused infesting of guinea pig and rat. In small, concentrations, all drugs produced a contraction, which with increasing concentration, was Hocked. Occasionally, a contraction and a relaxation or vice versa was recorded. A partial antagonism and a potentiation on the action of acetylcholine (Ach during recovery was observed. In very high concentrations, all drugs produced a graded contraction of intestine, except adiphenine which produced a sustained contraction. Some- times, a contraction and a relaxation was also observed.

  9. Plebanski-like action for general relativity and anti-self-dual gravity

    CERN Document Server

    Celada, Mariano; Montesinos, Merced

    2016-01-01

    We present a new $BF$-type action for complex general relativity with or without a cosmological constant resembling Plebanski's action, which depends on an SO(3,$\\mathbb{C}$) connection, a set of 2-forms, a symmetric matrix, and a 4-form. However, it differs from the Plebanski formulation in the way that the symmetric matrix enters into the action. The advantage of this fact is twofold. First, as compared to Plebanski's action, the symmetric matrix can now be integrated out, which leads to a pure $BF$-type action principle for general relativity; the canonical analysis of the new action then shows that it has the same phase space of the Ashtekar formalism up to a canonical transformation induced by a topological term. Second, a particular choice of the parameters involved in the formulation produces a $BF$-type action principle describing conformally anti-self-dual gravity. Therefore, the new action unifies both general relativity and anti-self-dual gravity.

  10. Acting in solidarity: Testing an extended dual pathway model of collective action by bystander group members.

    Science.gov (United States)

    Saab, Rim; Tausch, Nicole; Spears, Russell; Cheung, Wing-Yee

    2015-09-01

    We examined predictors of collective action among bystander group members in solidarity with a disadvantaged group by extending the dual pathway model of collective action, which proposes one efficacy-based and one emotion-based path to collective action (Van Zomeren, Spears, Fischer, & Leach, 2004). Based on two proposed functions of social identity performance (Klein, Spears, & Reicher, 2007), we distinguished between the efficacy of collective action at consolidating the identity of a protest movement and its efficacy at achieving social change (political efficacy). We expected identity consolidation efficacy to positively predict collective action tendencies directly and indirectly via political efficacy. We also expected collective action tendencies to be positively predicted by moral outrage and by sympathy in response to disadvantaged outgroup's suffering. These hypotheses were supported in two surveys examining intentions to protest for Palestine in Britain (Study 1), and intentions to attend the June 4th vigil in Hong Kong to commemorate the Tiananmen massacre among a sample of Hong Kong citizens (Study 2). The contributions of these findings to research on the dual pathway model of collective action and the different functions of collective action are discussed.

  11. Melatonin nephroprotective action in Zucker diabetic fatty rats involves its inhibitory effect on NADPH oxidase.

    Science.gov (United States)

    Winiarska, Katarzyna; Dzik, Jolanta M; Labudda, Mateusz; Focht, Dorota; Sierakowski, Bartosz; Owczarek, Aleksandra; Komorowski, Lukasz; Bielecki, Wojciech

    2016-01-01

    Excessive activity of NADPH oxidase (Nox) is considered to be of importance for the progress of diabetic nephropathy. The aim of the study was to elucidate the effect of melatonin, known for its nephroprotective properties, on Nox activity under diabetic conditions. The experiments were performed on three groups of animals: (i) untreated lean (?/+) Zucker diabetic fatty (ZDF) rats; (ii) untreated obese diabetic (fa/fa) ZDF rats; and (iii) ZDF fa/fa rats treated with melatonin (20 mg/L) in drinking water. Urinary albumin excretion was measured weekly. After 4 wk of the treatment, the following parameters were determined in kidney cortex: Nox activity, expression of subunits of the enzyme, their phosphorylation and subcellular distribution. Histological studies were also performed. Compared to ?/+ controls, ZDF fa/fa rats exhibited increased renal Nox activity, augmented expression of Nox4 and p47(phox) subunits, elevated level of p47(phox) phosphorylation, and enlarged phospho-p47(phox) and p67(phox) content in membrane. Melatonin administration to ZDF fa/fa rats resulted in the improvement of renal functions, as manifested by considerable attenuation of albuminuria and some amelioration of structural abnormalities. The treatment turned out to nearly normalize Nox activity, which was accompanied by considerably lowered expression and diminished membrane distribution of regulatory subunits, that is, phospho-p47(phox) and p67(phox) . Thus, it is concluded that: (i) melatonin beneficial action against diabetic nephropathy involves attenuation of the excessive activity of Nox; and (ii) the mechanism of melatonin inhibitory effect on Nox is based on the mitigation of expression and membrane translocation of its regulatory subunits.

  12. Leukemia inhibitory factor antagonizes gonadotropin induced-testosterone synthesis in cultured porcine leydig cells: sites of action.

    Science.gov (United States)

    Mauduit, C; Goddard, I; Besset, V; Tabone, E; Rey, C; Gasnier, F; Dacheux, F; Benahmed, M

    2001-06-01

    In the present report, the action of leukemia inhibitory factor (LIF) on testicular steroid hormone formation was studied. For this purpose, the direct effects of LIF were evaluated on basal and human (h)CG-stimulated testosterone synthesis by cultured, purified Leydig cells isolated from porcine testes. LIF reduced (more than 60%) hCG-stimulated testosterone synthesis. This inhibitory effect was exerted in a dose- and time-dependent manner. The maximal and half-maximal effects were obtained with, respectively, 10 ng/ml (0.5 nM ) and 2.5 ng/ml (0.125 nM ) of LIF after a 48-h treatment of the Leydig cells. Such an effect of the cytokine was not a cytotoxic effect, because it was reversible and Leydig cells recovered most of their steroidogenic activity after the removal of LIF. Considering the sites of action of LIF in inhibiting gonadotropin-stimulated testosterone formation, it was shown that LIF significantly (P observation indicates that the antigonadotropic action of the cytokine is exerted in a predominant manner at a step (or steps) located beyond cAMP formation. Furthermore, incubation of Leydig cells with 22R-hydroxycholesterol (5 microg/ml, 2 h), a cholesterol substrate derivative that does not need an assisted process to be delivered to the inner mitochondrial membrane, reversed most of the inhibitory effect of LIF on the steroid hormone formation. Such results indicate that LIF acts by reducing cholesterol substrate availability in the mitochondria. Consequently, LIF action was tested on steroidogenic acute regulatory protein and PBR (peripheral benzodiazepine receptor) shown to be potentially involved in such a cholesterol transfer. LIF reduced, in a dose- and time-dependent manner, LH/hCG-induced steroidogenic acute regulatory protein messenger RNA levels. The maximal inhibitory effect was obtained with 6.6 ng/ml of LIF after 48 h of treatment. In contrast, LIF had no effect on PBR messenger RNA expression or PBR binding. This inhibitory effect of LIF

  13. In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450.

    Science.gov (United States)

    Labrie, Philippe; Maddaford, Shawn P; Lacroix, Jacques; Catalano, Concettina; Lee, David K H; Rakhit, Suman; Gaudreault, René C

    2006-12-01

    Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.

  14. A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials

    DEFF Research Database (Denmark)

    Calloe, Kirstine; Di Diego, José M; Hansen, Rie Schultz

    2016-01-01

    in cultured canine cardiac myocytes and determined whether a dual K(+) current activator can normalize K(+) currents and restore action potential (AP) configuration. METHODS AND RESULTS: Ventricular myocytes were isolated and cultured for up to 48h. Current and voltage clamp recordings were made using patch...... of EADs. Our results suggest a potential benefit of K(+) current activators under conditions of reduced repolarization reserve including heart failure....

  15. Dual actions of enflurane on postsynaptic currents abolished by the gamma-aminobutyric acid type A receptor beta3(N265M) point mutation.

    Science.gov (United States)

    Drexler, Berthold; Jurd, Rachel; Rudolph, Uwe; Antkowiak, Bernd

    2006-08-01

    At concentrations close to 1 minimum alveolar concentration (MAC)-immobility, volatile anesthetics display blocking and prolonging effects on gamma-aminobutyric acid type A receptor-mediated postsynaptic currents. It has been proposed that distinct molecular mechanisms underlie these dual actions. The authors investigated whether the blocking or the prolonging effect of enflurane is altered by a point mutation (N265M) in the beta3 subunit of the gamma-aminobutyric acid type A receptor. Furthermore, the role of the beta3 subunit in producing the depressant actions of enflurane on neocortical neurons was elucidated. Spontaneous inhibitory postsynaptic currents were sampled from neocortical neurons in cultured slices derived from wild-type and beta3(N265M) mutant mice. The effects of 0.3 and 0.6 mm enflurane on decay kinetics, peak amplitude, and charge transfer were quantified. Furthermore, the impact of enflurane-induced changes in spontaneous action potential firing was evaluated by extracellular recordings in slices from wild-type and mutant mice. In slices derived from wild-type mice, enflurane prolonged inhibitory postsynaptic current decays and decreased peak amplitudes. Both effects were almost absent in slices from beta3(N265M) mutant mice. At clinically relevant concentrations between MAC-awake and MAC-immobility, the anesthetic was less effective in depressing spontaneous action potential firing in slices from beta3(N265M) mutant mice compared with wild-type mice. At concentrations between MAC-awake and MAC-immobility, beta3-containing gamma-aminobutyric acid type A receptors contribute to the depressant actions of enflurane in the neocortex. The beta3(N265M) mutation affects both the prolonging and blocking effects of enflurane on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents in neocortical neurons.

  16. The dual role of serotonin in defense and the mode of action of antidepressants on generalized anxiety and panic disorders.

    Science.gov (United States)

    Graeff, Frederico G; Zangrossi, Hélio

    2010-09-01

    Antidepressants are widely used to treat several anxiety disorders, among which generalized anxiety disorder (GAD) and panic disorder (PD). Serotonin (5-HT) is believed to play a key role in the mode of action of these agents, a major question being which pathways and receptor subtypes are involved in each type of anxiety disorder. The dual role of 5-HT in defense hypothesis assumes that 5-HT facilitates defensive responses to potential threat, like inhibitory avoidance, related to anxiety, whereas it inhibits defensive responses to proximal danger, like one-way escape, related to panic. The former action would be exerted at the forebrain, chiefly the amygdala and medial prefrontal cortex (PFC), while the latter would be exerted at the dorsal periaqueductal gray (DPAG) matter of the midbrain. The present review is focused on studies designed to test this hypothesis, performed in animal models of anxiety and panic, as well as in human experimental anxiety tests. The reviewed results suggest that chronic, but not acute, administration of antidepressants suppress panic attacks by increasing the release of 5-HT and enhancing the responsivity of post-synaptic 5-HT1A and 5-HT2A receptors in the DPAG. The attenuation of generalized anxiety, also caused by the same drug treatment, would be due to the desensitization of 5-HT2C receptors and, less certainly, to increased stimulation of 5-HT1A receptors in forebrain structures. This action would result in less activation of the amygdala, medial PFC and insula by warning signals, as shown by the reviewed results obtained with functional neuroimaging in healthy volunteers and patients with anxiety disorders.

  17. Inhibitory action of two zinc oxide sources on the ex vivo growth of porcine small intestine bacteria.

    Science.gov (United States)

    Vahjen, W; Zentek, J; Durosoy, S

    2012-12-01

    Pharmacological dosage of zinc oxide in piglet weaning diets is a common practice to improve growth performance and gut health. However, high zinc excretion in animal wastes poses environmental challenges. Alternatives to current practice are studied. In this study, the inhibitory action of 2 zinc oxide sources on the ex vivo growth of small intestinal bacteria from weaned piglets was studied. Lag time was higher (P < 0.05) in media supplemented with a new zinc oxide preparation in stomach samples, but not in jejunum samples. Bacterial growth reduction (P < 0.05) was more drastic and more rapid in media supplemented with the new zinc oxide preparation.

  18. Filamenting temperature-sensitive mutant Z inhibitors from Glycyrrhiza glabra and their inhibitory mode of action.

    Science.gov (United States)

    Matsui, Takashi; Lallo, Subehan; Nisa, Khoirun; Morita, Hiroyuki

    2017-03-15

    FtsZ is an essential protein for bacterial cell division, and an attractive and underexploited novel antibacterial target protein. Screening of Indonesian plants revealed the inhibitory activity of the methanol extract of Glycyrrhiza glabra on the Bacillus subtilis FtsZ (BsFtsZ) GTPase, and further bioassay-guided fractionation of the active methanol extract led to the isolation of seven known polyketides (1-7). Among them, gancaonin I (1), glycyrin (3), and isolicoflavanol (5) exhibited anti-BsFtsZ GTPase activities, at levels comparable to that of the synthetic FtsZ inhibitor, Zantrin Z3. Enzymatic assays using a BsFtsZ Val307R mutant protein and in silico simulations suggested that 1, 3, and 5 bind to the cleft on BsFtsZ, as in the case of the previously reported uncompetitive FtsZ inhibitor, PC190723, and thereby display their significant anti-BsFtsZ inhibitory activities. Furthermore, 1 also showed significant inhibitory activity against B. subtilis, with a MIC value of 5μM. The present study provides new insights into the naturally occurring B. subtilis growth inhibitors.

  19. Self-dual variables, positive semi-definite action, and discrete transformations in 4-d quantum gravity

    CERN Document Server

    Soo, C P

    1995-01-01

    A positive semi-definite Euclidean action for arbitrary four-topologies can be constructed by adding appropriate Yang-Mills and topological terms to the Samuel-Jacobson-Smolin action of gravity with (anti)self-dual variables. Moreover, the (anti)self-dual sector of the new theory corresponds precisely to {\\it all} Einstein manifolds in four dimensions. The Lorentzian signature action, and its analytic continuations are also considered. A self-contained discussion is given on the effects of discrete transformations C, P and T on the Samuel-Jacobson-Smolin action and other proposed actions which utilize self- or anti-self-dual variables as fundamental variables in the description of four-dimensional gravity.

  20. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Jin-Hang Gao

    Full Text Available BACKGROUND: Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2 in the cirrhotic liver might be a potential target to ameliorate portal hypertension. OBJECTIVE: To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. METHODS: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA. 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF, VEGF receptor-2 (VEGFR-2 and related signal molecules were quantitated. RESULTS: Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2, phosphorylated extracellular signal-regulated kinase (p-ERK, hypoxia-inducible factor-1α (HIF-1α, and c-fos were also down-regulated after celecoxib treatment. CONCLUSIONS: Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its

  1. Mechanism of inhibitory action of the local anaesthetic trimecaine on the growth of algae (Chlorella vulgaris).

    Science.gov (United States)

    Sersen, F; Král'ová, K

    1994-08-01

    Using the model compound trimecaine, it was found that algicidal effects exhibited by the local anaesthetics of the acetanilide type were caused by two different mechanisms. The first inhibitory mechanism occurring at low concentrations of the anaesthetic is connected with the uncoupling of the photophosphorylations in algal chloroplasts and is accompanied by the enhancement of the oxygen evolving rate in algal photosynthesis. The second mechanism of inhibition of the photosynthesis in algae, taking place at higher concentrations of the anaesthetic, is connected with the damaging of the manganese containing protein on the donor side of photosystem 2 and is accompanied by a decrease of the oxygen evolving rate in algal photosynthesis.

  2. Lubiprostone Reverses the Inhibitory Action of Morphine on Intestinal Secretion in Guinea Pig and Mouse

    OpenAIRE

    Fei, Guijun; Raehal, Kirsten; Liu, Sumei; Qu, Mei-Hua; Sun, Xiaohong; Wang, Guo-Du; Wang, Xi-Yu; Xia, Yun; Schmid, Cullen L.; Bohn, Laura M.; Wood, Jackie D.

    2010-01-01

    Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. M...

  3. Mode of action of the dual-action cephalosporin Ro 23-9424.

    Science.gov (United States)

    Georgopapadakou, N H; Bertasso, A; Chan, K K; Chapman, J S; Cleeland, R; Cummings, L M; Dix, B A; Keith, D D

    1989-07-01

    Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biological properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decomposition product, desacetyl cefotaxime, Ro 23-9424 bound at less than or equal to 2 micrograms/ml to the essential penicillin-binding proteins 1b and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureus. In E. coli, Ro 23-9424 produced filaments exclusively and decreased cell growth; cefotaxime produced both filaments and lysis. Like its decomposition product fleroxacin but unlike quinolone esters, Ro 23-9424 also inhibited replicative DNA biosynthesis in E. coli. In an E. coli strain lacking OmpF, growth continued after addition of Ro 23-9424, decreased after addition of cefotaxime, and stopped immediately after addition of fleroxacin. The results, together with the chemical stability of Ro 23-9424 (half-life, approximately 3 h at pH 7.4 and 37 degrees C), suggest that in E. coli the compound acts initially as a cephalosporin with intrinsic activity comparable to that of cefotaxime but with poorer penetration. Subsequent to the decomposition of Ro 23-9424 to fleroxacin and desacetyl cefotaxime, quinolone activity appears. The in vitro antibacterial activity reflects both mechanisms of action.

  4. A dual action of saturated fatty acids on electrical activity in rat pancreatic β-cells. Role of volume-regulated anion channel and KATP channel currents.

    Science.gov (United States)

    Best, L; Jarman, E; Brown, P D

    2011-03-15

    Free fatty acids (FFAs) exert complex actions on pancreatic β-cells. Typically, an initial potentiation of insulin release is followed by a gradual impairment of β-cell function, the latter effect being of possible relevance to hyperlipidaemia in type 2 diabetes mellitus. The molecular actions of FFAs are poorly understood. The present study investigated the acute effects of saturated FFAs on electrophysiological responses of rat pancreatic β-cells. Membrane potential and KATP channel activity were recorded using the perforated patch technique. Volume-regulated anion channel (VRAC) activity was assessed from conventional whole-cell recordings. Cell volume regulation was measured using a video-imaging technique. Addition of octanoate caused a transient potentiation of glucose-induced electrical activity, followed by a gradual hyper-polarisation and a prolonged inhibition of electrical activity. Octanoate caused an initial increase in VRAC activity followed by a secondary inhibition coinciding with increased KATP channel activity. Similar effects were observed with palmitate and 2-bromopalmitate whereas butyrate was virtually ineffective. Octanoate and palmitate also exerted a dual effect on electrical activity evoked by tolbutamide. Octanoate significantly attenuated cell volume regulation in hypotonic solutions, consistent with VRAC inhibition. It is concluded that medium and long chain FFAs have a dual action on glucose-induced electrical activity in rat pancreatic β-cells: an initial stimulatory effect followed by a secondary inhibition. These effects appear to be the result of reciprocal actions on VRAC and KATP channel currents, and could contribute towards the stimulatory and inhibitory actions of FFAs on pancreatic β-cell function.

  5. Inhibitory actions of Pseuderanthemum palatiferum(Nees) Radlk. leaf ethanolic extract and its phytochemicals against carbohydrate-digesting enzymes

    Institute of Scientific and Technical Information of China (English)

    Pawitra Pulbutr; Somsak Nualkaew; Sakulrat Rattanakiat; Benjamart Cushnie; Achida Jaruchotikamol

    2016-01-01

    Objective: To investigate the effects of the leaf ethanolic extract of Pseuderanthemum palatiferum(PPE) and its isolated phytochemicals, stigmasterol and sitosterol-3-O-b-Dglucopyranoside, against a-amylase and a-glucosidase enzyme activities both in vitro and in vivo.Methods: A concentration of maltose, which is a product released in a-amylase-catalyzing reaction, was used as an index of in vitro a-amylase activity. Meanwhile, in vitro a-glucosidase enzyme activity was indicated by the amount of liberated p-nitrophenol in a-glucosidase-catalyzing reaction. In vivo a-amylase and a-glucosidase enzyme activities were evaluated in the normal rats by using oral starch tolerance test and oral sucrose tolerance test, respectively.Results: PPE exerted a concentration-dependent inhibitory action against both aamylase and a-glucosidase in vitro with the IC50 values of(11.79 ± 8.10) mg/m L and(1.00 ± 0.11) mg/m L, respectively. Stigmasterol and sitosterol-3-O-b-D-glucopyranoside also exerted an in vitro a-amylase inhibition with the IC50 values of(59.41 ± 8.22) mg/m L and(111.19 ± 9.02) mg/m L, respectively. However, these phytochemicals did not produce a concentration-dependent inhibition against in vitro a-glucosidase activity. PPE and its isolated phytochemicals significantly decreased the blood glucose levels at t = 30 min in the oral starch tolerance test. From the sucrose tolerance test, only PPE but not its isolated phytochemicals significantly caused a depletion in the blood glucose levels at t = 30 min Conclusions: These results indicate an inhibitory action against carbohydrate-digesting enzymes as the anti-diabetic mechanism of action of PPE. Nonetheless, further clinical study is required to justify its role in the treatment of diabetes.

  6. Inhibitory effect of selenium against Penicillium expansum and its possible mechanisms of action.

    Science.gov (United States)

    Wu, Zhi-Lin; Yin, Xue-Bin; Lin, Zhi-Qing; Bañuelos, Gary S; Yuan, Lin-Xi; Liu, Ying; Li, Miao

    2014-08-01

    Some organic and inorganic salts could inhibit the growth of many pathogens. Selenium (Se), as an essential micronutrient, was effective in improving the plant resistance and antioxidant capacity at a low concentration. Penicillium expansum is one of the most important postharvest fungal pathogens, which can cause blue mold rot in various fruits and vegetables. In this study, the inhibitory effect of Se against P. expansum was evaluated. The result showed that Se strongly inhibited spore germination, germ tube elongation, and mycelial spread of P. expansum in the culture medium. The inhibitory effect was positively related to the concentration of Se used. Fluorescence microscopy observation of P. expansum conidia stained with propidium iodide (PI) indicated that the membrane integrity decreased to 37 % after the conidia were treated with Se (20 mg/l) for 9 h. With the use of an oxidant-sensitive probe 2,7-dichlorofluorescin (DCHF-DA), we found that Se at 15 mg/l could induce the generation of intracellular reactive oxygen species (ROS). Furthermore, methane dicarboxylic aldehyde (MDA) content, hydrogen peroxide (H2O2), and superoxide anion (O2 (-)) production rate in P. expansum spores exposed to Se increased markedly. Compared with the control, the activities of superoxide dismutase (SOD) and the content of glutathione (GSH) were reduced, confirming that damage of Se to cellular oxygen-eliminating system is the main reason. These results suggest that Se might serve as a potential alternative to synthetic fungicides for the control of the postharvest disease of fruit and vegetables caused by P. expansum.

  7. The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action.

    Science.gov (United States)

    Lee, Margaret S; Johansen, Lisa; Zhang, Yanzhen; Wilson, Amy; Keegan, Mitchell; Avery, William; Elliott, Peter; Borisy, Alexis A; Keith, Curtis T

    2007-12-01

    Combination therapy has proven successful in treating a wide variety of aggressive human cancers. Historically, combination treatments have been discovered through serendipity or lengthy trials using known anticancer agents with similar indications. We have used combination high-throughput screening to discover the unexpected synergistic combination of an antiparasitic agent, pentamidine, and a phenothiazine antipsychotic, chlorpromazine. This combination, CRx-026, inhibits the growth of tumor cell lines in vivo more effectively than either pentamidine or chlorpromazine alone. Here, we report that CRx-026 exerts its antiproliferative effect through synergistic dual mitotic action. Chlorpromazine is a potent and specific inhibitor of the mitotic kinesin KSP/Eg5 and inhibits tumor cell proliferation through mitotic arrest and accumulation of monopolar spindles. Pentamidine treatment results in chromosomal segregation defects and delayed progression through mitosis, consistent with inhibition of the phosphatase of regenerating liver family of phosphatases. We also show that CRx-026 synergizes in vitro and in vivo with the microtubule-binding agents paclitaxel and vinorelbine. These data support a model where dual action of pentamidine and chlorpromazine in mitosis results in synergistic antitumor effects and show the importance of systematic screening for combinations of targeted agents.

  8. Dual Axis Radiographic Hydrodynamic Test Facility mitigation action plan. Annual report for 1997

    Energy Technology Data Exchange (ETDEWEB)

    Haagenstad, H.T.

    1998-01-15

    This Mitigation Action Plan Annual Report (MAPAR) has been prepared by the US Department of Energy (DOE) as part of implementing the Dual Axis Radiographic Hydrodynamic Test Facility (DARHT) Mitigation Action Plan (MAP). This MAPAR provides a status on specific DARHT facility design- and construction-related mitigation actions that have been initiated in order to fulfill DOE`s commitments under the DARHT MAP. The functions of the DARHT MAP are to (1) document potentially adverse environmental impacts of the Phased Containment Option delineated in the Final EIS, (2) identify commitments made in the Final EIS and ROD to mitigate those potential impacts, and (3) establish Action Plans to carry out each commitment (DOE 1996). The DARHT MAP is divided into eight sections. Sections 1--5 provide background information regarding the NEPA review of the DARHT project and an introduction to the associated MAP. Section 6 references the Mitigation Action Summary Table which summaries the potential impacts and mitigation measures; indicates whether the mitigation is design-, construction-, or operational-related; the organization responsible for the mitigation measure; and the projected or actual completion data for each mitigation measure. Sections 7 and 8 discuss the Mitigation Action Plan Annual Report and Tracking System commitment and the Potential Impacts, Commitments, and Action Plans respectively. Under Section 8, potential impacts are categorized into five areas of concern: General Environment, including impacts to air and water; Soils, especially impacts affecting soil loss and contamination; Biotic Resources, especially impacts affecting threatened and endangered species; Cultural/Paleontological Resources, especially impacts affecting the archeological site known as Nake`muu; and Human Health and Safety, especially impacts pertaining to noise and radiation. Each potential impact includes a brief statement of the nature of the impact and its cause(s). The commitment

  9. Suppression of cell membrane permeability by suramin: involvement of its inhibitory actions on connexin 43 hemichannels.

    Science.gov (United States)

    Chi, Yuan; Gao, Kun; Zhang, Hui; Takeda, Masayuki; Yao, Jian

    2014-07-01

    Suramin is a clinically prescribed drug for treatment of human African trypanosomiasis, cancer and infection. It is also a well-known pharmacological antagonist of P2 purinoceptors. Despite its clinical use and use in research, the biological actions of this molecule are still incompletely understood. Here, we investigated the effects of suramin on membrane channels, as exemplified by its actions on non-junctional connexin43 (Cx43) hemichannels, pore-forming α-haemolysin and channels involved in ATP release under hypotonic conditions. Hemichannels were activated by removing extracellular Ca(2+) . The influences of suramin on hemichannel activities were evaluated by its effects on influx of fluorescent dyes and efflux of ATP. The membrane permeability and integrity were assessed through cellular retention of preloaded calcein and LDH release. Suramin blocked Cx43 hemichannel permeability induced by removal of extracellular Ca(2+) without much effect on Cx43 expression and gap junctional intercellular communication. This action of suramin was mimicked by its analogue NF023 and NF449 but not by another P2 purinoceptor antagonist PPADS. Besides hemichannels, suramin also significantly blocked intracellular and extracellular exchanges of small molecules caused by α-haemolysin from Staphylococcus aureus and by exposure of cells to hypotonic solution. Furthermore, it prevented α-haemolysin- and hypotonic stress-elicited cell injury. Suramin blocked membrane channels and protected cells against toxin- and hypotonic stress-elicited injury. Our finding provides novel mechanistic insights into the pharmacological actions of suramin. Suramin might be therapeutically exploited to protect membrane integrity under certain pathological situations. © 2014 The British Pharmacological Society.

  10. Inhibitory and bactericidal action of the biocorrosion agents «INCORGAS» and «AMDOR».

    Science.gov (United States)

    Tsygankova, L E; Vigdorovich, V I; Esina, M N; Nazina, T N; Dubinskaya, E V

    2014-06-01

    Inhibiting action of A, B and M-X compositions against hydrosulfide corrosion of carbon steel, hydrogen diffusion through the steel membrane has been studied along with their bactericidal effect with respect to sulfate-reducing bacteria of Desulfomicrobium type. Bactericidal properties of the compositions have been studied in the Postgate medium. Corrosion tests have been made in the NACE medium saturated by hydrogen sulfide and carbon dioxide separately and together by methods of gravimetrical measurements and linear polarization resistance (LRP). Potentiodynamic polarization and electrochemical diffusion method have been used. Steel protection is determined in the inhibited solutions by combined action of corrosion products film and inhibitor. Presence of sulfate-reducing bacteria in medium increases hydrogen diffusion flux through the steel membrane by 2-3 times and essentially stimulates effect of the inhibitors. The inhibiting compositions decrease quantity of sulfate-reducing bacteria (SRB) by 95-98%. The obtained results testify about predominately bacteriostatic action of the inhibiting compositions, which has influence on the enzymatic systems of SRB cells responsible directly for the sulfate reduction because of substantially decreasing the biogenic hydrogen sulfide concentration in the system.

  11. Molecular characterization of a dual inhibitory and mutagenic activity of 5-fluorouridine triphosphate on viral RNA synthesis. Implications for lethal mutagenesis.

    Science.gov (United States)

    Agudo, Rubén; Arias, Armando; Pariente, Nonia; Perales, Celia; Escarmís, Cristina; Jorge, Alberto; Marina, Anabel; Domingo, Esteban

    2008-10-10

    The basis for a dual inhibitory and mutagenic activity of 5-fluorouracil (5-FU) on foot-and-mouth disease virus (FMDV) RNA replication has been investigated with purified viral RNA-dependent RNA polymerase (3D) in vitro. 5-Fluorouridine triphosphate acted as a potent competitive inhibitor of VPg uridylylation, the initial step of viral replication. Peptide analysis by mass spectrometry has identified a VPg fragment containing 5-fluorouridine monophosphate (FUMP) covalently attached to Tyr3, the amino acid target of the uridylylation reaction. During RNA elongation, FUMP was incorporated in the place of UMP or CMP by FMDV 3D, using homopolymeric and heteropolymeric templates. Incorporation of FUMP did not prevent chain elongation, and, in some sequence contexts, it favored misincorporations at downstream positions. When present in the template, FUMP directed the incorporation of AMP and GMP, with ATP being a more effective substrate than GTP. The misincorporation of GMP was 17-fold faster opposite FU than opposite U in the template. These results in vitro are consistent with the mutational bias observed in the mutant spectra of 5-FU-treated FMDV populations. The dual mutagenic and inhibitory activity of 5-fluorouridine triphosphate may contribute to the effective extinction of FMDV by 5-FU through virus entry into error catastrophe.

  12. Rational design, synthesis and preliminary antitumor activity evaluation of a chlorambucil derivative with potent DNA/HDAC dual-targeting inhibitory activity.

    Science.gov (United States)

    Xie, Rui; Li, Yan; Tang, Pingwah; Yuan, Qipeng

    2017-09-15

    Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6. Vorambucil showed potent antiproliferative activity against all the test four cancer cell lines with IC50 values of as low as 3.2-6.2μM and exhibited 5.0-18.3-fold enhanced antiproliferative activity than chlorambucil. Vorambucil also significantly inhibits colony formation of A375 cancer cells. Further investigation showed that vorambucil remarkably induced apoptosis and arrested the cell cycle of A375 cells at G2/M phase. Vorambucil could be a promising candidate and a useful tool to elucidate the role of those DNA/HDAC dual-targeting inhibitors for cancer therapy. Copyright © 2017. Published by Elsevier Ltd.

  13. Characterizing the inhibitory action of zinc oxide nanoparticles on allergic-type mast cell activation.

    Science.gov (United States)

    Feltis, B N; Elbaz, A; Wright, P F A; Mackay, G A; Turney, T W; Lopata, A L

    2015-08-01

    The development of nanoparticles (NPs) for commercial products is undergoing a dramatic expansion. Many sunscreens and cosmetics now use zinc oxide (ZnO) or titania (TiO2) NPs, which are effective ultraviolet (UV) filters. Zinc oxide topical creams are also used in mild anti-inflammatory treatments. In this study we evaluated the effect of size and dispersion state of ZnO and TiO2 NPs, compared to "bulk" ZnO, on mast cell degranulation and viability. ZnO and TiO2 NPs were characterized using dynamic light scattering and disc centrifugation. Rat basophilic leukaemia (RBL-2H3) cells and primary mouse bone marrow-derived mast cells (BMMCs) were exposed to ZnO and TiO2 NPs of different sizes (25-200 nm) and surface coatings at concentrations from 1 to 200 μg/mL. The effect of NPs on immunoglobulin E (IgE)-dependent mast cell degranulation was assessed by measuring release of both β-hexosaminidase and histamine via colorimetric and ELISA assays. The intracellular level of Zn(2+) and Ca(2+) ions were measured using zinquin ethyl ester and Fluo-4 AM fluorescence probes, respectively. Cellular viability was determined using the soluble tetrazolium-based MTS colorimetric assay. Exposure of RBL-2H3 and primary mouse BMMC to ZnO NPs markedly inhibited both histamine and β-hexosaminidase release. This effect was both particle size and dispersion dependent. In contrast, TiO2 NPs did not inhibit the allergic response. These effects were independent of cytotoxicity, which was observed only at high concentrations of ZnO NPs, and was not observed for TiO2 NPs. The inhibitory effects of ZnO NPs on mast cells were inversely proportional to particle size and dispersion status, and thus these NPs may have greater potential than "bulk" zinc in the inhibition of allergic responses.

  14. Polysulfated Trehalose as a Novel Anticoagulant Agent with Dual Mode of Action

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    Qudsia Rashid

    2015-01-01

    Full Text Available Physiological hemostatic balance is a coordinated outcome of counteracting coagulation and fibrinolytic systems. An imbalance of procoagulant and anticoagulant factors may result in life threatening thromboembolism. Presently, anticoagulant administration is the first line of therapy for the treatment of these conditions and several anticoagulants have been approved, including various forms of heparin. However, the polyanionic nature and multispecificity of heparin pose several complications. Generally, the polysulfated compounds with antithrombotic potential are thought to have feasible synthetic procedures with much less bleeding, thus having favourable safety profiles. Here we report the synthesis of a novel compound, trehalose octasulfate and the assessment of its anticoagulation potential. Molecular docking of trehalose and trehalose octasulfate with antithrombin showed a specificity switch in binding affinity on sulfation, where trehalose octasulfate interacts with critical residues of AT that are either directly involved in heparin binding or in the conformational rearrangement of AT on heparin binding. An in vitro analysis of trehalose octasulfate demonstrated prolonged clotting time. Lead compound when intravenously injected in occlusion induced thrombotic rats showed remarkable reduction in the size and weight of the clot at a low dose. Delay in coagulation time was observed by analysing blood plasma isolated from rats preinjected with trehalose octasulfate. A decrease in Adenosine 5′-Diphosphate (ADP induced platelet aggregation indicated a probable dual anticoagulant and antiplatelet mechanism of action. To summarize, this study presents trehalose octasulfate as a novel, effective, dual acting antithrombotic agent.

  15. Review: Gonadotropin-inhibitory hormone action in the brain and pituitary

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    Takayoshi eUbuka

    2012-11-01

    Full Text Available Gonadotropin-inhibitory hormone (GnIH was first identified in the Japanese quail as a hypothalamic neuropeptide inhibitor of gonadotropin secretion. Subsequent studies have shown that GnIH is present in the brains of birds including songbirds, and mammals including humans. The identified avian and mammalian GnIH peptides universally possess an LPXRFamide (X = L or Q motif at their C-termini. Mammalian GnIH peptides are also designated as RFamide-related peptides from their structures. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147, which is thought to be coupled to Gαi protein. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN in birds and the dorsomedial hypothalamic area (DMH in mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function. GPR147 is expressed in the gonadotropes and GnIH suppresses synthesis and release of gonadotropins. It was further shown in immortalized mouse gonadotrope cell line (LT2 cells that GnIH inhibits gonadotropin-releasing hormone (GnRH induced gonadotropin subunit gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA dependent ERK pathway. GnIH neurons also project to GnRH neurons in the preoptic area, and GnRH neurons express GPR147 in birds and mammals. Accordingly, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as directly acting on the gonadotropes. GnIH also inhibits reproductive behavior possibly by acting within the brain. GnIH expression is regulated by a nocturnal hormone melatonin and stress in birds and mammals. Accordingly, GnIH may play a role in translating environmental information to inhibit reproductive physiology and behavior of birds and mammals. Finally, GnIH has therapeutic potential in the treatment of reproductive cycle and hormone-dependent diseases, such as precocious puberty, endometriosis, uterine fibroids, and prostatic and

  16. Mechanistic Studies of Anti-Hyperpigmentary Compounds: Elucidating Their Inhibitory and Regulatory Actions

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    Rosanna Y. Y. Lam

    2014-08-01

    Full Text Available Searching for depigmenting agents from natural sources has become a new direction in the cosmetic industry as natural products are generally perceived as relatively safer. In our previous study, selected Chinese medicines traditionally used to treat hyperpigmentation were tested for anti-hyperpigmentary effects using a melan-a cell culture model. Among the tested chemical compounds, 4-ethylresorcinol, 4-ethylphenol and 1-tetradecanol were found to possess hypopigmentary effects. Western blot analysis, reverse transcriptase polymerase chain reaction (RT-PCR, cyclic adenosine monophosphate (cAMP assay, protein kinase A (PKA activity assay, tyrosinase inhibition assay and lipid peroxidation inhibition assay were performed to reveal the underlying cellular and molecular mechanisms of the hypopigmentary effects. 4-Ethylresorcinol and 4-ethylphenol attenuated mRNA and protein expression of tyrosinase-related protein (TRP-2, and possessed antioxidative effect by inhibiting lipid peroxidation. 1-Tetradecanol was able to attenuate protein expression of tyrosinase. The hypopigmentary actions of 4-ethylresorcinol, 4-ethylphenol and 1-tetradecanol were associated with regulating downstream proteins along the PKA pathway. 4-Ethylresorcinol was more effective in inhibiting melanin synthesis when compared to 4-ethylphenol and 1-tetradecanol.

  17. Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370.

    Science.gov (United States)

    Hayouka, Zvi; Levin, Aviad; Maes, Michal; Hadas, Eran; Shalev, Deborah E; Volsky, David J; Loyter, Abraham; Friedler, Assaf

    2010-04-01

    The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound.

  18. Inhibitory action of oestrogen on calcium-induced mitosis in rat bone marrow and thymus.

    Science.gov (United States)

    Smith, G R; Gurson, M L; Riddell, A J; Perris, A D

    1975-04-01

    In the male rat injections of CaCl-2 and MgCl-2 stimulated mitosis in bone marrow and thymus tissue. The magnesium salt was also mitogenic in the normal female, but calcium only exerted its mitogenic effect after ovariectomy. Oestradiol, but not progesterone replacement therpy abolished calcium-induced mitosis in the ovariectomized rat. The inability of calcium to stimulate cell division was also apparent in the thyroparathyroidectomized female rat, suggesting the oestradiol blockage did not operate via some indirect action on the calcium homeostatic hormones calcitonin or parathyroid hormone. When thymic lymphocytes derived from male or female rats were isolated and maintained in suspension, increased calcium or magnesium concentrations in the culture medium stimulated the entry of cells into mitosis. Addition of oestradiol to the culture medium abolished the mitogenic effect of increased calcium levels, but had no effect on magnesium-induced proliferation. These experiments suggested that oestradiol might act at the cell surface to prevent the influx of calcium but not magnesium ions into the interior of the cell and thus to block the sequence of biochemical events which led to the initiation of DNA synthesis and culminate in mitosis.

  19. Mechanism of inhibitory actions of minocycline and doxycycline on ascitic fluid production induced by mouse fibrosarcoma cells.

    Science.gov (United States)

    Wakai, K; Ohmura, E; Satoh, T; Murakami, H; Isozaki, O; Emoto, N; Demura, H; Shizume, K; Tsushima, T

    1994-01-01

    Semisynthetic tetracyclines (TCNs) are used for the management of malignant pleural effusions as sclerosing agents. However, their precise mechanism of actions are uncertain. In the present study, the mechanism of inhibitory effects of minocycline (MINO) and doxycycline (DOXY), on the accumulation of ascitic fluid induced by mouse fibrosarcoma (Meth-A) cells were investigated using male mice. Meth-A cells inoculated intraperitoneally elicited 2.5-4 ml of bloody ascites 10 days after implantation. The production of ascitic fluid was suppressed in a dose-related manner by daily intraperitoneal injections of MINO or DOXY, whereas vehicle (normal saline with 0.01N HCl) did not exert a significant effect. The inhibitory activity of these two substances was quite similar; one mg/mouse of MINO or DOXY inhibited the accumulation of fluid by 87% and 84%, respectively. The survival rate of Meth-A-bearing mice treated with MINO or DOXY was higher than that of the controls. Macroscopic examination of the peritoneal cavity did not reveal any obvious effects, such as adhesions, in mice treated with either MINO or DOXY. In vitro studies showed that MINO and DOXY suppressed Meth-A cell growth with IC50s of 5 microM and 8 microM, respectively. Maximal suppression (95%) was achieved at MINO and DOXY concentrations of 25 microM. The above observations suggest that MINO and DOXY inhibit the accumulation of ascites by a direct effect on Meth-A cell growth. Therefore, it appears that TCNs injected into the pleural cavity to manage malignant effusions in man exert their activity, at least in part, by suppressing malignant cell growth.

  20. Perinatal protein restriction reduces the inhibitory action of serotonin on food intake.

    Science.gov (United States)

    Lopes de Souza, Sandra; Orozco-Solis, Ricardo; Grit, Isabelle; Manhães de Castro, Raul; Bolaños-Jiménez, Francisco

    2008-03-01

    Early malnutrition has been associated with a high risk of developing obesity, diabetes and cardiovascular diseases in adulthood. In animals, poor perinatal nutrition produces hyperphagia and persistent increased levels of serotonin (5-HT) in the brain. Inasmuch as 5-HT is directly related to the negative regulation of food intake, here we have investigated whether the anorexic effects of 5-HT are altered by protein malnutrition. Pregnant Sprague-Dawley rats were fed ad libitum either a control (20% protein) or a low-protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 35 days their feeding behaviour was evaluated after the administration of DL-fenfluramine (DL-FEN), an anorexic compound that blocks the reuptake of 5-HT and stimulates its release. Male offspring born to protein-restricted dams exhibited significantly decreased body weight and hyperphagia compared with controls. DL-FEN dose-dependently reduced the 1 h chow intake at the onset of the dark cycle in both control and undernourished rats. However, the hypophagic effects of DL-FEN were significantly attenuated in animals submitted perinatally to protein restriction. The stimulatory action of DL-FEN on c-fos immunoreactivity within the paraventricular nucleus of the hypothalamus was also decreased in low-protein-fed rats. Further pharmacological analysis with selective 5-HT(1B) and 5-HT(2C) receptor agonist showed that the reduced anorexic effects of 5-HT in malnourished animals were coupled to a desensitization of 5-HT(1B) receptors. These observations indicate that the hyperphagia associated with metabolic programming is at least partially related to a reduced regulatory function of 5-HT on food intake.

  1. The Impact of a Dual-Project Action Learning Program: A Case of a Large IT Manufacturing Company in South Korea

    Science.gov (United States)

    Yoon, Hyung Joon; Cho, Yonjoo; Bong, Hyeon-Cheol

    2012-01-01

    The primary purpose of this article is to evaluate the impact of a dual-project action learning program (DPALP) conducted in South Korea. A dual-project program requires each participant to carry out both team and individual projects. Cho and Egan's [2009. Action learning research: A systematic review and conceptual framework. "Human Resource…

  2. Structure activity relationship of dendrimer microbicides with dual action antiviral activity.

    Directory of Open Access Journals (Sweden)

    David Tyssen

    Full Text Available BACKGROUND: Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. METHODS AND FINDINGS: Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115 and fourth generation (SPL7013 DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4 and CCR5-using (R5 HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. CONCLUSIONS: Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is

  3. Localization of chondromodulin-I at the feto-maternal interface and its inhibitory actions on trophoblast invasion in vitro

    Science.gov (United States)

    2011-01-01

    Background Chondromodulin-I (ChM-I) is an anti-angiogenic glycoprotein that is specifically localized at the extracellular matrix of the avascular mesenchyme including cartilage and cardiac valves. In this study, we characterized the expression pattern of ChM-I during early pregnancy in mice in vivo and its effect on invasion of trophoblastic cells into Matrigel in vitro. Results Northern blot analysis clearly indicated that ChM-I transcripts were expressed in the pregnant mouse uterus at 6.5-9.5 days post coitum. In situ hybridization and immunohistochemistry revealed that ChM-I was localized to the mature decidua surrounding the matrix metalloproteinase-9 (MMP-9)-expressing trophoblasts. Consistent with this observation, the expression of ChM-I mRNA was induced in decidualizing endometrial stromal cells in vitro, in response to estradiol and progesterone. Recombinant human ChM-I (rhChM-I) markedly inhibited the invasion through Matrigel as well as the chemotactic migration of rat Rcho-1 trophoblast cells in a manner independent of MMP activation. Conclusions This study demonstrates the inhibitory action of ChM-I on trophoblast migration and invasion, implying the potential role of the ChM-I expression in decidual cells for the regulated tissue remodeling and angiogenesis at feto-maternal interface. PMID:21849085

  4. Dual mode action of mangiferin in mouse liver under high fat diet.

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    Jihyeon Lim

    Full Text Available Chronic over-nutrition is a major contributor to the spread of obesity and its related metabolic disorders. Development of therapeutics has been slow compared to the speedy increase in occurrence of these metabolic disorders. We have identified a natural compound, mangiferin (MGF (a predominant component of the plants of Anemarrhena asphodeloides and Mangifera indica, that can protect against high fat diet (HFD induced obesity, hyperglycemia, insulin resistance and hyperlipidemia in mice. However, the molecular mechanisms whereby MGF exerts these beneficial effects are unknown. To understand MGF mechanisms of action, we performed unbiased quantitative proteomic analysis of protein profiles in liver of mice fed with HFD utilizing 15N metabolically labeled liver proteins as internal standards. We found that out of 865 quantified proteins 87 of them were significantly differentially regulated by MGF. Among those 87 proteins, 50% of them are involved in two major processes, energy metabolism and biosynthesis of metabolites. Further classification indicated that MGF increased proteins important for mitochondrial biogenesis and oxidative activity including oxoglutarate dehydrogenase E1 (Dhtkd1 and cytochrome c oxidase subunit 6B1 (Cox6b1. Conversely, MGF reduced proteins critical for lipogenesis such as fatty acid stearoyl-CoA desaturase 1 (Scd1 and acetyl-CoA carboxylase 1 (Acac1. These mass spectrometry data were confirmed and validated by western blot assays. Together, data indicate that MGF upregulates proteins pivotal for mitochondrial bioenergetics and downregulates proteins controlling de novo lipogenesis. This novel mode of dual pharmacodynamic actions enables MGF to enhance energy expenditure and inhibit lipogenesis, and thereby correct HFD induced liver steatosis and prevent adiposity. This provides a molecular basis supporting development of MGF or its metabolites into therapeutics to treat metabolic disorders.

  5. Dual Mode Action of Mangiferin in Mouse Liver under High Fat Diet

    Science.gov (United States)

    Lim, Jihyeon; Liu, Zhongbo; Apontes, Pasha; Feng, Daorong; Pessin, Jeffrey E.; Sauve, Anthony A.; Angeletti, Ruth H.; Chi, Yuling

    2014-01-01

    Chronic over-nutrition is a major contributor to the spread of obesity and its related metabolic disorders. Development of therapeutics has been slow compared to the speedy increase in occurrence of these metabolic disorders. We have identified a natural compound, mangiferin (MGF) (a predominant component of the plants of Anemarrhena asphodeloides and Mangifera indica), that can protect against high fat diet (HFD) induced obesity, hyperglycemia, insulin resistance and hyperlipidemia in mice. However, the molecular mechanisms whereby MGF exerts these beneficial effects are unknown. To understand MGF mechanisms of action, we performed unbiased quantitative proteomic analysis of protein profiles in liver of mice fed with HFD utilizing 15N metabolically labeled liver proteins as internal standards. We found that out of 865 quantified proteins 87 of them were significantly differentially regulated by MGF. Among those 87 proteins, 50% of them are involved in two major processes, energy metabolism and biosynthesis of metabolites. Further classification indicated that MGF increased proteins important for mitochondrial biogenesis and oxidative activity including oxoglutarate dehydrogenase E1 (Dhtkd1) and cytochrome c oxidase subunit 6B1 (Cox6b1). Conversely, MGF reduced proteins critical for lipogenesis such as fatty acid stearoyl-CoA desaturase 1 (Scd1) and acetyl-CoA carboxylase 1 (Acac1). These mass spectrometry data were confirmed and validated by western blot assays. Together, data indicate that MGF upregulates proteins pivotal for mitochondrial bioenergetics and downregulates proteins controlling de novo lipogenesis. This novel mode of dual pharmacodynamic actions enables MGF to enhance energy expenditure and inhibit lipogenesis, and thereby correct HFD induced liver steatosis and prevent adiposity. This provides a molecular basis supporting development of MGF or its metabolites into therapeutics to treat metabolic disorders. PMID:24598864

  6. Dual-action hypoglycemic and hypocholesterolemic agents that inhibit glycogen phosphorylase and lanosterol demethylase.

    Science.gov (United States)

    Harwood, H James; Petras, Stephen F; Hoover, Dennis J; Mankowski, Dayna C; Soliman, Victor F; Sugarman, Eliot D; Hulin, Bernard; Kwon, Younggil; Gibbs, E Michael; Mayne, James T; Treadway, Judith L

    2005-03-01

    Diabetic dyslipidemia requires simultaneous treatment with hypoglycemic agents and lipid-modulating drugs. We recently described glycogen phosphorylase inhibitors that reduce glycogenolysis in cells and lower plasma glucose in ob/ob mice (J. Med. Chem., 41: 2934, 1998). In evaluating the series prototype, CP-320626, in dogs, up to 90% reduction in plasma cholesterol was noted after 2 week treatment. Cholesterol reductions were also noted in ob/ob mice and in rats. In HepG2 cells, CP-320626 acutely and dose-dependently inhibited cholesterolgenesis without affecting fatty acid synthesis. Inhibition occurred together with a dose-dependent increase in the cholesterol precursor, lanosterol, suggesting that cholesterolgenesis inhibition was due to lanosterol 14alpha-demethylase (CYP51) inhibition. In ob/ob mice, acute treatment with CP-320626 resulted in a decrease in hepatic cholesterolgenesis with concomitant lanosterol accumulation, further implicating CYP51 inhibition as the mechanism of cholesterol lowering in these animals. CP-320626 and analogs directly inhibited rhCYP51, and this inhibition was highly correlated with HepG2 cell cholesterolgenesis inhibition (R2 = 0.77). These observations indicate that CP-320626 inhibits cholesterolgenesis via direct inhibition of CYP51, and that this is the mechanism whereby CP-320626 lowers plasma cholesterol in experimental animals. Dual-action glycogenolysis and cholesterolgenesis inhibitors therefore have the potential to favorably affect both the hyperglycemia and the dyslipidemia of type 2 diabetes.

  7. A dual action of valproic acid upon morphine analgesia and morphine withdrawal.

    Science.gov (United States)

    Tamayo, L; Contreras, E

    1983-01-01

    Effects of valproic acid administration on morphine analgesia and on morphine tolerance and dependence were investigated in mice. Valproate increased the reaction time to thermal stimulation in naive animals. This effect was additive with morphine when valproate was administered shortly before the analgesic. However, an antagonism was observed if a 4-hour period elapsed between valproate and morphine administration. When administered to mice receiving a sustained release preparation of morphine, valproate antagonized the development of tolerance to morphine. Valproate elicited a dual action on the abstinence signs observed after naloxone administration in morphine-treated mice. The effect consisted in a reduction of abstinence behavior if the anticonvulsant was administered a few minutes before naloxone; the same treatment increased the severity of the abstinence behavior when valproate was injected 1 h before the precipitating dose of naloxone. In this latter schedule, concomitant administration of gamma-vinyl-GABA failed to reduce the severity of the convulsions observed during the abstinence syndrome. These results suggest that valproate is metabolized to a compound responsible for decreased analgesia and intensified withdrawal signs.

  8. Inhibitory noise

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    Alain Destexhe

    2010-03-01

    Full Text Available Cortical neurons in vivo may operate in high-conductance states, in which the major part of the neuron's input conductance is due to synaptic activity, sometimes several-fold larger than the resting conductance. We examine here the contribution of inhibition in such high-conductance states. At the level of the absolute conductance values, several studies have shown that cortical neurons in vivo are characterized by strong inhibitory conductances. However, conductances are balanced and spiking activity is mostly determined by fluctuations, but not much is known about excitatory and inhibitory contributions to these fluctuations. Models and dynamic-clamp experiments show that, during high-conductance states, spikes are mainly determined by fluctuations of inhibition, or by inhibitory noise. This stands in contrast to low-conductance states, in which excitatory conductances determine spiking activity. To determine these contributions from experimental data, maximum likelihood methods can be designed and applied to intracellular recordings in vivo. Such methods indicate that action potentials are indeed mostly correlated with inhibitory fluctuations in awake animals. These results argue for a determinant role for inhibitory fluctuations in evoking spikes, and do not support feed-forward modes of processing, for which opposite patterns are predicted.

  9. Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus.

    Directory of Open Access Journals (Sweden)

    Sooyun Kim

    Full Text Available Oriens-lacunosum moleculare (O-LM interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.

  10. Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus.

    Science.gov (United States)

    Kim, Sooyun

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.

  11. Dual Mode of Action for Plusbacin A3 in Staphylococcus aureus.

    Science.gov (United States)

    O'Connor, Robert D; Singh, Manmilan; Chang, James; Kim, Sung Joon; VanNieuwenhze, Michael; Schaefer, Jacob

    2017-02-23

    We have used C{F}, N{F}, and N{P} rotational-echo double resonance NMR to determine the location and conformation of (19)F and (15)N double-labeled plusbacin A3 and of double-labeled deslipo-plusbacin A3, each bound to the cell walls of whole cells of Staphyloccocus aureus grown in media containing [1-(13)C]glycine. The (31)P is primarily in wall teichoic acid. Approximately 25% of plusbacin headgroups (the cyclic depsipeptide backbone) are in a closed conformation (N-F separation of 6 Å), while 75% are in a more open conformation (N-F separation of 12 Å). The closed headgroups have no contact with wall teichoic acid, whereas the open headgroups have a strong contact. This places the closed headgroups in hydrophobic regions of the cell wall and the open headgroups in hydrophilic regions. None of the plusbacin tails have contact with the (31)P of either wall teichoic acid or the cell membrane and thus are in hydrophobic regions of the cell wall. In addition, both heads and tails of plusbacin A3 have contact with the glycyl (13)C incorporated in cell-wall peptidoglycan pentaglycyl bridges and with (13)C-labeled purines near the membrane surface. We interpret these results in terms of a dual mode of action for plusbacin A3: first, disruption of the peptidoglycan layer nearest to the membrane surface by closed-conformation plusbacin A3 leading to an inhibition of chain extension by transglycosylation; second, thinning and disruption of the membrane (possibly including disruption of ATP-binding cassette transporters embedded in the membrane) by open-conformation plusbacin A3, thereby leading to release of ATP to the hydrophilic regions of the cell wall and subsequent binding by plusbacin A3.

  12. Exploring dual inhibitory role of febrifugine analogues against Plasmodium utilizing structure-based virtual screening and molecular dynamic simulation.

    Science.gov (United States)

    Pandey, Rajan Kumar; Narula, Aruna; Naskar, Manisha; Srivastava, Shubham; Verma, Parmila; Malik, Ruchi; Shah, Priyanka; Prajapati, Vijay Kumar

    2017-03-01

    Malaria is an endemic disease caused by the protozoan parasite Plasomodium falciparum. Febrifugine analogues are natural compound obtained from the traditional Chinese herbs have shown significant antimalarial and anticancerous efficacy in experimental model. Development of resistance against the existing antimalarial drug has alarmed the scientific innovators to find a potential antimalarial molecule which can be further used by endemic countries for the elimination of this disease. In this study, structure-based virtual screening and molecular dynamics (MD) base approaches were used to generate potential antimalarial compound against plasmepsin II and prolyl-tRNA synthetase of Plasmodium. Here, we have docked series of febrifugine analogues (n = 11,395) against plasmepsin II in three different docking modes and then it was compared with previously reported target prolyl-tRNA synthetase. Extra precision docking resulted into 235 ligands having better docking score were subject for QikProp analysis. Better ligands (n = 39) obtained from QikProp analysis were subject for ADMET prediction and docking protocol validation through the estimation of receiver operator characteristics. In the later stage, 24 ligands obtained from ADMET study were subject for the estimation of binding energy through MM-GBSA and same were also docked against prolyl-tRNA synthetase to get compounds with dual inhibitor role. Finally, MD simulation and 2D fingerprint MACCS study of two best ligands have shown significant interaction with plasmepsin II and homology against known active ligand with noteworthy MACCS index, respectively. This study concludes that FA12 could be potential drug candidate to fight against Plasmodium falciparum parasites.

  13. Negative inotropic action of denbufylline through interfering with the calcium channel independently of its PDE IV inhibitory activity in guinea pig ventricle papillary muscles.

    Science.gov (United States)

    Sanae, F; Ohmae, S; Kobayashi, D; Takag, K; Miyamoto, K

    1996-04-01

    The inotropic actions of xanthine derivatives with long alkyl chains were investigated in guinea pig ventricular papillary muscle. A potent and nonselective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine, elicited a positive inotropy and inhibited the negative inotropic effects of calcium channel inhibitors, as did a selective PDE III inhibitor, amrinone, and these effects were canceled by a protein kinase inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89). However, 1,3-di-n-butyl-7-(2'oxopropyl)xanthine (denbufylline) and 1-n-butyl-3-n-propylxanthine (XT-044), which have potent and selective PDE IV-inhibitory activities, showed negative inotropic actions that became more potent in the presence of H-89. Denbufylline abolished the late restoration phase induced by ryanodine. This xanthine derivative attenuated the effects of both the calcium channel acting agents Bay K 8644 and verapamil, without interaction with caffeine and dihydropyridine calcium channel inhibitors, and denbufylline had little direct influence on the specific binding of [(3)H]azidopine and [(3)H]desmethoxyverapamil to cardiac membranes. A nonxanthine PDE IV inhibitor, Ro 20-1724, did not affect the inotropic actions of calcium channel inhibitors. The attenuation by denbufylline or XT-044 of the negative inotropic action of verapamil was not influenced by treatment with H-89. These results suggest that in the ventricular papillary muscle, these xanthine derivatives elicit negative inotropy by acting on a verapamil-sensitive site of the calcium channel without involving their PDE-inhibitory activity.

  14. In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity on CYP-450 (Part 2).

    Science.gov (United States)

    Labrie, Philippe; Maddaford, Shawn P; Lacroix, Jacques; Catalano, Concettina; Lee, David K H; Rakhit, Suman; Gaudreault, René C

    2007-06-01

    Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency on the P-glycoprotein (P-gp) transporter. Previous studies showed that the replacement of the aromatic spacer group between nitrogen atoms (N(1) and N(2)) in the P-gp inhibitor XR9576 with ethyl or propyl chain is optimal for P-gp inhibition potency. To confirm that observation, the ethyl or the propyl linker arm was replaced with a pyrrolidine or an alicyclic group such as cyclohexyl. In addition, an arylpiperazinyl group and two methoxyl groups onto the anthranilic part were introduced to assess their effect on the anti P-gp activity. Five molecules were prepared and evaluated on CEM/VLB500. All new anthranilamides were more potent than verapamil, most of them exhibited a lower cytotoxicity than XR9576. Compound 5 was the most potent and its inhibition activity was similar to XR9576. Interestingly, in vitro biotransformation studies of compounds 4 and 5 using human CYP-450 isoforms revealed, that conversely to XR9576, compounds 4 and 5 inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of numerous drugs, notably paclitaxel. In that context, 5 might be suitable for further drug development.

  15. Vasorelaxant Effect of a Newly Synthesized Dihydropyridine Ethyl Ester (DHPEE on Rat Thoracic Aorta: Dual Mechanism of Action

    Directory of Open Access Journals (Sweden)

    Hossein Babaei

    2011-06-01

    Full Text Available Introduction: DHPEE is a newly synthesized compound by merging the key structural elements in an angiotensin receptor blocker (Telmisartan with key structural elements in 1,4- dihydropyridine calcium channel blocker (Nifedipine. In this study, we examined dual calcium channel blocking and AT1 antagonist activity for DHPEE. Methods: The functional inhibitory characteristics of DHPEE were studied in vitro in rat thoracic aorta preparations precontracted by phenylephrine (1µM or KCl (80µM or Ang II in normal or calcium-free solutions. Results: Concentration–dependent significant relaxation was observed in aortic rings precontracted with phenylephrine, KCl or Ang II. The tension increment produced by increasing external calcium was also reduced by DHPEE. DHPEE caused a marked decrease in the maximal contractile response of the vasoactive agents and shifted their concentration-response curves to the right. Conclusion: DHPEE possesses dual characteristics and cause vasorelaxation by blocking the L-type calcium channels and blocking Ang II receptors (AT1 in rat aortic smooth muscle.

  16. 3D Clustering of GABAergic Neurons Enhances Inhibitory Actions on Excitatory Neurons in the Mouse Visual Cortex

    Directory of Open Access Journals (Sweden)

    Teppei Ebina

    2014-12-01

    Full Text Available Neocortical neurons with similar functional properties assemble into spatially coherent circuits, but it remains unclear how inhibitory interneurons are organized. We applied in vivo two-photon functional Ca2+ imaging and whole-cell recording of synaptic currents to record visual responses of cortical neurons and analyzed their spatial arrangements. GABAergic interneurons were clustered in the 3D space of the mouse visual cortex, and excitatory neurons located within the clusters (insiders had a lower amplitude and sharper orientation tuning of visual responses than outsiders. Inhibitory synaptic currents recorded from the insiders were larger than those of the outsiders. Single, isolated interneurons did not show such a location-tuning/amplitude relationship. The two principal subtypes of interneurons, parvalbumin- and somatostatin-expressing neurons, also formed clusters with only slightly overlapping each other and exhibited a different location-tuning relationship. These findings suggest that GABAergic interneurons and their subgroups form clusters to make their inhibitory function more effective than isolated interneurons.

  17. On the Interacting Chiral Gauge Field Theory in D=6 and the Off-Shell Equivalence of Dual Born-Infeld-Like Actions

    CERN Document Server

    De Castro, A S

    1999-01-01

    A canonical action describing the interaction of chiral gauge fields in D=6 Minkowski space-time is constructed. In a particular partial gauge fixing it reduces to the action found by Perry and Schwarz. The additional gauge symmetries are used to show the off-shell equivalence of the dimensional reduction to D=5 Minkowski space-time of the chiral gauge field canonical action and the Born-Infeld canonical action describing an interacting D=5 Abelian vector field. Its extension to improve the on-shell equivalence arguments of dual D-brane actions to off-shell ones is discussed.

  18. Linear biocompatible glyco-polyamidoamines as dual action mode virus infection inhibitors with potential as broad-spectrum microbicides for sexually transmitted diseases

    Science.gov (United States)

    Mauro, Nicolò; Ferruti, Paolo; Ranucci, Elisabetta; Manfredi, Amedea; Berzi, Angela; Clerici, Mario; Cagno, Valeria; Lembo, David; Palmioli, Alessandro; Sattin, Sara

    2016-09-01

    The initial steps of viral infections are mediated by interactions between viral proteins and cellular receptors. Blocking the latter with high-affinity ligands may inhibit infection. DC-SIGN, a C-type lectin receptor expressed by immature dendritic cells and macrophages, mediates human immunodeficiency virus (HIV) infection by recognizing mannose clusters on the HIV-1 gp120 envelope glycoprotein. Mannosylated glycodendrimers act as HIV entry inhibitors thanks to their ability to block this receptor. Previously, an amphoteric, but prevailingly cationic polyamidoamine named AGMA1 proved effective as infection inhibitor for several heparan sulfate proteoglycan-dependent viruses, such as human papilloma virus HPV-16 and herpes simplex virus HSV-2. An amphoteric, but prevailingly anionic PAA named ISA23 proved inactive. It was speculated that the substitution of mannosylated units for a limited percentage of AGMA1 repeating units, while imparting anti-HIV activity, would preserve the fundamentals of its HPV-16 and HSV-2 infection inhibitory activity. In this work, four biocompatible linear PAAs carrying different amounts of mannosyl-triazolyl pendants, Man-ISA7, Man-ISA14, Man-AGMA6.5 and Man-AGMA14.5, were prepared by reaction of 2-(azidoethyl)-α-D-mannopyranoside and differently propargyl-substituted AGMA1 and ISA23. All mannosylated PAAs inhibited HIV infection. Both Man-AGMA6.5 and Man-AGMA14.5 maintained the HPV-16 and HSV-2 activity of the parent polymer, proving broad-spectrum, dual action mode virus infection inhibitors.

  19. A class of sulfonamides with strong inhibitory action against the α-carbonic anhydrase from Trypanosoma cruzi.

    Science.gov (United States)

    Güzel-Akdemir, Özlen; Akdemir, Atilla; Pan, Peiwen; Vermelho, Alane B; Parkkila, Seppo; Scozzafava, Andrea; Capasso, Clemente; Supuran, Claudiu T

    2013-07-25

    Trypanosoma cruzi, the causative agent of Chagas disease, encodes for an α-carbonic anhydrase (CA, EC 4.2.1.1) possessing high catalytic activity (TcCA) which was recently characterized (Pan et al. J. Med. Chem. 2013, 56, 1761-1771). A new class of sulfonamides possessing low nanomolar/subnanomolar TcCA inhibitory activity is described here. Aromatic/heterocyclic sulfonamides incorporating halogeno/methoxyphenacetamido tails inhibited TcCA with KIs in the range of 0.5-12.5 nM, being less effective against the human off-target isoforms hCA I and II. A homology model of TcCA helped us to rationalize the excellent inhibition profile of these compounds against the protozoan enzyme, a putative new antitrypanosoma drug target. These compounds were ineffective antitrypanosomal agents in vivo due to penetrability problems of these highly polar molecules that possess sulfonamide moieties.

  20. Anticipatory affect during action preparation: evidence from backward compatibility in dual-task performance.

    Science.gov (United States)

    Eder, Andreas B; Pfister, Roland; Dignath, David; Hommel, Bernhard

    2016-07-14

    Upcoming responses in the second of two subsequently performed tasks can speed up compatible responses in the temporally preceding first task. Two experiments extend previous demonstration of such backward compatibility to affective features: responses to affective stimuli were faster in Task 1 when an affectively compatible response effect was anticipated for Task 2. This emotional backward-compatibility effect demonstrates that representations of the affective consequences of the Task 2 response were activated before the selection of a response in Task 1 was completed. This finding is problematic for the assumption of a serial stimulus-response translation stage. It also shows that the affective consequence of a response is anticipated during, and has an impact on stimulus-response translation, which implies that action planning considers codes representing and predicting the emotional consequences of actions. Implications for the control of emotional actions are discussed.

  1. The stimulatory and inhibitory components of cocaine's actions on the 5-HTP-induced 5-HT2A receptor response.

    Science.gov (United States)

    Darmani, N A; Reeves, S L

    1996-11-01

    Previously we have shown that cocaine attenuates the 5-HT2A receptor-mediated head-twitch response (HTR) in mice produced by the 5-HT2A/C direct agonist (+/-)-1 (2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). This inhibition appears to be due to cocaine-induced indirect stimulation of the inhibitory serotonergic 5-HT1A and noradrenergic alpha 2 receptors via the inhibition of reuptake of synaptic serotonin (5-HT) and norepinephrine (NE), respectively. In the present study, we investigated the effects of cocaine, its phenyltropane analogue WIN 35428, and the selective 5-HT (sertraline). NE (nisoxetine) and dopamine (DA) (GBR 12935) reuptake inhibitors on the 5-hydroxytryptophan (5-HTP)-induced HTR. We utilized two experimental protocols where cocaine or the cited drugs were administered either after (protocol 1) or prior (protocol 2) to 5-HTP injection. Cocaine in both protocols produced a dose-dependent enhancement in the 5-HTP-induced HTR (ED50 4.68 +/- 1.21 and 3.55 +/- 1.31, respectively). Sertraline was more potent (ED50 2.64 +/- 1.1 and 2.1 +/- 1.54, respectively) in enhancing the induced behavior and dose by dose produced greater (3 to 10 times) HTRs than cocaine. On the other hand, nisoxetine dose dependently and completely attenuated the induced behavior (ID50 3.33 +/- 1.32 and 1.72 +/- 1.34, respectively), whereas GBR 12935 only at high doses (ID50 15.34 +/- 1.52 and 11.91 +/- 1.3, respectively) decreased the induced response. The inability of cocaine to induce as many HTRs as sertraline appears to lie in its ability to also indirectly stimulate the inhibitory 5-HT1A and alpha 2 receptors because the stimulant caused greater enhancement in the 5-HTP-induced HTRs in the presence of their corresponding antagonists [S(-)-UH 301 and yohimbine, respectively]. WIN 35428 was more potent (ED50 2.87 +/- 1.3 and 1.79 +/- 1.1 for protocols 1 and 2, respectively) in stimulating the 5-HTP-induced HTR and produced a bell-shaped dose-response curve. The results

  2. Action Potential Modulation in CA1 Pyramidal Neuron Axons Facilitates OLM Interneuron Activation in Recurrent Inhibitory Microcircuits of Rat Hippocampus

    OpenAIRE

    Sooyun Kim

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive ...

  3. Evidence for dual mechanisms of action prediction dependent on acquired visual-motor experiences.

    Science.gov (United States)

    Mulligan, Desmond; Lohse, Keith R; Hodges, Nicola J

    2016-10-01

    To test mechanisms underpinning action prediction, we directly controlled experience in a dart-throwing training study. A motor-visual group physically practiced throwing darts and a perceptual training group learned to associate dart throw actions (occluded video clips) with landing outcomes. A final control group did not practice. Accuracy was assessed on related prediction tests before and after practice (involving temporally occluded video clips). These tests were performed while additionally performing simple, action-incongruent secondary motor tasks with either the right (observed throwing arm) or left effector, in addition to an attention control task. Motor proficiency tests were also performed. Although both trained groups improved their prediction accuracy after training, only the motor-visual group showed interference associated with the right-arm secondary motor task after practice. No interference was shown for the left-arm motor task. These effects were evidenced regardless of whether predictions were made in response to video stimuli or static clips. Moreover, improvements on the motor proficiency test were only shown for the motor-visual group. These results show evidence in support of motor simulation processes during action prediction among observers with motor experience. Prediction accuracy can be achieved via nonmotor processes (for the perceptual group), but there was no evidence that physically experienced performers could effectively switch processes to maintain prediction accuracy. (PsycINFO Database Record

  4. Stimulation of the pre-SMA influences cerebral blood flow in frontal areas involved with inhibitory control of action.

    Science.gov (United States)

    Obeso, I; Cho, S S; Antonelli, F; Houle, S; Jahanshahi, M; Ko, J H; Strafella, A P

    2013-09-01

    Selection of the most appropriate response necessitates inhibition of competing or prepotent responses. It is important to characterize which cortical areas are relevant to achieve response inhibition. Using the stop signal task, previous imaging studies revealed consistent activation in the right pre-supplementary motor area (pre-SMA). However, imaging alone suffers from the limitation that it can only provide neuronal correlates and cannot establish causality between brain activation and behavior. Repetitive transcranial magnetic stimulation (rTMS) can be used to temporarily interfere with the function of a cortical area considered to play a specific role in the behavior. Thus, we combined rTMS with H(2)(15)O positron emission tomography (PET) scans during the stop signal task, to test whether rTMS-induced changes in excitability of the right pre-SMA influenced response inhibition. We found that rTMS over the pre-SMA increased the efficiency of the inhibitory control over prepotent ongoing responses. A significant interaction was present in the left inferior frontal gyrus (IFG) along with an increase in regional cerebral blood flow (rCBF) in the left pre-SMA, left IFG, right premotor and right inferior parietal cortex. These areas best fitted the path analysis model in the effective connectivity model. The results of this study suggest that stimulation of the right pre-SMA, by interfering with its activity, may have a significant impact on response inhibition. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Inhibitory action of some essential oils and phytochemicals on the growth of various moulds isolated from foods

    Directory of Open Access Journals (Sweden)

    Evandro Leite de Souza

    2005-03-01

    Full Text Available The aim of this study was to determine the sensitivity profile of mould strains isolated from foods to some essential oils and phytochemicals. The assayed mould strains were: Fusarium spp., Rhizopus spp., Aspergillus flavus, A. niger and Penicillium spp. According to results, Lippia alba N.E. Brown, Peumus boldus Molina, Lippia microphylla Phil., Citrus limon Risso and Cymbopogon citratus Stapf. essential oil and the phytochemicals citral, eugenol and mircene showed prominent antimould activity. Among the products that evidenced antimould activity, citral and eugenol showed the lowest minimum inhibitory concentrations, which was 1% and 4%, respectively, for the most of the tested mould strains.O objetivo deste estudo foi determinar o perfil de sensibilidade de cepas de fungos filamentosos isolados de alimento a alguns óleos essenciais e fitoconstituintes. As cepas fúngicas utilizadas nos ensaios antimicrobianos foram: Fusarium spp., Rhizopus spp., Aspergillus flavus, A. niger e Penicillium spp. De acordo com os resultados obtidos, os óleos essenciais de L. Alba N.R. Brown, P. boldus Molina, L. microphylla Phill, C. limon Risso e C. citratus Stapf. e os fitoconstituintes citral, eugenol e mirceno mostraram destacada atividade antifúngica. Dentre os produtos que apresentaram atividade antifúngica, o citral e eugenol mostraram as menores CIM's, as quais foram 1% e 4%, respectivamente, para a maioria das cepas fúngicas testadas.

  6. Structural basis for matrix metalloproteinase-2 (MMP-2)-selective inhibitory action of β-amyloid precursor protein-derived inhibitor.

    Science.gov (United States)

    Hashimoto, Hiroshi; Takeuchi, Tomoka; Komatsu, Kyoko; Miyazaki, Kaoru; Sato, Mamoru; Higashi, Shouichi

    2011-09-23

    Unlike other synthetic or physiological inhibitors for matrix metalloproteinases (MMPs), the β-amyloid precursor protein-derived inhibitory peptide (APP-IP) having an ISYGNDALMP sequence has a high selectivity toward MMP-2. Our previous study identified amino acid residues of MMP-2 essential for its selective inhibition by APP-IP and demonstrated that the N to C direction of the decapeptide inhibitor relative to the substrate-binding cleft of MMP-2 is opposite that of substrate. However, detailed interactions between the two molecules remained to be clarified. Here, we determined the crystal structure of the catalytic domain of MMP-2 in complex with APP-IP. We found that APP-IP in the complex is indeed embedded into the substrate-binding cleft of the catalytic domain in the N to C direction opposite that of substrate. With the crystal structure, it was first clarified that the aromatic side chain of Tyr(3) of the inhibitor is accommodated into the S1' pocket of the protease, and the carboxylate group of Asp(6) of APP-IP coordinates bidentately to the catalytic zinc of the enzyme. The Ala(7) to Pro(10) and Tyr(3) to Ile(1) strands of the inhibitor extend into the nonprime and the prime sides of the cleft, respectively. Therefore, the decapeptide inhibitor has long range contact with the substrate-binding cleft of the protease. This mode of interaction is probably essential for the high MMP-2 selectivity of the inhibitor because MMPs share a common architecture in the vicinity of the catalytic center, but whole structures of their substrate-binding clefts have sufficient variety for the inhibitor to distinguish MMP-2 from other MMPs.

  7. Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors.

    Science.gov (United States)

    Karkhanis, Anushree N; Huggins, Kimberly N; Rose, Jamie H; Jones, Sara R

    2016-11-01

    Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs "rescued" dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of

  8. Jak/Stat Signaling Stimulates Zebrafish Optic Nerve Regeneration and Overcomes the Inhibitory Actions of Socs3 and Sfpq

    Science.gov (United States)

    Elsaeidi, Fairouz; Bemben, Michael A.; Zhao, Xiao-Feng

    2014-01-01

    The regenerative failure of mammalian optic axons is partly mediated by Socs3-dependent inhibition of Jak/Stat signaling (Smith et al., 2009, 2011). Whether Jak/Stat signaling is part of the normal regenerative response observed in animals that exhibit an intrinsic capacity for optic nerve regeneration, such as zebrafish, remains unknown. Nor is it known whether the repression of regenerative inhibitors, such as Socs3, contributes to the robust regenerative response of zebrafish to optic nerve damage. Here we report that Jak/Stat signaling stimulates optic nerve regeneration in zebrafish. We found that IL-6 family cytokines, acting via Gp130-coupled receptors, stimulate Jak/Stat3 signaling in retinal ganglion cells after optic nerve injury. Among these cytokines, we found that CNTF, IL-11, and Clcf1/Crlf1a can stimulate optic axon regrowth. Surprisingly, optic nerve injury stimulated the expression of Socs3 and Sfpq (splicing factor, proline/glutamine rich) that attenuate optic nerve regeneration. These proteins were induced in a Jak/Stat-dependent manner, stimulated each other's expression and suppressed the expression of regeneration-associated genes. In vivo, the injury-dependent induction of Socs3 and Sfpq inhibits optic nerve regeneration but does not block it. We identified a robust induction of multiple cytokine genes in zebrafish retinal ganglion cells that may contribute to their ability to overcome these inhibitory factors. These studies not only identified mechanisms underlying optic nerve regeneration in fish but also suggest new molecular targets for enhancing optic nerve regeneration in mammals. PMID:24523552

  9. Inhibitory Action of Artemisia annua Extracts and Artemisinin on the Corrosion of Mild Steel in H2SO4 Solution

    Directory of Open Access Journals (Sweden)

    P. C. Okafor

    2012-01-01

    Full Text Available The action of ethanol (EEAA, acid (AEAA, and toluene (TEAA extracts from Artemisia annua and Artemisinin (ATS on mild steel corrosion in H2SO4 solutions was investigated using gravimetric and gasometric techniques. The extracts and ATS functioned as good inhibitors, and their inhibition efficiencies (%IE followed the trend: EEAA > AEAA > TEAA > ATS. %IE increased with increase in inhibitors concentration and decreased with increase in temperature. The enhanced %IE values of the extracts were attributed to synergistic effect of the components of the plant extracts with ATS. The adsorption of the inhibitors was consistent with Langmuir isotherm. Physisorption is proposed as the mechanism of inhibition.

  10. The anticonvulsant action of the galanin receptor agonist NAX-5055 involves modulation of both excitatory- and inhibitory neurotransmission

    DEFF Research Database (Denmark)

    Walls, Anne B; Flynn, Sean P; West, Peter J

    2016-01-01

    -based anti-convulsant drugs was prompted. Based on this, a rationally designed GalR1 preferring galanin analogue, NAX-5055, was synthesized. This compound demonstrates anti-convulsant actions in several animal models of epilepsy. However, the alterations at the cellular level leading to this anti-convulsant......M NAX-5055 led to a reduction in the extracellular level of glutamate and an elevation of the extracellular level of GABA. Altogether these findings may at least partly explain the anti-convulsant effect of NAX-5055 observed in vivo....

  11. Dual mode of action of Bt proteins: protoxin efficacy against resistant insects

    OpenAIRE

    2015-01-01

    Transgenic crops that produce Bacillus thuringiensis (Bt) proteins for pest control are grown extensively, but insect adaptation can reduce their effectiveness. Established mode of action models assert that Bt proteins Cry1Ab and Cry1Ac are produced as inactive protoxins that require conversion to a smaller activated form to exert toxicity. However, contrary to this widely accepted paradigm, we report evidence from seven resistant strains of three major crop pests showing that Cry1Ab and Cry1...

  12. Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans.

    Directory of Open Access Journals (Sweden)

    Deming Xu

    2007-06-01

    Full Text Available Candida albicans is a prevalent fungal pathogen amongst the immunocompromised population, causing both superficial and life-threatening infections. Since C. albicans is diploid, classical transmission genetics can not be performed to study specific aspects of its biology and pathogenesis. Here, we exploit the diploid status of C. albicans by constructing a library of 2,868 heterozygous deletion mutants and screening this collection using 35 known or novel compounds to survey chemically induced haploinsufficiency in the pathogen. In this reverse genetic assay termed the fitness test, genes related to the mechanism of action of the probe compounds are clearly identified, supporting their functional roles and genetic interactions. In this report, chemical-genetic relationships are provided for multiple FDA-approved antifungal drugs (fluconazole, voriconazole, caspofungin, 5-fluorocytosine, and amphotericin B as well as additional compounds targeting ergosterol, fatty acid and sphingolipid biosynthesis, microtubules, actin, secretion, rRNA processing, translation, glycosylation, and protein folding mechanisms. We also demonstrate how chemically induced haploinsufficiency profiles can be used to identify the mechanism of action of novel antifungal agents, thereby illustrating the potential utility of this approach to antifungal drug discovery.

  13. Dual action of neurokinin-1 antagonists on Mas-related GPCRs

    Science.gov (United States)

    Azimi, Ehsan; Reddy, Vemuri B.; Shade, Kai-Ting C.; Anthony, Robert M.; Pereira, Paula Juliana Seadi; Lerner, Ethan A.

    2016-01-01

    The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists. PMID:27734033

  14. Characterising the inhibitory actions of ceramide upon insulin signaling in different skeletal muscle cell models: a mechanistic insight.

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    Rana Mahfouz

    Full Text Available Ceramides are known to promote insulin resistance in a number of metabolically important tissues including skeletal muscle, the predominant site of insulin-stimulated glucose disposal. Depending on cell type, these lipid intermediates have been shown to inhibit protein kinase B (PKB/Akt, a key mediator of the metabolic actions of insulin, via two distinct pathways: one involving the action of atypical protein kinase C (aPKC isoforms, and the second dependent on protein phosphatase-2A (PP2A. The main aim of this study was to explore the mechanisms by which ceramide inhibits PKB/Akt in three different skeletal muscle-derived cell culture models; rat L6 myotubes, mouse C2C12 myotubes and primary human skeletal muscle cells. Our findings indicate that the mechanism by which ceramide acts to repress PKB/Akt is related to the myocellular abundance of caveolin-enriched domains (CEM present at the plasma membrane. Here, we show that ceramide-enriched-CEMs are markedly more abundant in L6 myotubes compared to C2C12 myotubes, consistent with their previously reported role in coordinating aPKC-directed repression of PKB/Akt in L6 muscle cells. In contrast, a PP2A-dependent pathway predominantly mediates ceramide-induced inhibition of PKB/Akt in C2C12 myotubes. In addition, we demonstrate for the first time that ceramide engages an aPKC-dependent pathway to suppress insulin-induced PKB/Akt activation in palmitate-treated cultured human muscle cells as well as in muscle cells from diabetic patients. Collectively, this work identifies key mechanistic differences, which may be linked to variations in plasma membrane composition, underlying the insulin-desensitising effects of ceramide in different skeletal muscle cell models that are extensively used in signal transduction and metabolic studies.

  15. Discovery of dual-action membrane-anchored modulators of incretin receptors.

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Fortin

    Full Text Available BACKGROUND: The glucose-dependent insulinotropic polypeptide (GIP and the glucagon-like peptide-1 (GLP-1 receptors are considered complementary therapeutic targets for type 2 diabetes. Using recombinant membrane-tethered ligand (MTL technology, the present study focused on defining optimized modulators of these receptors, as well as exploring how local anchoring influences soluble peptide function. METHODOLOGY/PRINCIPAL FINDINGS: Serial substitution of residue 7 in membrane-tethered GIP (tGIP led to a wide range of activities at the GIP receptor, with [G(7]tGIP showing enhanced efficacy compared to the wild type construct. In contrast, introduction of G(7 into the related ligands, tGLP-1 and tethered exendin-4 (tEXE4, did not affect signaling at the cognate GLP-1 receptor. Both soluble and tethered GIP and GLP-1 were selective activators of their respective receptors. Although soluble EXE4 is highly selective for the GLP-1 receptor, unexpectedly, tethered EXE4 was found to be a potent activator of both the GLP-1 and GIP receptors. Diverging from the pharmacological properties of soluble and tethered GIP, the newly identified GIP-R agonists, (i.e. [G(7]tGIP and tEXE4 failed to trigger cognate receptor endocytosis. In an attempt to recapitulate the dual agonism observed with tEXE4, we conjugated soluble EXE4 to a lipid moiety. Not only did this soluble peptide activate both the GLP-1 and GIP receptors but, when added to receptor expressing cells, the activity persists despite serial washes. CONCLUSIONS: These findings suggest that conversion of a recombinant MTL to a soluble membrane anchored equivalent offers a means to prolong ligand function, as well as to design agonists that can simultaneously act on more than one therapeutic target.

  16. Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation.

    Science.gov (United States)

    Pujadas-Mestres, Lluis; Lopez-Vilchez, Irene; Arellano-Rodrigo, Eduardo; Reverter, Joan Carles; Lopez-Farre, Antonio; Diaz-Ricart, Maribel; Badimon, Juan Jose; Escolar, Gines

    2017-01-01

    Mechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories. However, effects of DOACs on platelet activation and aggregation have not been explored in detail. We have investigated the effects of apixaban on platelet and fibrin components of thrombus formation under static and flow conditions. We assessed the effects of apixaban (10, 40 and 160 ng/mL) on: 1) platelet deposition and fibrin formation onto a thrombogenic surface, with blood circulating at arterial shear-rates; 2) viscoelastic properties of forming clots, and 3) thrombin generation in a cell-model of coagulation primed by platelets. In studies with flowing blood, only the highest concentration of apixaban, equivalent to the therapeutic Cmax, was capable to significantly reduce thrombus formation, fibrin association and platelet-aggregate formation. Apixaban significantly prolonged thromboelastometry parameters, but did not affect clot firmness. Interestingly, results in a platelet-based model of thrombin generation under more static conditions, revealed a dose dependent persistent inhibitory action by apixaban, with concentrations 4 to 16 times below the therapeutic Cmax significantly prolonging kinetic parameters and reducing the total amount of thrombin generated. Our studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban. Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis.

  17. Dual mode of action of Bt proteins: protoxin efficacy against resistant insects.

    Science.gov (United States)

    Tabashnik, Bruce E; Zhang, Min; Fabrick, Jeffrey A; Wu, Yidong; Gao, Meijing; Huang, Fangneng; Wei, Jizhen; Zhang, Jie; Yelich, Alexander; Unnithan, Gopalan C; Bravo, Alejandra; Soberón, Mario; Carrière, Yves; Li, Xianchun

    2015-10-12

    Transgenic crops that produce Bacillus thuringiensis (Bt) proteins for pest control are grown extensively, but insect adaptation can reduce their effectiveness. Established mode of action models assert that Bt proteins Cry1Ab and Cry1Ac are produced as inactive protoxins that require conversion to a smaller activated form to exert toxicity. However, contrary to this widely accepted paradigm, we report evidence from seven resistant strains of three major crop pests showing that Cry1Ab and Cry1Ac protoxins were generally more potent than the corresponding activated toxins. Moreover, resistance was higher to activated toxins than protoxins in eight of nine cases evaluated in this study. These data and previously reported results support a new model in which protoxins and activated toxins kill insects via different pathways. Recognizing that protoxins can be more potent than activated toxins against resistant insects may help to enhance and sustain the efficacy of transgenic Bt crops.

  18. Utilizing redox-mediated Bergman cyclization toward the development of dual-action metalloenediyne therapeutics.

    Science.gov (United States)

    Lindahl, Sarah E; Park, Hyunsoo; Pink, Maren; Zaleski, Jeffrey M

    2013-03-13

    resulting cisplatin-like byproduct represents an intriguing new strategy for potential dual-threat metalloenediyne therapeutics.

  19. Mussel-inspired superhydrophobic surfaces with enhanced corrosion resistance and dual-action antibacterial properties.

    Science.gov (United States)

    Qian, Hongchang; Li, Minglu; Li, Zhong; Lou, Yuntian; Huang, Luyao; Zhang, Dawei; Xu, Dake; Du, Cuiwei; Lu, Lin; Gao, Jin

    2017-11-01

    In this study, a multilayer antibacterial film was assembled onto 316L stainless steel via mussel-inspired depositions of polydopamine (PDA) and silver (Ag) nanoparticles followed by post-modification with 1H, 1H, 2H, 2H-perfluorodecanethiol. The resulting surface exhibited excellent superhydrophobicity with hierarchical micro/nanostructures that were constructed by both PDA and Ag nanoparticles. The crystal structure and chemical composition of these surfaces were investigated using X-ray photoelectron spectroscopy (XPS) analysis. Potentiodynamic polarization measurements revealed that the corrosion resistance of the as-prepared surfaces were sequentially increased after each step of the fabrication process. Compared with the surface covered with only Ag nanoparticles, the superhydrophobic surfaces exhibited substantially enhanced antibacterial activity against the Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, resulting from the synergistic antibacterial actions of the superhydrophobic surface and Ag nanoparticles. The superhydrophobic surface exhibited lower cytotoxicity, compared to the surface covered with Ag nanoparticles. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis.

    Science.gov (United States)

    Xie, Haibo; Chen, Gang; Young, Robert N

    2017-08-24

    A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized conjugate 16 was designed so that esterase activity will liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K cleavable peptide-linked conjugate for targeting of bisphosphonate prodrugs to bone and slow release liberation of the active constituents in vivo. Such conjugates are potential therapies for the treatment of bone disorders such as osteoporosis.

  1. GLATIRAMER ACETATE IS A FIRST-LINE DUAL-ACTION DRUG FOR THE TREATMENT OF RELAPSING-REMITTING MULTIPLE SCLEROSIS

    Directory of Open Access Journals (Sweden)

    T. E. Shmidt

    2016-01-01

    Full Text Available Multiple sclerosis (MS is the most common and potentially disabling disease of the central nervous system in young people. Not only inflammatory, but also neurodegenerative processes are involved in the pathogenesis of MS. The use of MS-modifying drugs (MSMDs  has led to a substantial reduction in the frequency of MS exacerbations and to the slower development of irreversible neurological deficit. Glatiramer acetate is one of the MSMDs of first choice and has a dual (anti-inflammatory and neuroprotective action. The drug has proven to be effective and safe if administered long-term. Therapy with glatiramer acetate has been established to promote the production of anti-inflammatory cytokines and neurotrophic factors, which prevent the development of a degenerative process and stimulate remyelination, and to slow the progression of cerebral atrophy. Experimental findings suggest that the drug improves the processes of neurogenesis.The efficiency of treatment is known to be associated with patient medication adherence. This largely depends on the frequency and route of drug administration and on the development of adverse events (AEs. To improve treatment adherence to glatiramer acetate, its new 40-mg formulation has been designed, which allows it to be administered only thrice weekly. The use of the formulation has demonstrated its efficacy and safety and resulted in a considerable reduction in the incidence rate of AEs.

  2. Dual Action of Lysophosphatidate-Functionalised Titanium: Interactions with Human (MG63) Osteoblasts and Methicillin Resistant Staphylococcus aureus.

    Science.gov (United States)

    Skindersoe, Mette Elena; Krogfelt, Karen A; Blom, Ashley; Zhang, Jianxing; Jiang, Guowei; Prestwich, Glenn D; Mansell, Jason Peter

    2015-01-01

    Titanium (Ti) is a widely used material for surgical implants; total joint replacements (TJRs), screws and plates for fixing bones and dental implants are forged from Ti. Whilst Ti integrates well into host tissue approximately 10% of TJRs will fail in the lifetime of the patient through a process known as aseptic loosening. These failures necessitate revision arthroplasties which are more complicated and costly than the initial procedure. Finding ways of enhancing early (osseo)integration of TJRs is therefore highly desirable and continues to represent a research priority in current biomaterial design. One way of realising improvements in implant quality is to coat the Ti surface with small biological agents known to support human osteoblast formation and maturation at Ti surfaces. Lysophosphatidic acid (LPA) and certain LPA analogues offer potential solutions as Ti coatings in reducing aseptic loosening. Herein we present evidence for the successful bio-functionalisation of Ti using LPA. This modified Ti surface heightened the maturation of human osteoblasts, as supported by increased expression of alkaline phosphatase. These functionalised surfaces also deterred the attachment and growth of Staphylococcus aureus, a bacterium often associated with implant failures through sepsis. Collectively we provide evidence for the fabrication of a dual-action Ti surface finish, a highly desirable feature towards the development of next-generation implantable devices.

  3. Dual Action of Lysophosphatidate-Functionalised Titanium: Interactions with Human (MG63 Osteoblasts and Methicillin Resistant Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Mette Elena Skindersoe

    Full Text Available Titanium (Ti is a widely used material for surgical implants; total joint replacements (TJRs, screws and plates for fixing bones and dental implants are forged from Ti. Whilst Ti integrates well into host tissue approximately 10% of TJRs will fail in the lifetime of the patient through a process known as aseptic loosening. These failures necessitate revision arthroplasties which are more complicated and costly than the initial procedure. Finding ways of enhancing early (osseointegration of TJRs is therefore highly desirable and continues to represent a research priority in current biomaterial design. One way of realising improvements in implant quality is to coat the Ti surface with small biological agents known to support human osteoblast formation and maturation at Ti surfaces. Lysophosphatidic acid (LPA and certain LPA analogues offer potential solutions as Ti coatings in reducing aseptic loosening. Herein we present evidence for the successful bio-functionalisation of Ti using LPA. This modified Ti surface heightened the maturation of human osteoblasts, as supported by increased expression of alkaline phosphatase. These functionalised surfaces also deterred the attachment and growth of Staphylococcus aureus, a bacterium often associated with implant failures through sepsis. Collectively we provide evidence for the fabrication of a dual-action Ti surface finish, a highly desirable feature towards the development of next-generation implantable devices.

  4. Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action.

    Science.gov (United States)

    Geoghegan, James C; Diedrich, Gundo; Lu, Xiaojun; Rosenthal, Kim; Sachsenmeier, Kris F; Wu, Herren; Dall'Acqua, William F; Damschroder, Melissa M

    2016-01-01

    CD73 (ecto-5'-nucleotidase) has recently been established as a promising immuno-oncology target. Given its role in activating purinergic signaling pathways to elicit immune suppression, antagonizing CD73 (i.e., releasing the brake) offers a complimentary pathway to inducing anti-tumor immune responses. Here, we describe the mechanistic activity of a new clinical therapeutic, MEDI9447, a human monoclonal antibody that non-competitively inhibits CD73 activity. Epitope mapping, structural, and mechanistic studies revealed that MEDI9447 antagonizes CD73 through dual mechanisms of inter-CD73 dimer crosslinking and/or steric blocking that prevent CD73 from adopting a catalytically active conformation. To our knowledge, this is the first report of an antibody that inhibits an enzyme's function through 2 distinct modes of action. These results provide a finely mapped epitope that can be targeted for selective, potent, and non-competitive inhibition of CD73, as well as establish a strategy for inhibiting enzymes that function in both membrane-bound and soluble states.

  5. Inhibitory actions by ibandronate sodium, a nitrogen-containing bisphosphonate, on calcium-activated potassium channels in Madin–Darby canine kidney cells

    Directory of Open Access Journals (Sweden)

    Sheng-Nan Wu

    2015-01-01

    Full Text Available The nitrogen-containing bisphosphonates used for management of the patients with osteoporosis were reported to influence the function of renal tubular cells. However, how nitrogen-containing bisphosphates exert any effects on ion currents remains controversial. The effects of ibandronate (Iban, a nitrogen-containing bisphosphonate, on ionic channels, including two types of Ca2+-activated K+ (KCa channels, namely, large-conductance KCa (BKCa and intermediate-conductance KCa (IKCa channels, were investigated in Madin–Darby canine kidney (MDCK cells. In whole-cell current recordings, Iban suppressed the amplitude of voltage-gated K+ current elicited by long ramp pulse. Addition of Iban caused a reduction of BKCa channels accompanied by a right shift in the activation curve of BKCa channels, despite no change in single-channel conductance. Ca2+ sensitivity of these channels was modified in the presence of this compound; however, the magnitude of Iban-mediated decrease in BKCa-channel activity under membrane stretch with different negative pressure remained unchanged. Iban suppressed the probability of BKCa-channel openings linked primarily to a shortening in the slow component of mean open time in these channels. The dissociation constant needed for Iban-mediated suppression of mean open time in MDCK cells was 12.2 μM. Additionally, cell exposure to Iban suppressed the activity of IKCa channels, and DC-EBIO or 9-phenanthrol effectively reversed its suppression. Under current-clamp configuration, Iban depolarized the cells and DC-EBIO or PF573228 reversed its depolarizing effect. Taken together, the inhibitory action of Iban on KCa-channel activity may contribute to the underlying mechanism of pharmacological or toxicological actions of Iban and its structurally similar bisphosphonates on renal tubular cells occurring in vivo.

  6. Dual Diverse Dynamic Reversible Actions of Ankaferd on EPCR and PAI-1 Inside Vascular Endothelial Cells With and Without LPS

    Directory of Open Access Journals (Sweden)

    Afife Karabıyık

    2012-12-01

    Full Text Available OBJECTIVE: Ankaferd Blood Stopper (ABS comprises a mixture of the plants Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum ve Urtica dioica. ABS has been used as a topical haemostatic agent because of its antihaemorrhagic effect. Its haemostatic mechanism of action remains to be investigated. ABS does not affect individual levels of the coagulation factors II, V, VII, VIII, IX, X, XI and XIII. The aim of this study was to investigate the effects of ABS on endothelium and immune response. So, we investigated the possible changes in EPCR and PAI-1 without and with LPS-challenge inside HUVECs. METHODS: 10 μL and 100 μL ABS is given to HUVECs in 5 min., 25 min., and 50 min.,6 hour and 24 hour time periods. 10 μg/ mL LPS has been added for one hour to observe the effects of LPS challenge on HUVECs and then the cells have been treated with ABS for the time period of 5 min., 25 min., 50 min. and 6 hours to observe ABS-effects on HUVECs. Total RNAs were isolated from HUVECs and then EPCR ve PAI-1 mRNA expression levels were investigated. RESULTS: It was microscopically observed that cells arised from the surface and adhered to each other after the ABS application to the HUVECs. Also, after 24 hours cells returned the normal growth and physiology. It suggests that the adhesive cellular functions of ABS may be reversible. 10 µl ABS have negative effect on EPCR and PAI-1 expressions. Moreover the effects increases with 100 µl ABS. EPCR and PAI-1 expression increased by time with LPS and 10 µl ABS. Expressions were very low during the first hour when LPS and 100 µl ABS were given but at the end of 6 hour, EPCR and PAI-1 expression increased similar to LPS and 10 µl ABS experiment. CONCLUSION: In this study, we observed that Ankaferd has dual diverse dynamic reversible actions depend on dose and concentration on EPCR and PAI-1 inside vascular endothelial cells in the model of HUVEC. ABS might have a role on numerous cellular

  7. Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: a potential local regulator of IGF action.

    Science.gov (United States)

    Mohan, S; Bautista, C M; Wergedal, J; Baylink, D J

    1989-11-01

    Inhibitory insulin-like growth factor binding protein (In-IGF-BP) has been purified to homogeneity from medium conditioned by TE89 human osteosarcoma cells by two different methods using Sephadex G-100 gel filtration, FPLC Mono Q ion-exchange, HPLC C4 reverse-phase, HPLC CN reverse-phase, and affinity chromatographies. In-IGF-BP thus purified appeared to be homogeneous and unique by the following criteria. (i) N-terminal sequence analysis yielded a unique sequence (Asp-Glu-Ala-Ile-His-Cys-Pro-Pro-Glu-Ser-Glu-Ala-Lys-Leu-Ala). (ii) Amino acid composition of In-IGF-BP revealed marked differences with the amino acid compositions of other known BPs. (iii) In-IGF-BP exhibited a single band with a molecular mass of 25 kDa under reducing conditions on sodium dodecyl sulfate/polyacrylamide gels. IGF-I and IGF-II but not insulin displaced the binding of 125I-labeled IGF-I or 125I-labeled IGF-II binding to In-IGF-BP. In-IGF-BP inhibited basal, IGF-stimulated bone cell proliferation and serum-stimulated bone cell proliferation. Forskolin increased synthesis of In-IGF-BP in TE85 human osteosarcoma cells in a dose-dependent manner. Based on these findings, we conclude that In-IGF-BP is a protein that has a unique sequence and significant biological actions on bone cells.

  8. Evaluation of nystatin containing chitosan hydrogels as potential dual action bio-active restorative materials: in vitro approach.

    Science.gov (United States)

    Perchyonok, V Tamara; Reher, Vanessa; Zhang, Shengmiao; Basson, Nicki; Grobler, Sias

    2014-11-28

    Healing is a specific biological process related to the general phenomenon of growth and tissue regeneration and is a process generally affected by several systemic conditions or as detrimental side-effects of chemotherapy- and radiotherapy-induced inflammation of the oral mucosa. The objectives of this study is to evaluate the novel chitosan based functional drug delivery systems, which can be successfully incorporated into "dual action bioactive restorative materials", capable of inducing in vitro improved wound healing prototype and containing an antibiotic, such as nystatin, krill oil as an antioxidant and hydroxyapatite as a molecular bone scaffold, which is naturally present in bone and is reported to be successfully used in promoting bone integration when implanted as well as promoting healing. The hydrogels were prepared using a protocol as previously reported by us. The physico-chemical features, including surface morphology (SEM), release behaviors, stability of the therapeutic agent-antioxidant-chitosan, were measured and compared to the earlier reported chitosan-antioxidant containing hydrogels. Structural investigations of the reactive surface of the hydrogel are reported. Release of nystatin was investigated for all newly prepared hydrogels. Bio-adhesive studies were performed in order to assess the suitability of these designer materials. Free radical defense capacity of the biomaterials was evaluated using established in vitro model. The bio-adhesive capacity of the materials in the in vitro system was tested and quantified. It was found that the favorable synergistic effect of free radical built-in defense mechanism of the new functional materials increased sustainable bio-adhesion and therefore acted as a functional multi-dimensional restorative material with potential application in wound healing in vitro.

  9. Evaluation of Nystatin Containing Chitosan Hydrogels as Potential Dual Action Bio-Active Restorative Materials: in Vitro Approach

    Directory of Open Access Journals (Sweden)

    V. Tamara Perchyonok

    2014-11-01

    Full Text Available Healing is a specific biological process related to the general phenomenon of growth and tissue regeneration and is a process generally affected by several systemic conditions or as detrimental side-effects of chemotherapy- and radiotherapy-induced inflammation of the oral mucosa. The objectives of this study is to evaluate the novel chitosan based functional drug delivery systems, which can be successfully incorporated into “dual action bioactive restorative materials”, capable of inducing in vitro improved wound healing prototype and containing an antibiotic, such as nystatin, krill oil as an antioxidant and hydroxyapatite as a molecular bone scaffold, which is naturally present in bone and is reported to be successfully used in promoting bone integration when implanted as well as promoting healing. The hydrogels were prepared using a protocol as previously reported by us. The physico-chemical features, including surface morphology (SEM, release behaviors, stability of the therapeutic agent-antioxidant-chitosan, were measured and compared to the earlier reported chitosan-antioxidant containing hydrogels. Structural investigations of the reactive surface of the hydrogel are reported. Release of nystatin was investigated for all newly prepared hydrogels. Bio-adhesive studies were performed in order to assess the suitability of these designer materials. Free radical defense capacity of the biomaterials was evaluated using established in vitro model. The bio-adhesive capacity of the materials in the in vitro system was tested and quantified. It was found that the favorable synergistic effect of free radical built-in defense mechanism of the new functional materials increased sustainable bio-adhesion and therefore acted as a functional multi-dimensional restorative material with potential application in wound healing in vitro.

  10. Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex.

    Science.gov (United States)

    Nowak, Lionel G; Rosay, Benoît; Czégé, Dávid; Fonta, Caroline

    2015-01-01

    Tissue non-specific alkaline phosphatase (TNAP) may be involved in the synthesis of GABA and adenosine, which are the main inhibitory neurotransmitters in cortex. We explored this putative TNAP function through electrophysiological recording (local field potential ) in slices of mouse somatosensory cortex maintained in vitro. We used tetramisole, a well documented TNAP inhibitor, to block TNAP activity. We expected that inhibiting TNAP with tetramisole would lead to an increase of neuronal response amplitude, owing to a diminished availability of GABA and/or adenosine. Instead, we found that tetramisole reduced neuronal response amplitude in a dose-dependent manner. Tetramisole also decreased axonal conduction velocity. Levamisole had identical effects. Several control experiments demonstrated that these actions of tetramisole were independent from this compound acting on TNAP. In particular, tetramisole effects were not stereo-specific and they were not mimicked by another inhibitor of TNAP, MLS-0038949. The decrease of axonal conduction velocity and preliminary intracellular data suggest that tetramisole blocks voltage-dependent sodium channels. Our results imply that levamisole or tetramisole should not be used with the sole purpose of inhibiting TNAP in living excitable cells as it will also block all processes that are activity-dependent. Our data and a review of the literature indicate that tetramisole may have at least four different targets in the nervous system. We discuss these results with respect to the neurological side effects that were observed when levamisole and tetramisole were used for medical purposes, and that may recur nowadays due to the recent use of levamisole and tetramisole as cocaine adulterants.

  11. Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation; Accion inhibidora de la clorofilina de letales recesivos autosonicos inducidos por irradiacion

    Energy Technology Data Exchange (ETDEWEB)

    Salceda, V.M.; Pimentel, P.A.E.; Cruces, M.P. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)]. e-mail: vmss@nuclear.inin.mx

    2006-07-01

    The chlorolin is a sodium salt of the chlorophyll that has a strong protective action of the damage induced by different agents so much physical as chemical. In Drosophila there is reported this effect in somatic cells. In contrast, in germinal cells using tests with the sexual chromosomes has not been found such inhibitory action. For this reason, in this occasion we will refer to the effect of the lethality induced in autosome chromosomes, in particular to the chromosome II of this species. For such effect groups of males of the line Canton-S its were pre-treated for 24h with or without 69 mm of CCS and later on treaties with or without 40 Gy of gamma irradiation. The males were then subjected to the technical Cy L / Pm for the detection of recessive lethals. In the third generation the respective counts of the descendant of each one of them to determine the corresponding categories for each extracted chromosome were made. To be mendelian crosses it is expected for a normal chromosome a proportion 2:1 of individuals with genotype Cy L / +: +/+. The absence of individuals +/+ it is indicative of a lethal gene, until 10% of these individuals of each male's total descendant, it is considered that is carrying of a semi lethal gene. The sum of lethal and semi lethals constitutes the category detrimental. The obtained results indicated that the pre-treatment with CCS reduces in a significant way the frequency of induced lethals by 40 Gy of gamma rays. The fact that an effect inhibitor has not been observed in the test of recessive lethal bound to the sex obtained previously, it contrasts with the effect observed in the chromosome II, results of this study and with the one observed in the chromosome III in somatic cells. The above-mentioned shows a differential action of the CCS between sexual chromosomes and autosomal before the effect of the gamma radiation. At the moment we don't have an explanation to these evidences. To evaluate the action of the

  12. Dual Inhibitory Pathways of Metallofullerenol Gd@C82(OH)22 on Matrix Metalloproteinase-2: Molecular insight into drug-like nanomedicine

    Science.gov (United States)

    Kang, Seung-Gu; Araya-Secchi, Raul; Wang, Deqiang; Wang, Bo; Huynh, Tien; Zhou, Ruhong

    2014-04-01

    Cancer metastasis is an important criterion to evaluate tumor malignancy. Matrix metalloproteinases (MMPs) play a crucial role in cancer proliferation and migration by virtue of their proteolytic functions in angiogenesis and extracelluar matrix (ECM) degradation, making them potential targets of anti-metastaic therapeutics. Recently we showed with both in vivo and in vitro experiments that metallofullerenol Gd@C82(OH)22 can effectively inhibit MMP-2 and MMP-9 with high antitumoral efficacy. Furthermore, our in silico study revealed that Gd@C82(OH)22 could indirectly inhibit the proteolysis of MMP-9 via allosteric modulation exclusively at the ligand specificity S1' loop. Here, we expand our study toward another gelatinase, MMP-2, using molecular dynamics simulations. Despite the high structural similarity with 64.3% sequence identity, their responses to Gd@C82(OH)22 were quite different. Toward MMP-2, Gd@C82(OH)22 could block either the Zn2+-catalylitic site directly or the S1' loop indirectly. Surface electrostatics uniquely determines the initial adsorption of Gd@C82(OH)22 on MMP-2, and then its further location of the most favorable binding site(s). These findings not only illustrated how the inhibitory mechanism of Gd@C82(OH)22 is distinguished between the two gelatinase MMPs with atomic details, but also shed light on the de novo design of anti-metastatic nanotherapeutics with enhanced target specificity.

  13. Co-lateralized bilingual mechanisms for reading in single and dual language contexts: evidence from visual half-field processing of action words in proficient bilinguals

    Directory of Open Access Journals (Sweden)

    Marlena eKrefta

    2015-08-01

    Full Text Available When reading, proficient bilinguals seem to engage the same cognitive circuits regardless of the language in use. Yet, whether or not such ‘bilingual’ mechanisms would be lateralized in the same way in distinct – single or dual – language contexts is a question for debate. To fill this gap, we tested 18 highly proficient Polish (L1 – English (L2 childhood bilinguals whose task was to read aloud one of the two laterally presented action verbs, one stimulus per visual half field. While in the single-language blocks only L1 or L2 words were shown, in the subsequent mixed-language blocks words from both languages were concurrently displayed. All stimuli were presented for 217 ms followed by masks in which letters were replaced with hash marks. Since in non-simultaneous bilinguals the control of language, skilled actions (including reading, and representations of action concepts are typically left lateralized, the vast majority of our participants showed the expected, significant right visual field advantage for L1 and L2, both for accuracy and response times. The observed effects were nevertheless associated with substantial variability in the strength of the lateralization of the mechanisms involved. Moreover, although it could be predicted that participants’ performance should be better in a single-language context, accuracy was significantly higher and response times were significantly shorter in a dual-language context, irrespective of the language tested. Finally, for both accuracy and response times, there were significant positive correlations between the laterality indices (LIs of both languages independent of the context, with a significantly greater left-sided advantage for L1 vs. L2 in the mixed-language blocks, based on LIs calculated for response times. Thus, despite similar representations of the two languages in the bilingual brain, these results also point to the functional separation of L1 and L2 in the dual

  14. Novel N-(pyrimidin-4-ylthiazol-2-amine derivatives as dual-action hypoglycemic agents that activate GK and PPARγ

    Directory of Open Access Journals (Sweden)

    Hui-peng Song

    2011-10-01

    Full Text Available A series of novel N-(pyrimidin-4-ylthiazol-2-amine derivatives have been synthesized and evaluated as glucokinase (GK activators. Ethyl 2-(6-(4-(2-hydroxyethylpiperazin-1-yl-2-methylpyrimidin-4-yl-aminothiazole-5-carboxylate was found to be a potent dual-acting hypoglycemic agent activating both GK and PPARγ. When given orally to normal mice, the compound demonstrated significant efficacy in decreasing the glucose level after oral glucose loading.

  15. Synthesis and HIV-1 RT inhibitory action of novel (4/6-substituted benzo[d]thiazol -2-yl)thiazolidin-4-ones. Divergence from the non-competitive inhibition mechanism.

    Science.gov (United States)

    Pitta, Eleni; Geronikaki, Athina; Surmava, Sofiko; Eleftheriou, Phaedra; Mehta, Vaibhav P; Van der Eycken, Erik V

    2013-02-01

    Reverse transcriptase (RT) inhibitors play a major role in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Although, many compounds are already used as anti-HIV drugs, research on development of novel inhibitors continues, since drug resistant strains appear because of prolonged therapy. In this paper, we present the synthesis and evaluation of HIV-1 RT inhibitory action of eighteen novel (4/6-halogen/MeO/EtO-substituted benzo[d]thiazol-2-yl)thiazolidin-4-ones. The two more active compounds (IC50 : 0.04 µM and 0.25 µM) exhibited better inhibitory action than the reference compound, nevirapine. Docking analysis supports a stable binding of the most active derivative to the allosteric centre of RT. Kinetic analysis of two of the most active compounds indicate an uncompetitive inhibition mode. This is a desired characteristic, since mutations that affect activity of traditional non-competitive NNRTIs may not affect activity of compounds of this series. Interestingly, the less active derivatives (IC50 > 40 µM) exhibit a competitive mode of action.

  16. Dual optical recordings for action potentials and calcium handling in induced pluripotent stem cell models of cardiac arrhythmias using genetically encoded fluorescent indicators.

    Science.gov (United States)

    Song, LouJin; Awari, Daniel W; Han, Elizabeth Y; Uche-Anya, Eugenia; Park, Seon-Hye E; Yabe, Yoko A; Chung, Wendy K; Yazawa, Masayuki

    2015-05-01

    Reprogramming of human somatic cells to pluripotency has been used to investigate disease mechanisms and to identify potential therapeutics. However, the methods used for reprogramming, in vitro differentiation, and phenotyping are still complicated, expensive, and time-consuming. To address the limitations, we first optimized a protocol for reprogramming of human fibroblasts and keratinocytes into pluripotency using single lipofection and the episomal vectors in a 24-well plate format. This method allowed us to generate multiple lines of integration-free and feeder-free induced pluripotent stem cells (iPSCs) from seven patients with cardiac diseases and three controls. Second, we differentiated human iPSCs derived from patients with Timothy syndrome into cardiomyocytes using a monolayer differentiation method. We found that Timothy syndrome cardiomyocytes showed slower, irregular contractions and abnormal calcium handling compared with the controls. The results are consistent with previous reports using a retroviral method for reprogramming and an embryoid body-based method for cardiac differentiation. Third, we developed an efficient approach for recording the action potentials and calcium transients simultaneously in control and patient cardiomyocytes using genetically encoded fluorescent indicators, ArcLight and R-GECO1. The dual optical recordings enabled us to observe prolonged action potentials and abnormal calcium handling in Timothy syndrome cardiomyocytes. We confirmed that roscovitine rescued the phenotypes in Timothy syndrome cardiomyocytes and that these findings were consistent with previous studies using conventional electrophysiological recordings and calcium imaging with dyes. The approaches using our optimized methods and dual optical recordings will improve iPSC applicability for disease modeling to investigate mechanisms underlying cardiac arrhythmias and to test potential therapeutics.

  17. Dual-action Hybrid Compounds - A New Dawn in the Discovery of Multi-target Drugs: Lead Generation Approaches.

    Science.gov (United States)

    Abdolmalekia, Azizeh; Ghasemi, Jahan B

    2016-09-27

    Finding high quality beginning compounds is a critical job at the start of the lead generation stage for multi-target drug discovery (MTDD). Designing hybrid compounds as a selective multi-target chemical entity is a challenge, opportunity, and new idea to better act against specific multiple targets. One hybrid molecule is formed by two (or more) pharmacophore group's participation. So, these new compounds often exhibit two or more activities going about as multi-target drugs (mt-drugs) and may have superior safety or efficacy. Application of integrating a range of information and sophisticated new in silico, bioinformatics, structural biology, pharmacogenomics methods may be useful to discover/design, and synthesis of the new hybrid molecules. In this regard, many rational and screening approaches have followed by medicinal chemists for the lead generation in MTDD. Here, we review some popular lead generation approaches that have been used for designing multiple ligands (DMLs). This paper focuses on dual- acting chemical entities that incorporate a part of two drugs or bioactive compounds to compose hybrid molecules. Also, it presents some of key concepts and limitations/strengths of lead generation methods by comparing combination framework method with screening approaches. Besides, a number of examples to represent applications of hybrid molecules in the drug discovery are included.

  18. Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area.

    Science.gov (United States)

    Lamsa, Karri; Taira, Tomi

    2003-09-01

    Cortical inhibitory interneurons set the pace of synchronous neuronal oscillations implicated in synaptic plasticity and various cognitive functions. The hyperpolarizing nature of inhibitory postsynaptic potentials (IPSPs) in interneurons has been considered crucial for the generation of oscillations at beta (15-30 Hz) and gamma (30-100 Hz) frequency. Hippocampal basket cells and axo-axonic cells in stratum pyramidale-oriens (S-PO) play a central role in the synchronization of the local interneuronal network as well as in pacing of glutamatergic principal cell firing. A lack of conventional forms of plasticity in excitatory synapses onto interneurons facilitates their function as stable neuronal oscillators. We have used gramicidin-perforated and whole cell clamp recordings to study properties of GABAAR-mediated transmission in CA3 SP-O interneurons and in CA3 pyramidal cells in rat hippocampal slices during electrical 5- to 100-Hz stimulation and during spontaneous activity. We show that GABAergic synapses onto SP-O interneurons can easily switch their mode from inhibitory to excitatory during heightened activity. This is based on a depolarizing shift in the GABAA reversal potential (EGABA-A), which is much faster and more pronounced in interneurons than in pyramidal cells. We also found that the shift in interneuronal function was frequency dependent, being most prominent at 20- to 40-Hz activation of the GABAergic synapses. After 40-Hz tetanic stimulation (100 pulses), GABAA responses remained depolarizing for approximately 45 s in the interneurons, promoting bursting in the GABAergic network. Hyperpolarizing EGABA-A was restored >60 s after the stimulus train. Similar but spontaneous GABAergic bursting was induced by application of 4-aminopyridine (100 microM) to slices. A shift to depolarizing IPSPs by the GABAAR permeant weak acid anion formate provoked interneuronal population bursting, supporting the role of GABAergic excitation in burst generation

  19. The Diversity of Cortical Inhibitory Synapses

    Directory of Open Access Journals (Sweden)

    Yoshiyuki eKubota

    2016-04-01

    Full Text Available The most typical and well known inhibitory action in the cortical microcircuit is a strong inhibition on the target neuron by axo-somatic synapses. However, it has become clear that synaptic inhibition in the cortex is much more diverse and complicated. Firstly, at least ten or more inhibitory non-pyramidal cell subtypes engage in diverse inhibitory functions to produce the elaborate activity characteristic of the different cortical states. Each distinct non-pyramidal cell subtype has its own independent inhibitory function. Secondly, the inhibitory synapses innervate different neuronal domains, such as axons, spines, dendrites and soma, and their IPSP size is not uniform. Thus cortical inhibition is highly complex, with a wide variety of anatomical and physiological modes. Moreover, the functional significance of the various inhibitory synapse innervation styles and their unique structural dynamic behaviors differ from those of excitatory synapses. In this review, we summarize our current understanding of the inhibitory mechanisms of the cortical microcircuit.

  20. Presynaptic α₂-adrenoceptors control the inhibitory action of presynaptic CB₁ cannabinoid receptors on prefrontocortical norepinephrine release in the rat.

    Science.gov (United States)

    Richter, Hardy; Teixeira, Filipe M; Ferreira, Samira G; Kittel, Ágnes; Köfalvi, Attila; Sperlágh, Beáta

    2012-10-01

    Endocannabinoids play a crucial neuromodulator role in both physiological and pathological states in various brain regions including the prefrontal cortex (PFC). We examined, whether presynaptic cannabinoid receptors are involved in the modulation of basal and electrical field stimulation-evoked [³H]norepinephrine ([³H]NE) release from rat PFC slices. WIN55,212-2, a nonselective CB₁ receptor (CB₁R) agonist, inhibited the electrical stimulation-evoked efflux of [³H]NE in a concentration-dependent fashion, which was antagonized by the CB₁R antagonist/inverse agonist, AM251 (1 μM). Idazoxan, a selective α₂-adrenoceptor antagonist, augmented the evoked [³H]NE release. In the presence of idazoxan, the effect of WIN55,212-2 was exacerbated or attenuated, depending on the applied concentration and stimulation frequency. Moreover their combined, but not individual application elicited a depressive-like phenomenon in the forced-swim test. These data were bolstered with fluorescent and confocal microscopy analysis, which revealed that CB₁R immunoreactivity co-localized with dopamine-β-hydroxylase positive (i.e. noradrenergic) fibers and the inhibitory α(2A) adrenergic autoreceptors (α(2A)R) in the PFC. Furthermore, idazoxan triggered a decrease in CB₁R density in the PFC, suggesting that high extracellular level of norepinephrine downregulates CB₁Rs.

  1. Retinoic acid exerts dual regulatory actions on the expression and nuclear localization of interferon regulatory factor-1.

    Science.gov (United States)

    Luo, Xin M; Ross, A Catharine

    2006-05-01

    Interferon regulatory factor-1 (IRF-1), a transcription factor and tumor suppressor involved in cell growth regulation and immune responses, has been shown to be induced by all-trans retinoic acid (ATRA). However, the factors controlling the cellular location and activity of IRF-1 are not well understood. In this study, we examined the expression of IRF-1 and its nuclear localization, DNA-binding activity, and target gene expression in human mammary epithelial MCF10A cells, a model of breast epithelial cell differentiation and carcinogenesis. Following initial treatment with ATRA, IRF-1 mRNA and protein were induced within 2 hrs, reached a peak (>30-fold induction) at 8 hrs, and declined afterwards. IRF-1 protein was predominantly cytoplasmic during this treatment. Although a second dose of ATRA or Am580 (a related retinoid selective for retinoic acid receptor-alpha [RARalpha]), given 16 hrs after the first dose, restimulated IRF-1 mRNA and protein levels to a similar level to that obtained by the first dose, IRF-1 was predominantly concentrated in the nucleus after restimulation. ATRA and Am580 also increased nuclear RARalpha, whereas retinoid X receptor-alpha (RXRalpha)--a dimerization partner for RARalpha, was localized to the nucleus upon second exposure to ATRA. However, ATRA and Am580 did not regulate the expression or activation of signal transducer and activator of transcription-1 (STAT-1), a transcription factor capable of inducing the expression of IRF-1, indicating an STAT-1-independent mechanism of regulation by ATRA and Am580. The increase in nuclear IRF-1 after retinoid restimulation was accompanied by enhanced binding to an IRF-E DNA response element, and elevated expression of an IRF-1 target gene, 2',5'-oligoadenylate synthetase-2. The dual effect of retinoids in increasing IRF-1 mRNA and protein and in augmenting the nuclear localization of IRF-1 protein may be essential for maximizing the tumor suppressor activity and the immunosurveillance

  2. Insights into the influence of 5-HT2c aminoacidic variants with the inhibitory action of serotonin inverse agonists and antagonists.

    Science.gov (United States)

    Galeazzi, Roberta; Massaccesi, Luca; Piva, Francesco; Principato, Giovanni; Laudadio, Emilioano

    2014-03-01

    Specific modulation of serotonin 5-HT(2C) G protein-coupled receptors may be therapeutic for obesity and neuropsychiatric disorders. The different efficacy of drugs targeting these receptors are due to the presence of genetic variants in population and this variability is still hard to predict. Therefore, in order to administer the more suitable drug, taking into account patient genotype, it is necessary to know the molecular effects of its gene nucleotide variations. In this work, starting from an accurate 3D model of 5-HT(2C), we focus on the prediction of the possible effect of some single nucleotide polymorphisms (SNPs) producing amino acidic changes in proximity of the 5-HT(2C) ligand binding site. Particularly we chose a set of 5-HT(2C) inverse agonists and antagonists which have high inhibitory activity. After prediction of the structures of the receptor-ligand complexes using molecular docking tools, we performed full atom molecular dynamics simulations in explicit lipid bilayer monitoring the interactions between ligands and trans-membrane helices of the receptor, trying to infer relations with their biological activity. Serotonin, as the natural ligand was chosen as reference compound to advance a hypothesis able to explain the receptor inhibition mechanism. Indeed we observed a different behavior between the antagonists and inverse agonist with respect to serotonin or unbounded receptor, which could be responsible, even if not directly, of receptor's inactivation. Furthermore, we analyzed five aminoacidic variants of 5HT(2C) receptor observing alterations in the interactions between ligands and receptor which give rise to changes of free energy values for every complex considered.

  3. The Inhibitory Effects of Ketamine on Human Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Action Potential in Rabbit Sinoatrial Node.

    Science.gov (United States)

    Xing, Junlian; Zhang, Chi; Jiang, Wanzhen; Hao, Jie; Liu, Zhipei; Luo, Antao; Zhang, Peihua; Fan, Xinrong; Ma, Jihua

    2017-01-01

    To investigate the effects of ketamine on human hyperpolarization-activated cyclic nucleotide-gated (hHCN) 1, 2, 4 channel currents expressed in Xenopus oocytes and spontaneous action potentials (APs) of rabbit sinoatrial node (SAN). The 2-electrode voltage clamp and standard microelectrode techniques were respectively applied to record hHCN channels currents expressed in Xenopus oocytes and APs of SAN separated from rabbit heart. Ketamine (1-625 µmol/L) blocked hHCN1, 2, and 4 currents with IC50 of 67.0, 89.1, and 84.0 µmol/L, respectively, in a concentration-dependent manner. The currents were rapidly blocked by ketamine and partially recovered after washout. The steady-state activation curves of hHCN1, 2, and 4 currents demonstrated a concentration-dependent shift to the left and the rates of activation were significantly decelerated. But ketamine blocked hHCN channels in a voltage-independence and non-use-dependent manner, and did not modify the voltage dependence of activation and reversal potentials. Furthermore, ketamine suppressed phase-4 spontaneous depolarization rate in isolated rabbit SAN and decreased the beat rates in a concentration-dependent manner. Ketamine could inhibit hHCN channels expressed in Xenopus oocytes in a concentration-dependent manner as a close-state blocker and decrease beat rates of isolated rabbit SAN. This study may provide novel insights into other unexplained actions of ketamine. © 2017 S. Karger AG, Basel.

  4. Behavioral responses of dopamine beta-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action.

    Science.gov (United States)

    Mitchell, Heather A; Bogenpohl, James W; Liles, L Cameron; Epstein, Michael P; Bozyczko-Coyne, Donna; Williams, Michael; Weinshenker, David

    2008-12-01

    Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine beta-hydroxylase knockout (Dbh -/-) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency). Dbh -/- mice completely lack NE but have hypersensitive DA signaling. It was hypothesized that Dbh -/- mice would be unresponsive to modafinil if the compound acts primarily via NE, but would be hypersensitive to modafinil if it acts primarily via DA. Dbh -/- mice had increased sensitivity to the locomotor-activating and wake-promoting effects of modafinil. Paradoxically, the alpha1-adrenergic receptor antagonist, prazosin, attenuated the effects of modafinil in control mice, but not in Dbh -/- mice. Blockade of DA receptors with flupenthixol decreased modafinil-induced locomotion and wake in both control and Dbh -/- mice. These results suggest that both NE and DA are involved in the behavioral effects of modafinil in control mice, but the requirement for NE can be bypassed by hypersensitive DA signaling.

  5. Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

    Institute of Scientific and Technical Information of China (English)

    Wen LEI; Hong-bin LIU; Shi-bing WANG; Xiu-mei ZHOU; Shui-di ZHENG; Ke-ni GUO; Bu-yun MA

    2013-01-01

    Aim:The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer,and frequently inactivated in primary non-small cell lung cancer (NSCLC).In this study,we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer,and the mechanisms underlying the antitumor actions.Methods:The recombinant virus Ad·sp-E1A(△24)-TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·spE1A(△24) vector,which contained the survivin promoter and a 24 bp deletion within E1A.The antitumor effects of Ad·sp-E1A(△24)-TSLC1 were evaluated in NCI-H460,A549,and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5,as well as in A549 xenograft model in nude mice.Cell viability was assessed using MTT assay.The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses.The tumor tissues from the xenograft models were examined using H&E staining,IHC,TUNEL,and TEM analyses.Results:Infection of A549 lung cancer cells with Ad·sp-E1A(△24)-TSLC1 induced high level expression of TSLC1.Furthermore,the Ad·spE1A(△△24)-TSLC1 virus dose-dependently suppressed the viability of NCI-H460,A549,and H1299 lung cancer cells,and did not affect MRC-5 normal fibroblast cells.Infection of NCI-H460,A549,and H1299 lung cancer cells with Ad·sp-E1A(△24)-TSLC1 induced apoptosis,and increased activation of caspase-8,caspase-3 and PARR.In A549 xenograft model in nude mice,intratumoral injection of Ad.spE1A(△24)-TSLC1 significantly suppressed the tumor volume,and increased the survival rate (from less than 15% to 87.5% at d 60).Histological studies showed that injection of Ad·sp-E1A(△24)-TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues.Conclusion:The oncolytic adenovirus Ad·sp-E1A(△24)-TSLC1 exhibits specific antitumor effects,and is a promising agent for the treatment of lung cancer.

  6. Inhibitory action and mechanism of trail combined with cisplatin on transplanted hepatocellular carcinoma in mice%TRAIL联合顺铂对小鼠移植型肝癌抑制作用及机制研究

    Institute of Scientific and Technical Information of China (English)

    李京敏; 宁巍巍; 刘同慎; 王东; 白咸勇

    2012-01-01

    目的 探讨肿瘤坏死因子相关的凋亡诱导配体(tumor necrosis factor-related apoptosis inducing ligand,TRAIL)联合顺铂( cisplatin,DDP)对小鼠移植型肝癌的抑制作用及机制.方法 将H22小鼠移植型肝癌模型随机分为生理盐水组、TRAIL组、TRAIL+ DDP组和DDP组,称取瘤重并分析抑瘤率,Hoechst 33342荧光染色法检测细胞凋亡,免疫组织化学染色检测Caspase-3表达.结果 与生理盐水组比较,TRAIL、DDP对小鼠移植型肝癌生长具有明显的抑制作用(P<0.05);TRAIL与DDP联合用药具有增效作用(P<0.05),可明显提高肝癌细胞的凋亡率(P<0.05)、上调Caspase-3表达(P<0.01).结论 TRAIL与DDP联合用药对小鼠移植型肝癌生长具有协同抑制作用,其机制可能与其协同促进Caspase-3的表达有关.%Objective To study the mechanism and the inhibitory action of TRAIL combined with DDP on transplanted hepatocellular carcinoma in mice. Methods Mice bearing H22 hepatocellular carcinoma were randomly divided into normal saline (NS) group, TRAIL group. TRAIL+DDP group,and DDP group. Tumor tissues were weighted and the inhibitory rate was analysed. Hoechst 33342 stainning method was used to calculate the apoptotic cells. The expression of Caspase-3 was measured by immunohisto-chemistry. Results Compared with NS, both TRAIL and DDP obviously inhibited the growth of transplanted hepatocellular carcinoma in mice (P<0. 05). They had a synergistic effect (P<0. 05) and obviously increased the apoptotic rate of cancer cells(P<0. 05) and the expression of Caspase-3 (P<0. 01). Conclusion The combination of TRAIL with DDP has a synergisticly inhibitory effect on the growth of transplanted hepatocellular carcinoma in mice, and the mechanism may be associated with the synergistic upregulation of Caspase-3 expression.

  7. The Inhibitory Action of Resveratrol on Proliferation of MCF-7 Breast Cancer Cells%白藜芦醇抑制MCF-7乳腺癌细胞增殖的机制研究

    Institute of Scientific and Technical Information of China (English)

    郭慧琳; 张献全

    2011-01-01

    Objective: To investigate the inhibitory action of resveratrol on the proliferation of MCF-7 breast cancer cells and its underlying mechanisms. Methods: Human MCF-7 breast cancer cells were used and stimulated with resveratrol. The proliferation of MCF-7 breast cancer cells was determined using MTT assay. The changes in proliferation rate were also observed in cells co-stimulated with PD98059, an ERK1/2 inhibitor, and resveratrol. The effects of resveratrol expression on ERK1/2, p-ERKl/2, AKT, and p-AKT in the MCF-7 cancer cells were determined using immunoblotting. Results: The proliferation of MCF-7 breast cancer cells was obviously inhibited by resveratrol in a concentration-dependent manner. The inhibitory action of resveratrol on the MCF-7 cells was overtly repressed by PD98059. At the same time, resveratrol apparently increased p-ERKl/2 protein expression and decreased p-AKT protein expression. However, there was no change in the level of ERK1/2 and AKT protein expression after the resveratrol stimulation. Conclusion: Resveratrol effectively inhibits the proliferation of MCF-7 breast cancer cells, and its inhibitory action is through the regulation of the ERK1/2 and AKT signal pathway.%目的:研究白藜芦醇对MCF-7乳腺癌细胞抑制效应及其作用机制.方法:以人MCF-7乳腺癌细胞株为研究对象,利用MTT方法研究白藜芦醇抑制MCF-7乳腺癌细胞的生物学效应;观察在ERK1/2抑制剂PD98059预处理情况下,白藜芦醇抑制MCF-7乳腺癌细胞增殖效应的改变;利用免疫印迹方法观察白藜芦醇对MCF-7乳腺癌细胞中ERK1/2与AKT信号分子的蛋白表达.结果:白藜芦醇能够明显降低MCF-7乳腺癌细胞增殖能力,该作用呈一定的浓度依赖性关系.在ERK1/2抑制剂PD98059预处理情况下,白藜芦醇对MCF-7乳腺癌细胞增殖抑制效应能明显抑制,PD98059可明显减轻该效应.同时,白藜芦醇明显增加p-ERK1/2蛋白表达,降低p-AKT表达水平,但对ERK1/2与AKT蛋白

  8. Inhibitory action of niflumic acid on noradrenaline- and 5-hydroxytryptamine-induced pressor responses in the isolated mesenteric vascular bed of the rat.

    Science.gov (United States)

    Criddle, D N; de Moura, R S; Greenwood, I A; Large, W A

    1997-03-01

    1. The effects of niflumic acid, an inhibitor of calcium-activated chloride currents, were compared with the actions of the calcium channel blocker nifedipine on noradrenaline- and 5-hydroxytryptamine (5-HT)-induced pressor responses of the rat perfused isolated mesenteric vascular bed. 2. Bolus injections of noradrenaline (1 and 10 nmol) increased the perfusion pressure in a dose-dependent manner. Nifedipine (1 microM) inhibited the increase in pressure produced by 1 nmol noradrenaline by 31 +/- 5%. Niflumic acid (10 and 30 microM) also inhibited the noradrenaline-induced increase in perfusion pressure and 30 microM niflumic acid reduced the pressor response to 1 nmol noradrenaline by 34 +/- 6%. 3. The increases in perfusion elicited by 5-HT (0.3 and 3 nmol) were reduced by niflumic acid (10 and 30 microM) in a concentration-dependent manner and 30 microM niflumic acid inhibited responses to 0.3 and 3 nmol 5-HT by, respectively, 49 +/- 8% and 50 +/- 7%. Nifedipine (1 microM) decreased the pressor response to 3 nmol 5-HT by 44 +/- 9%. 4. In the presence of a combination of 30 microM niflumic acid and 1 microM nifedipine the inhibition of the pressor effects of noradrenaline (10 nmol) and 5-HT (3 nmol) was not significantly greater than with niflumic acid (30 microM) alone. Thus the effects of niflumic acid and nifedipine were not additive. 5. In Ca-free conditions the transient contractions induced by 5-HT (3 nmol) were not reduced by 30 microM niflumic acid, suggesting that this agent does not inhibit calcium release from the intracellular store or the binding of 5-HT to its receptor. 6. Niflumic acid 30 microM did not inhibit the pressor responses induced by KCl (20 and 60 mumol) which were markedly reduced by 1 microM nifedipine. In addition, 1 microM levcromakalim decreased pressor responses produced by 20 mumol KCl. These data suggest that niflumic acid does not block directly calcium channels or activate potassium channels. 7. It is concluded that niflumic

  9. Research on Cholinesterase Inhibitory Action and Chemical Constituents in the Volatile Oil of Radix Peucedani%前胡挥发油胆碱酯酶抑制作用及化学成分研究

    Institute of Scientific and Technical Information of China (English)

    刘亚旻; 宋波; 李宗阳; 姜保平; 潘瑞乐

    2012-01-01

    Using micro plate high-throughput screening assay to investigate the cholinesterase inhibitory action, and analyzing the main chemical constituents in the volatile oil of Radix Peucedani by the means of Gas Chromatography-Masa Spectrometer combined with Kovats index. The result shows that the volatile oil of Radix Peucedani has significant inhibitory activities of both Acetylcholinesterase ( AChE) and Butyr-ylcholinesterase (BuChE) ,the inhibition ratio of which were (63.76±1.99) % ,(51.53 ±1.70) % .respectively, when the content of the volatile oil of Radix Peucedani was lμL/mL. Meanwhile,32 main chemical constituents in the volatile oil of Radix Peueedani has been identified,the main constituents are alpha-pinene, beta-pinene, myrcene, 1 -Methyl-3 - (1 -methylethyl) -benzene, (R ) -1 -Methyl-4- (1 -methyl-ethenyl)-cyclohexene,2-(4-Methtlcyclohex-3-enyl)-propan-2-ol,2-hydroxyl-5-methyl-acetophenone,etc. The result suggests that Radix Peucedani maybe have a certain curative effect on neurodegenerative diseases,such as Alzheimer's disease.%运用微孔高通量筛选方法研究前胡挥发油胆碱酯酶抑制活性,并用气相色谱-质谱联用技术辅以Kovats 指数鉴定挥发油的主要化学成分.结果显示前胡挥发油对乙酰胆碱酯酶和丁酰胆碱酯酶均具有明显的抑制作用,当前胡挥发油浓度为1 μL/mL时,其抑制率分别为(63.76±1.99)%和(51.53±1.70)%;其挥发油共鉴定出32种化学成分,主要有α-蒎烯、左旋-β-蒎烯、月桂烯、1-甲基-3-(1-甲基乙基)苯、(R)-1-甲基-4-(1-甲基乙烯基)环己烯、萜品醇、2-羟基-5-甲基苯乙酮等.本研究结果提示前胡有可能对老年痴呆等神经退行性疾病有一定的治疗作用.

  10. Comprehension of action negation involves inhibitory simulation

    OpenAIRE

    Foroni, Francesco; Semin, Gün R.

    2013-01-01

    ORIGINALRESEARCHARTICLE published:30May2013 doi: 10.3389/fnhum.2013.00209 Comprehensionofactionnegationinvolvesinhibitorysimulation FrancescoForoni1* and Gün R.Semin2,3 1 CognitiveNeuroscienceSector,SISSA-Trieste,Trieste,Italy 2 FacultyofSocialandBehavioralSciences,RoyalNetherlandsAcademyofArtsandSciences,UtrechtUniversity,Utrecht,Netherlands 3 PsychologyDepartment,KoçUniversity,Istanbul,Turkey Editedby: BarbaraTomasino,IRCCSE.Medea, Italy Reviewedby: Cosim...

  11. Design and synthesis of new potent anticancer benzothiazole amides and ureas featuring pyridylamide moiety and possessing dual B-Raf(V600E) and C-Raf kinase inhibitory activities.

    Science.gov (United States)

    El-Damasy, Ashraf Kareem; Lee, Ju-Hyeon; Seo, Seon Hee; Cho, Nam-Chul; Pae, Ae Nim; Keum, Gyochang

    2016-06-10

    A new series of benzothiazole amide and urea derivatives tethered with the privileged pyridylamide moiety by ether linkage at the 6-position of benzothiazole (22 final compounds) has been designed and synthesized as potent anticancer sorafenib analogs. A selected group of twelve derivatives was appraised for its antiproliferative activity over a panel of 60 human cancer cell lines at a single dose concentration of 10 μM at National Cancer Institute (NCI, USA). Compounds 4b, 5a, 5b and 5d exhibited promising growth inhibitions and thus were further tested in advanced 5-dose testing assay to determine their GI50 values. The cellular based assay results revealed that 3,5-bis-trifluoromethylphenyl (5b) urea member is the best derivative with superior potency and efficacy compared to sorafenib as well as notable extended spectrum activity covering 57 human cancer cell lines. Kinase screening of compound 5b showed its kinase inhibitory effect against both B-Raf(V600E) and C-Raf. Moreover, the most potent derivatives in cells were investigated for their RAF inhibitory activities, and the results were rationalized with the molecular docking study. Profiling of CYP450 and hERG channel inhibitory effects for the active compounds revealed their low possibilities to exhibit undesirable drug-drug interactions and cardiac side effects.

  12. Distinct modifications of convergent excitatory and inhibitory inputs in developing olfactory circuits.

    Science.gov (United States)

    Ma, T-F; Chen, P-H; Hu, X-Q; Zhao, X-L; Tian, T; Lu, W

    2014-06-06

    The interaction between excitatory and inhibitory inputs is critical to neuronal signal processing. However, little is known about this fundamental property, largely due to the inability to clearly isolate the respective inputs. Here we took advantage of the characteristic stereotypical architecture of synaptic connections in the main olfactory bulb, which enabled us to entirely separate excitatory and inhibitory inputs. Using paired stimulation of two glomeruli located apart at different intensities, we separately elicited excitatory and inhibitory inputs and mimicked stimulation of competing mitral cells (MCs) with different odorants. We performed dual whole-cell patch recording of evoked excitatory postsynaptic responses (EPSPs) and inhibitory postsynaptic responses (IPSPs) in current-clamp mode from two competitive MCs that are connected to the two stimulated glomeruli in slices of the main olfactory bulb in 2-3-week-old rats. We deliberately held the recorded cells at a relative hyperpolarized potential. This manipulation not only suppressed action potential generation but also excluded the possible contamination of inhibitory components in excitatory inputs. We found that in weakly activated MCs repetitive EPSP-IPSP interactions (5 Hz, 180 times) induced long-term potentiation (LTP) and long-term depression (LTD) in convergent excitatory and inhibitory inputs, respectively. Unexpectedly, these forms of plasticity depend on activity of somatic (mainly non-synaptic) NMDA receptors (NMDARs). In contrast, the same repetitive stimulation induced the LTP of excitatory inputs in strongly activated MCs (MC2) that require activity of synaptic NMDARs. These distinct forms of plasticity in the developing olfactory circuit may represent a novel rule of modification in convergent inputs that leads to decorrelation of inputs and facilitates odor discrimination.

  13. 钼酸铵对结肠癌细胞增殖抑制作用的实验研究%Experimental study of inhibitory action of ammonium molybdate on cell proliferation of colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    吴银侠; 陈新胜; 程静; 王淑媛

    2012-01-01

    Objective To investigate the effect of ammonium molybdate on the cell proliferation of colorectal cancer. Methods Using three kinds of concentration of ammonium molybdate, namely 0.101, 0.202 and 0.404 mol/L, to treat three groups of the ectogenetic cultured colorectal cells (HCT-116) for 24, 48, 72 h respectively. And then measuring the cell proliferation by CCK-8 method, and the cell periodic variation and the cell mortality rate by flow cytometer (FCM) , observing cell shape by an inversion microscope. Results The actions of inhibitoringy cell proliferation and inducing apop-tosis of HCT-116 cell were more and more obvious with the increasement of ammonium molybdate concentration and the protraction of action time. The ratio of knubbly inhibition and cell apoptosis was positively relative to the drug concentration and action time and the cells was especially retarded in G1 period. Conclusions Ammonium molybdate has an obvious inhibitory action on the cell proliferation, and induces apoptosis of colorectal cancer cells, changes cell cycle and assumes positive direction reliant connection.%目的 探讨钼酸铵对人结肠癌细胞生长的影响.方法 以体外培养的人结肠癌细胞株HCT-116为研究对象,将钼酸铵分为浓度为0.101、0.202、0.404 mol/L 3组,对HCT-1 16细胞分别作用24、48、72 h,然后用CCK-8法检测细胞增殖、流式细胞仪检测细胞周期变化及细胞凋亡率,并在倒置显微镜下观察细胞形态变化.结果 随着钼酸铵浓度升高和作用时间延长,其对HCT-116细胞增殖有明显抑制和诱导凋亡作用,其抑瘤率和细胞凋亡率与药物浓度和作用时间呈正向依赖关系(P<0.05或<0.01),可将结肠癌细胞特异性地阻滞在G1期.结论 钼酸盐对人结肠癌细胞具有明显生长抑制作用,并可诱导细胞凋亡、改变细胞周期,且呈正向依赖关系.

  14. Dissociable yet tied inhibitory processes: the structure of inhibitory control.

    Science.gov (United States)

    Michael, George A; Mizzi, Raphaël; Couffe, Cyril; Gálvez-García, Germán

    2014-09-01

    Cognitive and neural models have proposed the existence of a single inhibitory process that regulates behavior and depends on the right frontal operculum (rFO). The aim of this study was to make a contribution to the ongoing debate as to whether inhibition is a single process or is composed of multiple, independent processes. Here, within a single paradigm, we assessed the links between two inhibitory phenomena-namely, resistance to involuntary visual capture by abrupt onsets and resolving of spatial stimulus-response conflict. We did so by conducting three experiments, two involving healthy volunteers (Exps. 1 and 3), and one with the help of a well-documented patient, R.J., with selectively weakened inhibition following a lesion of the rFO. The results suggest that resistance to capture and stimulus-response conflict are independent, because (a) additive effects were found (Exps. 1 and 3), (b) capture did not correlate with compatibility effects (Exp. 1), (c) dual tasking affected the two phenomena differently (Exp. 3), and (d) a dissociation was found between the two in patient R.J. (Exp. 2). However, the results also show that these two phenomena may share some processing components, given that (a) both were affected in patient R.J., but to different degrees (Exp. 2), and (b) increasing the difficulty of dual tasking produced an increasingly negative correlation between capture and compatibility (Exp. 3), which suggests that when resources are withdrawn from the control of the former, they are used to control the latter.

  15. Separation and Purification of ACE Inhibitory Peptides from Dual-Enzymatic Casein Hydrolysate%酪蛋白双酶水解物ACE抑制肽的分离纯化

    Institute of Scientific and Technical Information of China (English)

    杨铭; 胡志和

    2012-01-01

    采用胃蛋白酶和胰蛋白酶依次对酪蛋白进行双酶水解,制备ACE抑制肽。水解物经截留分子质量6ku的超滤膜初步分离,再通过Sephadex G-15进一步纯化,体外测定各分离产物ACE活性的半数抑制质量浓度(IC50值)。纯化得到的各组分经毛细管电泳分析肽谱、Q-TOF LC/MS检测分子质量范围。结果显示:双酶水解产物IC50值为560μg/mL,超滤流出物IC50值为250μg/mL;Sephadex G-15分离得到3个组分,组分Ⅰ的IC50值为123.41μg/mL,含有19个肽段;组分Ⅱ的IC50值为66.67μg/mL,含有14个肽段;组分Ⅲ的IC50值为64.29μg/mL,含有5个肽段。Q-TOF LC/MS测得纯化组分的分子质量范围为400~800u。%ACE inhibitory peptides were prepared from casein by sequential hydrolysis with pepsin and trypsin.Casein hydrolysate was preliminarily separated with 6 ku MWCO ultrafiltration membrane and further purified by Sephadex G-15 column chromatography.The ACE inhibitory activity(IC50) of the separated fractions was determined by an in vitro assay,and their peptide profiles and molecular weights were measured by capillary electrophoresis(CE) and Q-TOF LC/MS,respectively.The results showed that IC50 values of casein hydrolysate,filtrate,and three fractions obtained by Sephadex G-15 column chromatography,factions Ⅰ,Ⅱ and Ⅲ were 560,250,123.41,66.67μg/mL and 64.29μg/mL,respectively.FactionsⅠ,Ⅱ and Ⅲ were composed of 19,14 and 5 peptides,respectively and their molecular weights ranged from 400 to 800 u.

  16. 物体知觉中动作信息激活的双重通路%Dual Routes of Action Activation in Perceiving Obj ect

    Institute of Scientific and Technical Information of China (English)

    张恩涛; 高彬

    2014-01-01

    The theory of affordance by Gibson (1979)holds that observing an object can automatical-ly activate the implied action information and the crucial evidence supporting this view is the affordance compatibility effect.This effect refers to a decrease of reaction times when the subj ect executes a motor act which is compatible with that afforded by an observed obj ect.In the domain of affordance effect, most researchers think that the perception of obj ect can automatically evoke those possible actions affor-ded by the object,in the absence of observer’s action intention and conceptual knowledge.However,re-cent studies have showed that not only the features of an obj ect evokes action motor information,but al-so both the goal and abilities of observer influence the action motor information processes associated with the obj ect’s affordance,that is,there are down top and top down routes to action implied by ob-j ects.%Gibson (1979)的动允性(affordances)理论认为,观察物体能自动激活其隐含的动作信息。其关键的支持证据来自动允性效应,即当物体隐含的动作信息与被试的反应类型一致时,促进被试反应。最初研究发现,在缺少动作意图时,动作信息仍能自动激活。最近研究显示,注意、主体的能力和目的同样调节着动作信息的激活,即物体动作信息的激活存在自下而上和自上而下两种通路。

  17. Dual inhibitory roles of geldanamycin on the c-Jun NH2-terminal kinase 3 signal pathway through suppressing the expression of mixed-lineage kinase 3 and attenuating the activation of apoptosis signal-regulating kinase 1 via facilitating the activation of Akt in ischemic brain injury.

    Science.gov (United States)

    Wen, X-R; Li, C; Zong, Y-Y; Yu, C-Z; Xu, J; Han, D; Zhang, G-Y

    2008-10-15

    It is well documented that heat-shock protein (hsp90) plays an essential role in maintaining stability and activity of its clients. Recent studies have shown that geldanamycin (GA), an inhibitor of hsp90, could decrease the protein of mixed-lineage kinase (MLK) 3 and activate Akt; our previous research documented that MLK3 and Akt and subsequent c-Jun N-terminal kinase (JNK) were involved in neuronal cell death in ischemic brain injury. Here, we investigated whether GA could decrease the protein of MLK3 and activate Akt in rat four-vessel occlusion ischemic model. Our results showed that global cerebral ischemia followed by reperfusion could enhance the association of hsp90 with MLK3, the association of hsp90 with Src, and JNK3 activation. As a result, GA decreased the protein of MLK3 and down-regulated JNK activation. On the other hand, Src kinase was activated and phosphorylated Cbl, which then recruited the p85 subunit of phosphatidylinositol 3-kinase (PI-3K), resulting in PI-3K activation, and as a consequence increased Akt activation, which inhibited ASK1 activation and down-regulated JNK3 activation. In summary, our results indicated that GA showed a dual inhibitory role on JNK3 activation and exerted strong neuroprotection in vivo and in vitro, which provides a new possible approach for stroke therapy.

  18. Dual role of GABA in the neonatal rat hippocampus.

    Science.gov (United States)

    Khalilov, I; Dzhala, V; Ben-Ari, Y; Khazipov, R

    1999-11-01

    The effects of modulators of GABA-A receptors on neuronal network activity were studied in the neonatal (postnatal days 0-5) rat hippocampus in vitro. Under control conditions, the physiological pattern of activity of the neonatal hippocampal network was characterized by spontaneous network-driven giant depolarizing potentials (GDPs). The GABA-A receptor agonist isoguvacine (1-2 microM) and the allosteric modulator diazepam (2 microM) induced biphasic responses: initially the frequency of GDPs increased 3 to 4 fold followed by blockade of GDPs and desynchronization of the network activity. The GABA-A receptor antagonists bicuculline (10 microM) and picrotoxin (100 microM) blocked GDPs and induced glutamate (AMPA and NMDA)-receptor-mediated interictal- and ictal-like activities in the hippocampal slices and the intact hippocampus. These data suggest that at early postnatal ages GABA can exert a dual - both excitatory and inhibitory - action on the network activity.

  19. Proactive inhibitory control: A general biasing account.

    Science.gov (United States)

    Elchlepp, Heike; Lavric, Aureliu; Chambers, Christopher D; Verbruggen, Frederick

    2016-05-01

    Flexible behavior requires a control system that can inhibit actions in response to changes in the environment. Recent studies suggest that people proactively adjust response parameters in anticipation of a stop signal. In three experiments, we tested the hypothesis that proactive inhibitory control involves adjusting both attentional and response settings, and we explored the relationship with other forms of proactive and anticipatory control. Subjects responded to the color of a stimulus. On some trials, an extra signal occurred. The response to this signal depended on the task context subjects were in: in the 'ignore' context, they ignored it; in the 'stop' context, they had to withhold their response; and in the 'double-response' context, they had to execute a secondary response. An analysis of event-related brain potentials for no-signal trials in the stop context revealed that proactive inhibitory control works by biasing the settings of lower-level systems that are involved in stimulus detection, action selection, and action execution. Furthermore, subjects made similar adjustments in the double-response and stop-signal contexts, indicating an overlap between various forms of proactive action control. The results of Experiment 1 also suggest an overlap between proactive inhibitory control and preparatory control in task-switching studies: both require reconfiguration of task-set parameters to bias or alter subordinate processes. We conclude that much of the top-down control in response inhibition tasks takes place before the inhibition signal is presented.

  20. Graphene quantum dots decorated CdS doped graphene oxide sheets in dual action mode: As initiator and platform for designing of nimesulide imprinted polymer.

    Science.gov (United States)

    Patra, Santanu; Roy, Ekta; Choudhary, Raksha; Tiwari, Ashutosh; Madhuri, Rashmi; Sharma, Prashant K

    2017-03-15

    The present work describes the preparation of a nanohybrid by a combination of the 2D graphene sheet and 0D graphene quantum dots (GQDs). The GQDs were prepared from natural green precursors i.e. carrot juice by the one-step hydrothermal process. To get the maximum fluorescence property from nanohybrid, the graphene sheets were chemically doped with cadmium sulphide (CdS). The as prepared nanohybrid was characterized by means of X-ray diffraction analysis (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), fluorescence and UV-vis spectroscopic techniques. The nanohybrid was further modified to design a nano-iniferter, which shows dual property i.e. works as polymerization initiator as well as provides platform for synthesis of the nimesulide-imprinted polymer. For designing of imprinted polymer two biocompatible monomers (cystine monomer and N-vinyl caprolactam) were used, which provides biodegradability to the polymer matrix. The imprinted polymer shows a very good selectivity towards the detection of nimesulide with a limit of detection as low as 6.65ngL(-1) (S/N=3). The sensor was also applied for the detection of nimesulide in real samples like human blood serum, plasma and urine samples as well as some pharmaceutical tablets. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T

    2007-05-11

    A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches to low low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach - similar to that used in reference dose procedures for classic toxicity endpoints - can address MOA uncertainty in a way that avoids explicit modeling of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p

  2. All in action

    CERN Document Server

    Annila, Arto

    2010-01-01

    The principle of least action provides a holistic worldview in which nature in its entirety and every detail is pictured in terms of actions. Each and every action is ultimately composed of one or multiples of the most elementary action which corresponds to the Planck's constant. Elements of space are closed actions, known as fermions, whereas elements of time are open actions, known as bosons. The actions span energy landscape, the Universe which evolves irreversibly according to the 2nd law of thermodynamics by diminishing density differences in least time. During the step-by-step evolution densely-curled actions unfold by opening up and expelling one or multiple elementary actions to their surrounding sparser space. The manifold's varieties process from one symmetry group to another until the equivalence to their dual, i.e., the surrounding density has been attained. The scale-free physical portrayal of nature does not recognize any fundamental difference between fundamental particles and fundamental force...

  3. Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn

    Directory of Open Access Journals (Sweden)

    Ribeiro-da-Silva Alfredo

    2009-05-01

    Full Text Available Abstract Local inhibitory interneurons in the dorsal horn play an important role in the control of excitability at the segmental level and thus determine how nociceptive information is relayed to higher structures. Regulation of inhibitory interneuron activity may therefore have critical consequences on pain perception. Indeed, disinhibition of dorsal horn neuronal networks disrupts the balance between excitation and inhibition and is believed to be a key mechanism underlying different forms of pain hypersensitivity and chronic pain states. In this context, studying the source and the synaptic properties of the inhibitory inputs that the inhibitory interneurons receive is important in order to predict the impact of drug action at the network level. To address this, we studied inhibitory synaptic transmission in lamina II inhibitory interneurons identified under visual guidance in spinal slices taken from transgenic mice expressing enhanced green fluorescent protein (EGFP under the control of the GAD promoter. The majority of these cells fired tonically to a long depolarizing current pulse. Monosynaptically evoked inhibitory postsynaptic currents (eIPSCs in these cells were mediated by both GABAA and glycine receptors. Consistent with this, both GABAA and glycine receptor-mediated miniature IPSCs were recorded in all of the cells. These inhibitory inputs originated at least in part from local lamina II interneurons as verified by simultaneous recordings from pairs of EGFP+ cells. These synapses appeared to have low release probability and displayed potentiation and asynchronous release upon repeated activation. In summary, we report on a previously unexamined component of the dorsal horn circuitry that likely constitutes an essential element of the fine tuning of nociception.

  4. Solubilization and Inhibitory Action of Glycyrrhetinic Acid Lysinate on Cell Proliferation of Coloretal Cancer Cell Line HCT-8%赖氨甘草次酸增溶及对结肠癌HCT-8细胞增殖抑制作用∗

    Institute of Scientific and Technical Information of China (English)

    张丽娟; 钟家亮; 古同男; 魏秋芬

    2016-01-01

    目的:制备赖氨甘草次酸,研究其增溶作用及其对结肠癌HCT-8细胞增殖的抑制作用。方法采用共研磨法制备赖氨甘草次酸,采用粉末X射线衍射法与红外光谱法对制备的赖氨甘草次酸进行表征,采用高效液相色谱法测定赖氨甘草次酸的增溶作用,采用噻唑蓝( MTT)法评价赖氨甘草次酸对结肠癌HCT-8细胞增殖的抑制作用。结果制备获得赖氨甘草次酸。通过与赖氨酸成盐,甘草次酸溶解度提高约260倍,对结肠癌HCT-8细胞增殖的抑制作用提高约7倍。结论赖氨甘草次酸较甘草次酸溶解度高,抗结肠癌HCT-8细胞效果好。%Objective To prepare,characterize glycyrrhetinic acid lysinate,and study the solubilization and inhibitory action antitumor activity of glycyrrhetinic acid lysinate on cell proliferation of colorectal cancer cell line HCT-8. Methods Glycyrrhetinic acid lysinate was prepared by co-grinding glycyrrhetinic acid with lysine in 1∶1 molar mixture for 10 hours. Characterization of glycyrrhetinic acid lysinate was achieved by X-ray powder diffraction, infrared spectroscopy, and ultraviolet spectrum techniques.HPLC method was used to study the solubilization of glycyrrhetinic acid lysinate.The MTT method was used to assay the inhibitory action of glycyrrhetinic acid lysinate on cell proliferation. Results The solubility of glycyrrhetinic acid lysinate was enhanced 260 folds,compared with glycyrrhetinicacid in water. The inhibitory cell proliferation action on HCT-8 of glycyrrhetinic acid lysinate was 7 times higher than that of glycyrrhetinic acid. Conclusion The satisfactory water solubility and antitumor activity of glycyrrhetinic acid lysinate will be potentially useful for its application as a new pharmaceutical formulation in cancer treatment in the future.

  5. Noncommutative Self-dual Gravity

    CERN Document Server

    García-Compéan, H; Ramírez, C; Sabido, M

    2003-01-01

    Starting from a self-dual formulation of gravity, we obtain a noncommutative theory of pure Einstein theory in four dimensions. In order to do that, we use Seiberg-Witten map. It is shown that the noncommutative torsion constraint is solved by the vanishing of commutative torsion. Finally, the noncommutative corrections to the action are computed up to second order.

  6. Dual diagnosis

    OpenAIRE

    2013-01-01

    Dual diagnosis denotes intertwining of intellectual disabilities with mental disorders. With the help of systematic examination of literature, intellectual disabilities are determined (they are characterized by subaverage intellectual activity and difficulties in adaptive skills), along side mental disorders. Their influence is seen in changes of thinking, perception, emotionality, behaviour and cognition. Mental disorders often occur with people with intellectual disabilities (data differs f...

  7. Dual massive gravity

    Energy Technology Data Exchange (ETDEWEB)

    Morand, Kevin, E-mail: Kevin.Morand@lmpt.univ-tours.fr [Laboratoire de Mathematiques et Physique Theorique, Universite Francois-Rabelais Tours, Federation Denis Poisson - CNRS, Parc de Grandmont, 37200 Tours (France); Solodukhin, Sergey N., E-mail: Sergey.Solodukhin@lmpt.univ-tours.fr [Laboratoire de Mathematiques et Physique Theorique, Universite Francois-Rabelais Tours, Federation Denis Poisson - CNRS, Parc de Grandmont, 37200 Tours (France)

    2012-08-29

    The linearized massive gravity in three dimensions, over any maximally symmetric background, is known to be presented in a self-dual form as a first order equation which encodes not only the massive Klein-Gordon type field equation but also the supplementary transverse-traceless conditions. We generalize this construction to higher dimensions. The appropriate dual description in d dimensions, additionally to a (non-symmetric) tensor field h{sub {mu}{nu}}, involves an extra rank-(d-1) field equivalently represented by the torsion rank-3 tensor. The symmetry condition for h{sub {mu}{nu}} arises on-shell as a consequence of the field equations. The action principle of the dual theory is formulated. The focus has been made on four dimensions. Solving one of the fields in terms of the other and putting back in the action one obtains two other equivalent formulations of the theory in which the action is quadratic in derivatives. In one of these representations the theory is formulated entirely in terms of a rank-2 non-symmetric tensor h{sub {mu}{nu}}. This quadratic theory is not identical to the Fierz-Pauli theory and contains the coupling between the symmetric and antisymmetric parts of h{sub {mu}{nu}}. Nevertheless, the only singularity in the propagator is the same as in the Fierz-Pauli theory so that only the massive spin-2 particle is propagating. In the other representation, the theory is formulated in terms of the torsion rank-3 tensor only. We analyze the conditions which follow from the field equations and show that they restrict to 5 degrees of freedom thus producing an alternative description to the massive spin-2 particle. A generalization to higher dimensions is suggested.

  8. Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T

    2007-01-30

    As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate ''linear'' (genotoxic) vs. ''nonlinear'' (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach--similar to that used in reference dose procedures for classic toxicity endpoints--can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a ''nonlinear'' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Resulting

  9. A unified framework for inhibitory control.

    Science.gov (United States)

    Munakata, Yuko; Herd, Seth A; Chatham, Christopher H; Depue, Brendan E; Banich, Marie T; O'Reilly, Randall C

    2011-10-01

    Inhibiting unwanted thoughts, actions and emotions figures centrally in daily life, and the prefrontal cortex (PFC) is widely viewed as a source of this inhibitory control. We argue that the function of the PFC is best understood in terms of representing and actively maintaining abstract information, such as goals, which produces two types of inhibitory effects on other brain regions. Inhibition of some subcortical regions takes a directed global form, with prefrontal regions providing contextual information relevant to when to inhibit all processing in a region. Inhibition within neocortical (and some subcortical) regions takes an indirect competitive form, with prefrontal regions providing excitation of goal-relevant options. These distinctions are crucial for understanding the mechanisms of inhibition and how they can be impaired or improved.

  10. QCD Dual

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2009-01-01

    We uncover a novel solution of the 't Hooft anomaly matching conditions for QCD. Interestingly in the perturbative regime the new gauge theory, if interpreted as a possible QCD dual, predicts the critical number of flavors above which QCD in the nonperturbative regime, develops an infrared stable...... fixed point. Remarkably this value is identical to the maximum bound predicted in the nonpertubative regime via the all-orders conjectured beta function for nonsupersymmetric gauge theories.......We uncover a novel solution of the 't Hooft anomaly matching conditions for QCD. Interestingly in the perturbative regime the new gauge theory, if interpreted as a possible QCD dual, predicts the critical number of flavors above which QCD in the nonperturbative regime, develops an infrared stable...

  11. Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and epsilon-aminocaproic acid.

    Science.gov (United States)

    Alexandrov, V A; Bespalov, V G; Petrov, A S; Troyan, D N; Lidaks MYu

    1996-09-01

    The influence of the arachidonic acid metabolism inhibitors, indomethacin and voltaren; an inhibitor of phosphodiesterase activity, theophylline and the protease inhibitor epsilonaminocaproic acid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day after conception. Indomethacin and voltaren (20 p.p.m. in drinking water), theophylline (0.01% in diet) and EACA (1000 p.p.m. in drinking water) were given to the offspring throughout their post-natal life until all survivors were killed at 12 months. In the ENU-only control groups, 100% of the offspring developed tumors of brain, spinal cord, peripheral nervous system or kidneys, with a total average number of 3.1 tumors per rat. The most marked inhibitory effect was exerted by theophylline, which significantly decreased the incidence and multiplicity of total tumors, and at all main sites selectively (brain, spinal cord, peripheral nerves and kidneys). It also prolonged average survival time of the offspring. Indomethacin and voltaren significantly decreased total tumor incidence and multiplicity and brain tumor incidence and multiplicity. Indomethacin also decreased kidney tumor multiplicity and voltaren diminished spinal cord tumor multiplicity. EACA decreased multiplicities of total, brain, peripheral nerve and kidney tumors, and diminished the incidence of brain tumors. These chemopreventive agents decreased tumor incidences 20-33% and tumor multiplicities 1.4-2.7 times, compared with the ENU-only controls.

  12. [Electrophysiological properties of inhibitory neurones in cultured dissociated hippocampal cells].

    Science.gov (United States)

    Moskaliuk, A O; Kolodin, Iu O; Kravchenko, M O; Fedulova, S A; Veselovs'kyĭ, M S

    2004-01-01

    Electrophysiological properties of inhibitory (GABAergic) neurones were studied in dissociated hippocampal culture using simultaneous whole cell recordings from pairs of monosynaptically coupled neurons. Reliable identification of GABAergic neuron was performed by presence of monosynaptic inhibitory currents at postsynaptic cell in response to action potentials at stimulated cell. It was shown that GABAergic neurons in hippocampal culture are divided in two groups by their firing characteristics: first type generates action potentials at high frequency in response to injection of current (duration 0.5 s)--fast-spiking neurons (FS), cells from second type has no ability for high-frequency action potential generation--regular spiking neurons (RS). These two groups were distinguished by kinetic characteristics of action potentials, adaptation characteristics during continuous generation of action potentials and inhibitory effect making on postsynaptic cell. Application of potassium channel blocker 4-AP to somas of FS neurons in concentration, which selectively inhibits Kv3 potassium channels evoked reversible changes in kinetic of action potentials, frequency and adaptation characteristics during continuous generation of action potentials. It was concluded that there is hight level of expression of Kv3 potassium channels in the first group of neurons.

  13. Kellerer--Rossi dual action theory

    Energy Technology Data Exchange (ETDEWEB)

    Obaturov, G.M.

    1977-01-01

    It was demonstrated that the equation for cell survival proposed by Kellerer and Rossi for high-density particles (protons, neutrons, etc.) is incorrect. The author has derived a more general formula that defines the cell survival curve for any ionizing radiation. This formula for low-density ionizing radiation corresponds to the Kellerer-Rossi formula.

  14. Inhibitory Action of Essential Oil Extracted from Ponkan Mandarin (Citrus reticulata Blanco) Peels on Penicillium digitatum%椪柑精油对指状青霉的抑制作用

    Institute of Scientific and Technical Information of China (English)

    王华; 陶能国; 王长锋

    2012-01-01

    采用水蒸气蒸馏法提取椪柑(Citrus reticulate Blanco)果皮精油,并用GC-MS对其成分进行分析,共鉴定出39种成分,主要包括柠檬烯(12.18%)、β-芳樟醇(10.88%)、γ-松油烯(9.37%)、5-亚乙基-1-甲基-环庚烯(9.37%)、β-月桂烯(9.36%)、β-蒎烯(8.12%)、2-蒈烯(7.8%)、α-蒎烯(6.74%)、辛醛(5.14%)、α-侧柏烯(3.99%)和β-水芹烯(3.31%)等。并测定不同体积分数椪柑精油对指状青霉孢子萌发和菌丝体生长的影响。结果表明:当体积分数不高于0.25%时,椪柑精油对孢子萌发和菌丝体生长均有促进作用;精油体积分数高于5%时,对孢子萌发和菌丝体生长表现出抑制作用。本实验表明椪柑精油对指状青霉生长具有明显抑制作用。%Essential oil was extracted from poknkan mandarin peels by steam distillation and its chemical composition was analyzed by GC-MS. A total of 39 compounds were identified. Among them, the predominant compounds were limonene (12.18%), followed by β-linalool (10.88%), γ-terpinene (9.37%), cycloheptene, 5-ethylidene-1-methy (9.37%), β-myrcene (9.36%), β -pinene (8.12%), 2-carene (7.8%), α -pinene (6.74%), octanal (5.14%), α -thujene (3.99%) and β -phellandrene (3.31%). Meanwhile, the effect of the essential oil on the spore germination and mycelium growth of Penicillium digitatum was measured. The results revealed that the spore germination and mycelium growth of Penicillium digitatum could be promoted by the essential oil could promote at a concentration not exceeding 0.25% but be inhibited at a concentration exceeding 0.5%. In conclusion, this study demonstrates that essential oil from poknkan mandarin peels has a notable inhibitory effect on the growth of Penicillium digitatum.

  15. Unraveling Executive Functioning in Dual Diagnosis

    Science.gov (United States)

    Duijkers, Judith C. L. M.; Vissers, Constance Th. W. M.; Egger, Jos I. M.

    2016-01-01

    In mental health, the term dual-diagnosis is used for the co-occurrence of Substance Use Disorder (SUD) with another mental disorder. These co-occurring disorders can have a shared cause, and can cause/intensify each other’s expression. Forming a threat to health and society, dual-diagnosis is associated with relapses in addiction-related behavior and a destructive lifestyle. This is due to a persistent failure to control impulses and the maintaining of inadequate self-regulatory behavior in daily life. Thus, several aspects of executive functioning like inhibitory, shifting and updating processes seem impaired in dual-diagnosis. Executive (dys-)function is currently even seen as a shared underlying key component of most mental disorders. However, the number of studies on diverse aspects of executive functioning in dual-diagnosis is limited. In the present review, a systematic overview of various aspects of executive functioning in dual-diagnosis is presented, striving for a prototypical profile of patients with dual-diagnosis. Looking at empirical results, inhibitory and shifting processes appear to be impaired for SUD combined with schizophrenia, bipolar disorder or cluster B personality disorders. Studies involving updating process tasks for dual-diagnosis were limited. More research that zooms in to the full diversity of these executive functions is needed in order to strengthen these findings. Detailed insight in the profile of strengths and weaknesses that underlies one’s behavior and is related to diagnostic classifications, can lead to tailor-made assessment and indications for treatment, pointing out which aspects need attention and/or training in one’s self-regulative abilities. PMID:27445939

  16. Unraveling Executive Functioning in Dual Diagnosis.

    Science.gov (United States)

    Duijkers, Judith C L M; Vissers, Constance Th W M; Egger, Jos I M

    2016-01-01

    In mental health, the term dual-diagnosis is used for the co-occurrence of Substance Use Disorder (SUD) with another mental disorder. These co-occurring disorders can have a shared cause, and can cause/intensify each other's expression. Forming a threat to health and society, dual-diagnosis is associated with relapses in addiction-related behavior and a destructive lifestyle. This is due to a persistent failure to control impulses and the maintaining of inadequate self-regulatory behavior in daily life. Thus, several aspects of executive functioning like inhibitory, shifting and updating processes seem impaired in dual-diagnosis. Executive (dys-)function is currently even seen as a shared underlying key component of most mental disorders. However, the number of studies on diverse aspects of executive functioning in dual-diagnosis is limited. In the present review, a systematic overview of various aspects of executive functioning in dual-diagnosis is presented, striving for a prototypical profile of patients with dual-diagnosis. Looking at empirical results, inhibitory and shifting processes appear to be impaired for SUD combined with schizophrenia, bipolar disorder or cluster B personality disorders. Studies involving updating process tasks for dual-diagnosis were limited. More research that zooms in to the full diversity of these executive functions is needed in order to strengthen these findings. Detailed insight in the profile of strengths and weaknesses that underlies one's behavior and is related to diagnostic classifications, can lead to tailor-made assessment and indications for treatment, pointing out which aspects need attention and/or training in one's self-regulative abilities.

  17. Anion channelrhodopsins for inhibitory cardiac optogenetics

    Science.gov (United States)

    Govorunova, Elena G.; Cunha, Shane R.; Sineshchekov, Oleg A.; Spudich, John L.

    2016-01-01

    Optical control of the heart muscle is a promising strategy for cardiology because it is more specific than traditional electrical stimulation, and allows a higher temporal resolution than pharmacological interventions. Anion channelrhodopsins (ACRs) from cryptophyte algae expressed in cultured neonatal rat ventricular cardiomyocytes produced inhibitory currents at less than one-thousandth of the light intensity required by previously available optogenetic tools, such as the proton pump archaerhodopsin-3 (Arch). Because of their greater photocurrents, ACRs permitted complete inhibition of cardiomyocyte electrical activity under conditions in which Arch was inefficient. Most importantly, ACR expression allowed precisely controlled shortening of the action potential duration by switching on the light during its repolarization phase, which was not possible with previously used optogenetic tools. Optical shortening of cardiac action potentials may benefit pathophysiology research and the development of optogenetic treatments for cardiac disorders such as the long QT syndrome. PMID:27628215

  18. Complexity Equals Action

    CERN Document Server

    Brown, Adam R; Susskind, Leonard; Swingle, Brian; Zhao, Ying

    2015-01-01

    We conjecture that the quantum complexity of a holographic state is dual to the action of a certain spacetime region that we call a Wheeler-DeWitt patch. We illustrate and test the conjecture in the context of neutral, charged, and rotating black holes in AdS, as well as black holes perturbed with static shells and with shock waves. This conjecture evolved from a previous conjecture that complexity is dual to spatial volume, but appears to be a major improvement over the original. In light of our results, we discuss the hypothesis that black holes are the fastest computers in nature.

  19. Inhibitory effect of mycophenolic acid on the replication of infectious pancreatic necrosis virus and viral hemorrhagic septicemia virus.

    Science.gov (United States)

    Marroquí, Laura; Estepa, Amparo; Perez, Luis

    2008-12-01

    Infectious pancreatic necrosis virus (IPNV) and viral hemorrhagic septicemia virus (VHSV) remain two of the most important pathogens of farmed trout worldwide. Mycophenolic acid (MPA) is an inhibitor of cellular inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes an essential step in the biosynthesis of GTP. In this report, the antiviral activity of MPA against IPNV and VHSV in cell culture was assessed. Cell viability, virus yield, protein and RNA synthesis determinations were used to evaluate the inhibitory effect of MPA. MPA caused a dose-dependent inhibition of IPNV and VHSV replication. It was found that MPA had a particularly potent effect against IPNV, inhibiting the production of infectious virus more than 10(5)-fold. MPA was also highly effective in preventing viral protein synthesis. Quantitative real-time RT-PCR was used to measure viral RNA in cells infected by IPNV or VHSV to evaluate the inhibitory capacity of MPA as well as to compare MPA to the established antiviral drug ribavirin. MPA showed a good efficacy in decreasing accumulation of viral RNA at low concentrations. Finally, time of addition and wash out experiments suggested that MPA may have a dual mechanism of action, targeting both a cell and a viral function. This study provides evidence that MPA can function as a broad-spectrum antiviral drug for use in therapy of rainbow trout diseases.

  20. Duality symmetric actions

    CERN Document Server

    Schwarz, J H; Schwarz, John H.; Sen, Ashoke

    1994-01-01

    It is frequently useful to construct dual descriptions of theories containing antisymmetric tensor fields by introducing a new potential whose curl gives the dual field strength, thereby interchanging field equations with Bianchi identities. We describe a general procedure for constructing actions containing both potentials at the same time, such that the dual relationship of the field strengths arises as an equation of motion. The price for doing this is the sacrifice of manifest Lorentz invariance or general coordinate invariance, though both symmetries can be realized nonetheless. There are various examples of global symmetries that have been realized as symmetries of field equations but not actions. These can be elevated to symmetries of the action by our method. The main example that we focus on is the low-energy effective action description of the heterotic string theory compactified on a six-torus to four dimensions. We show that the SL(2,R) symmetry, whose SL(2,Z) subgroup has been conjectured to be a...

  1. All in Action

    Directory of Open Access Journals (Sweden)

    Arto Annila

    2010-11-01

    Full Text Available The principle of least action provides a holistic worldview in which Nature in its entirety and every detail is described in terms of actions. Each and every action is ultimately composed of one or multiple of the most elementary actions which relates to Planck’s constant. Elements of space are closed actions, known as fermions, whereas elements of time are open actions, known as bosons. The actions span an energy landscape, the Universe, which evolves irreversibly according to the 2nd law of thermodynamics by diminishing energy density differences in least time. During evolution densely-curled actions unfold step-by-step when opening up and expelling one or multiple elementary actions to their surrounding sparser space. The energy landscape will process from one symmetry group to another until the equivalence to its dual, i.e., the surrounding density has been attained. The scale-free physical portrayal of nature in terms of actions does not recognize any fundamental difference between fundamental particles and fundamental forces. Instead a plethora of particles and a diaspora of forces are perceived merely as diverse manifestations of a natural selection for various mechanisms and ways to decrease free energy in the least time.

  2. Homogeneous M2 duals

    CERN Document Server

    Figueroa-O'Farrill, José

    2015-01-01

    Motivated by the search for new gravity duals to M2 branes with $N>4$ supersymmetry --- equivalently, M-theory backgrounds with Killing superalgebra $\\mathfrak{osp}(N|4)$ for $N>4$ --- we classify (except for a small gap) homogeneous M-theory backgrounds with symmetry Lie algebra $\\mathfrak{so}(n) \\oplus \\mathfrak{so}(3,2)$ for $n=5,6,7$. We find that there are no new backgrounds with $n=6,7$ but we do find a number of new (to us) backgrounds with $n=5$. All backgrounds are metrically products of the form $\\operatorname{AdS}_4 \\times P^7$, with $P$ riemannian and homogeneous under the action of $\\operatorname{SO}(5)$, or $S^4 \\times Q^7$ with $Q$ lorentzian and homogeneous under the action of $\\operatorname{SO}(3,2)$. At least one of the new backgrounds is supersymmetric (albeit with only $N=2$) and we show that it can be constructed from a supersymmetric Freund--Rubin background via a Wick rotation. Two of the new backgrounds have only been approximated numerically.

  3. Rational decision-making in inhibitory control

    Directory of Open Access Journals (Sweden)

    Pradeep eShenoy

    2011-05-01

    Full Text Available An important aspect of cognitive flexibility is inhibitory control, the ability to dynamically modify or cancel planned actions in response to changes in the sensory environment or task demands. We formulate a probabilistic, rational decision-making framework for inhibitory control in the well-studied stop signal paradigm. Our model posits that subjects maintain a Bayes-optimal, continually updated representation of sensory inputs, and repeatedly assess the relative value of stopping and going on a fine temporal scale, in order to make an optimal decision on when and whether to go on each trial. We further posit that they implement this continual evaluation with respect to a global objective function capturing the various reward and penalties associated with different behavioral outcomes, such as speed and accuracy, or the relative costs of stop errors and go errors. We demonstrate that our rational decision-making model naturally gives rise to basic behavioral characteristics consistently observed for this paradigm, as well as more subtle effects due to contextual factors such as reward contingencies or motivational factors. Furthermore, we show that the classical race model can be seen as a computationally simpler, perhaps neurally plausible, approximation to optimal decision-making. This conceptual link allows us to predict how the parameters of the race model, such as the stopping latency, should change with task parameters and individual experiences/ability.

  4. Rational decision-making in inhibitory control.

    Science.gov (United States)

    Shenoy, Pradeep; Yu, Angela J

    2011-01-01

    An important aspect of cognitive flexibility is inhibitory control, the ability to dynamically modify or cancel planned actions in response to changes in the sensory environment or task demands. We formulate a probabilistic, rational decision-making framework for inhibitory control in the stop signal paradigm. Our model posits that subjects maintain a Bayes-optimal, continually updated representation of sensory inputs, and repeatedly assess the relative value of stopping and going on a fine temporal scale, in order to make an optimal decision on when and whether to go on each trial. We further posit that they implement this continual evaluation with respect to a global objective function capturing the various reward and penalties associated with different behavioral outcomes, such as speed and accuracy, or the relative costs of stop errors and go errors. We demonstrate that our rational decision-making model naturally gives rise to basic behavioral characteristics consistently observed for this paradigm, as well as more subtle effects due to contextual factors such as reward contingencies or motivational factors. Furthermore, we show that the classical race model can be seen as a computationally simpler, perhaps neurally plausible, approximation to optimal decision-making. This conceptual link allows us to predict how the parameters of the race model, such as the stopping latency, should change with task parameters and individual experiences/ability.

  5. Self-dual gravity with topological terms

    CERN Document Server

    Montesinos, M

    2001-01-01

    The canonical analysis of the (anti-) self-dual action for gravity supplemented with the (anti-) self-dual Pontrjagin term is carried out. The effect of the topological term is to add a `magnetic' term to the original momentum variable associated with the self-dual action leaving the Ashtekar connection unmodified. In the new variables, the Gauss constraint retains its form, while both vector and Hamiltonian constraints are modified. This shows, the contribution of the Euler and Pontrjagin terms is not the same as that coming from the term associated with the Barbero-Immirzi parameter, and thus the analogy between the theta-angle in Yang-Mills theory and the Barbero-Immirzi parameter of gravity is not appropriate.

  6. Role of cortical feedback in regulating inhibitory microcircuits.

    Science.gov (United States)

    Strowbridge, Ben W

    2009-07-01

    The olfactory bulb contains an impressive array of specialized inhibitory local circuits. The most frequent inhibitory microcircuit in this brain region is the reciprocal dendrodendritic synapse formed between the lateral dendrites of mitral cells and distal dendritic spines of GABAergic granule cells. Recent work discussed in this review suggests that release of GABA from granule cell spines may reflect near-coincident activation of both mitral cell-to-granule cell synapses and proximal excitatory synapses on granule cells that originate from pyramidal cells in piriform cortex. Recent work using two-photon guided microstimulation demonstrated that proximal and distal excitatory synapses onto granule cells exhibit different forms of short-term plasticity, with feedback inputs from piriform cortex facilitating when tested with brief ( approximately 50 ms) interstimulus intervals. One consequence of this synaptic plasticity is that short duration, gamma-frequency, oscillatory discharges in piriform cortical cells evoke summating excitatory postsynaptic potentials (EPSPs) in granule cells that effectively trigger action potentials. Piriform cortex stimulation can gate dendrodendritic inhibition onto mitral cells, presumably through the ability of EPSP-driven action potentials in granule cells to temporarily relieve the tonic blockade of NMDA receptors by extracellular Mg(2+) ions. Feedback projections in other CNS systems also may target inhibitory neurons, such as the backprojection from CA3 pyramidal neurons to GABAergic hilar interneurons. The ability of downstream processing areas to rapidly and selectively activate inhibitory interneurons in other brain regions may provide an important mechanism to dynamically modulate biological information processing.

  7. A deformation of the Curtright action

    CERN Document Server

    Hörtner, Sergio

    2016-01-01

    We present a deformation of the action principle for a free tensor field of mixed symmetry (2,1) --the Curtright action, a dual formulation of five-dimensional linearized gravity. It is constructed as the dual theory of the Einstein-Hilbert action linearized around a de Sitter background, and its derivation relies on the use of the two-potential formalism as an intermediate step. The resulting action principle is spatially non-local and space-time covariance is not manifest, thus overcoming previous no-go results.

  8. Inhibitory Control in Childhood Stuttering

    Science.gov (United States)

    Eggers, Kurt; De Nil, Luc F.; Van den Bergh, Bea R. H.

    2013-01-01

    Purpose: The purpose of this study was to investigate whether previously reported parental questionnaire-based differences in inhibitory control (IC; Eggers, De Nil, & Van den Bergh, 2010) would be supported by direct measurement of IC using a computer task. Method: Participants were 30 children who stutter (CWS; mean age = 7;05 years) and 30…

  9. Relation between temporal perception and inhibitory control in the Go/No-Go task.

    Science.gov (United States)

    Brown, Scott W; Perreault, Sara T

    2017-02-01

    This research was designed to replicate and extend findings concerning bidirectional interference between concurrent timing and inhibition tasks reported previously. Subjects performed serial temporal production and Go/No-Go (GNG) tasks under single-task and dual-task conditions in two experiments. The degree of inhibitory control required in the GNG tasks was manipulated by varying the proportion of go and no-go stimuli (experiment 1) and by instructing subjects to devote different amounts of attention to the dual tasks (experiment 2). The dual-task conditions in both experiments showed a pattern of mutual interference in which each task interfered with the other. In experiment 1, concurrent timing interfered more strongly with performance on a high inhibitory-demand GNG task compared with a low inhibitory-demand GNG task. In experiment 2, concurrent timing and GNG performance displayed a reciprocity effect in which greater attentiveness to one task improved performance for that task but diminished performance for the other task, and vice versa. These results support the view that temporal processing and inhibitory control depend upon a common pool of attentional resources, and point to the GNG task as a reliable research tool for investigators studying the role of attentional processes in time perception. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Death and rebirth of neural activity in sparse inhibitory networks

    OpenAIRE

    Angulo-Garcia, David; Luccioli, Stefano; Olmi, Simona; Torcini, Alessandro

    2016-01-01

    In this paper, we clarify the mechanisms underlying a general phenomenon present in pulse-coupled heterogeneous inhibitory networks: inhibition can induce not only suppression of the neural activity, as expected, but it can also promote neural reactivation. In particular, for globally coupled systems, the number of firing neurons monotonically reduces upon increasing the strength of inhibition (neurons' death). However, the random pruning of the connections is able to reverse the action of in...

  11. Supermembrane actions for Gaiotto-Maldacena backgrounds

    Science.gov (United States)

    Stefański, Bogdan

    2014-06-01

    We write down the supermembrane actions for M-theory backgrounds dual to general N=2 four-dimensional superconformal field theories. The actions are given to all orders in fermions and are in a particular κ-gauge. When an extra U(1) isometry is present, our actions reduce to κ-gauge fixed Green-Schwarz actions for the corresponding Type IIA backgrounds.

  12. Supermembrane actions for Gaiotto–Maldacena backgrounds

    Energy Technology Data Exchange (ETDEWEB)

    Stefański, Bogdan, E-mail: Bogdan.Stefanski.1@city.ac.uk

    2014-06-15

    We write down the supermembrane actions for M-theory backgrounds dual to general N=2 four-dimensional superconformal field theories. The actions are given to all orders in fermions and are in a particular κ-gauge. When an extra U(1) isometry is present, our actions reduce to κ-gauge fixed Green–Schwarz actions for the corresponding Type IIA backgrounds.

  13. A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats

    DEFF Research Database (Denmark)

    Andreassen, Kim V; Feigh, Michael; Hjuler, Sara T

    2014-01-01

    The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced o......The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet......-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced...... a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts...

  14. Action Research: An Approach to Student Work Based Learning.

    Science.gov (United States)

    Rowley, Jennifer

    2003-01-01

    Explains the application of action research to work-based learning, describing the action research cycle and meta learning. Outlines key processes for action research projects: keeping journals, managing dual roles of employee and researcher, managing politics and ethics. Offers suggestions for writing an action research dissertation. (SK)

  15. Cortical Neurodynamics of Inhibitory Control

    OpenAIRE

    Hwang, Kai; Ghuman, Avniel S.; Dara S Manoach; Stephanie R. Jones; Luna, Beatriz

    2014-01-01

    The ability to inhibit prepotent responses is critical for successful goal-directed behaviors. To investigate the neural basis of inhibitory control, we conducted a magnetoencephalography study where human participants performed the antisaccade task. Results indicated that neural oscillations in the prefrontal cortex (PFC) showed significant task modulations in preparation to suppress saccades. Before successfully inhibiting a saccade, beta-band power (18–38 Hz) in the lateral PFC and alpha-b...

  16. Impulsivity: A deficiency of inhibitory control?

    NARCIS (Netherlands)

    Lansbergen, M.M.

    2007-01-01

    Impulsivity has been defined as acting without thinking. Impulsivity can be quantified by impulsivity questionnaires, but also by behavioral paradigms which tax inhibitory control. Previous research has repeatedly demonstrated deficient inhibitory control in psychopathological samples characterized

  17. Dual Fluidized Bed Biomass Gasification

    Energy Technology Data Exchange (ETDEWEB)

    None

    2005-09-30

    The dual fluidized bed reactor is a recirculating system in which one half of the unit operates as a steam pyrolysis device for biomass. The pyrolysis occurs by introducing biomass and steam to a hot fluidized bed of inert material such as coarse sand. Syngas is produced during the pyrolysis and exits the top of the reactor with the steam. A crossover arm, fed by gravity, moves sand and char from the pyrolyzer to the second fluidized bed. This sand bed uses blown air to combust the char. The exit stream from this side of the reactor is carbon dioxide, water and ash. There is a second gravity fed crossover arm to return sand to the pyrolysis side. The recirculating action of the sand and the char is the key to the operation of the dual fluidized bed reactor. The objective of the project was to design and construct a dual fluidized bed prototype reactor from literature information and in discussion with established experts in the field. That would be appropriate in scale and operation to measure the relative performance of the gasification of biomass and low ranked coals to produce a high quality synthesis gas with no dilution from nitrogen or combustion products.

  18. Cortical neurodynamics of inhibitory control.

    Science.gov (United States)

    Hwang, Kai; Ghuman, Avniel S; Manoach, Dara S; Jones, Stephanie R; Luna, Beatriz

    2014-07-16

    The ability to inhibit prepotent responses is critical for successful goal-directed behaviors. To investigate the neural basis of inhibitory control, we conducted a magnetoencephalography study where human participants performed the antisaccade task. Results indicated that neural oscillations in the prefrontal cortex (PFC) showed significant task modulations in preparation to suppress saccades. Before successfully inhibiting a saccade, beta-band power (18-38 Hz) in the lateral PFC and alpha-band power (10-18 Hz) in the frontal eye field (FEF) increased. Trial-by-trial prestimulus FEF alpha-band power predicted successful saccadic inhibition. Further, inhibitory control enhanced cross-frequency amplitude coupling between PFC beta-band (18-38 Hz) activity and FEF alpha-band activity, and the coupling appeared to be initiated by the PFC. Our results suggest a generalized mechanism for top-down inhibitory control: prefrontal beta-band activity initiates alpha-band activity for functional inhibition of the effector and/or sensory system.

  19. Synaptic basis for intense thalamocortical activation of feedforward inhibitory cells in neocortex.

    Science.gov (United States)

    Cruikshank, Scott J; Lewis, Timothy J; Connors, Barry W

    2007-04-01

    The thalamus provides fundamental input to the neocortex. This input activates inhibitory interneurons more strongly than excitatory neurons, triggering powerful feedforward inhibition. We studied the mechanisms of this selective neuronal activation using a mouse somatosensory thalamocortical preparation. Notably, the greater responsiveness of inhibitory interneurons was not caused by their distinctive intrinsic properties but was instead produced by synaptic mechanisms. Axons from the thalamus made stronger and more frequent excitatory connections onto inhibitory interneurons than onto excitatory cells. Furthermore, circuit dynamics allowed feedforward inhibition to suppress responses in excitatory cells more effectively than in interneurons. Thalamocortical excitatory currents rose quickly in interneurons, allowing them to fire action potentials before significant feedforward inhibition emerged. In contrast, thalamocortical excitatory currents rose slowly in excitatory cells, overlapping with feedforward inhibitory currents that suppress action potentials. These results demonstrate the importance of selective synaptic targeting and precise timing in the initial stages of neocortical processing.

  20. Inhibitory action of antioxidants (ascorbic acid or α-tocopherol on seizures and brain damage induced by pilocarpine in rats Ação inibitória de antioxidantes (ácido ascórbico e α-tocoferol nas convulsões e dano cerebral em ratos induzidos pela pilocarpina

    Directory of Open Access Journals (Sweden)

    Adriana da Rocha Tomé

    2010-06-01

    Full Text Available Temporal lobe epilepsy is the most common form of epilepsy in humans. Oxidative stress is a mechanism of cell death induced by seizures. Antioxidant compounds have neuroprotective effects due to their ability to inhibit free radical production. The objectives of this work were to comparatively study the inhibitory action of antioxidants (ascorbic acid or α-tocopherol on behavioral changes and brain damage induced by high doses of pilocarpine, aiming to further clarify the mechanism of action of these antioxidant compounds. In order to determinate neuroprotective effects, we studied the effects of ascorbic acid (250 or 500 mg/kg, i.p. and α-tocopherol (200 or 400 mg/kg, i.p. on the behavior and brain lesions observed after seizures induced by pilocarpine (400 mg/kg, i.p., P400 model in rats. Ascorbic acid or α-tocopherol injections prior to pilocarpine suppressed behavioral seizure episodes. These findings suggested that free radicals can be produced during brain damage induced by seizures. In the P400 model, ascorbic acid and α-tocopherol significantly decreased cerebral damage percentage. Antioxidant compounds can exert neuroprotective effects associated with inhibition of free radical production. These results highlighted the promising therapeutic potential of ascorbic acid and α-tocopherol in treatments for neurodegenerative diseases.A epilepsia de lobo temporal é a mais comum forma de epilepsia em humanos. O estresse oxidativo é um dos mecanismos de morte celular induzida pelas crises convulsivas. Os compostos antioxidantes apresentam efeitos neuroprotetores devido à sua capacidade de inibir a produção de radicais livres. Os objetivos do presente trabalho foram estudar de forma comparativa a ação inibitória de antioxidantes (ácido ascórbico e α-tocoferol sobre as alterações comportamentais e histopatológicas no hipocampo de ratos após convulsões induzidas pela pilocarpina. A fim de determinar os efeitos neuroprotetores

  1. Minimum Inhibitory Concentration Analysis of Nerium oleander against Bacterial Pathogens

    Institute of Scientific and Technical Information of China (English)

    M Abu Hena Mostofa Jamal; Shahedur Rahman; Md Azizul Islam; Md Rezaul Karim; Md Samsul Alam; Md Ziaur Rahman

    2012-01-01

    Objective: In this present study, it is tried to find out the antimicrobial effect and Minimum Inhibitory Concentration (MIC) of Nerium oleander against Bacillus subtilis (IFO 3026), Sarcina lutea (IFO 3232), Escherichia coli (IFO 3007) and Klebsiella Pneumoniae (ATTC 10031). Methods:Powered leaves were prepared and used for extraction with various solvents, viz, the petroleum ether, and chloroform extract of the oleander. All the solvent extracts were evaporated to dryness. Using the disc diffusion method, the bacterial growth were inhibited, Results: Among the solvent extracts tested, petroleum ether extract inhibited the growth of all the tested bacteria having various degrees of inhibition zones. Highest inhibitory activity was observed against E. coli (1.9 cm) and minimum inhibitory concentration was observed 2μg/ml also against E. coli. Both results were observed in case of petroleum ether extract. Petroleum ether extract also showed inhibitory zones of 1.8 cm, 1.4 cm and 1.5cm against B. subtilis, S. lutea and K. pneumoniae. On the other hand chloroform extract was observed to have inhibition zones of 1.2 cm, 1.6 cm, 1.8 cm and 1.5 cm against B. subtilis, S. lutea, E. coli and K. pneumoniae respectively. Conclusions: The study demonstrated that the petroleum ether extract of N. oleander is potentially good source of antibacterial agents. Further evaluation is necessary to identify the specific bioactive compounds, their mode of action and their nontoxic nature in vivo condition.

  2. Inhibitory Control as a Core Process of Creative Problem Solving and Idea Generation from Childhood to Adulthood

    Science.gov (United States)

    Cassotti, Mathieu; Agogué, Marine; Camarda, Anaëlle; Houdé, Olivier; Borst, Grégoire

    2016-01-01

    Developmental cognitive neuroscience studies tend to show that the prefrontal brain regions (known to be involved in inhibitory control) are activated during the generation of creative ideas. In the present article, we discuss how a dual-process model of creativity--much like the ones proposed to account for decision making and reasoning--could…

  3. Inhibitory Control as a Core Process of Creative Problem Solving and Idea Generation from Childhood to Adulthood

    Science.gov (United States)

    Cassotti, Mathieu; Agogué, Marine; Camarda, Anaëlle; Houdé, Olivier; Borst, Grégoire

    2016-01-01

    Developmental cognitive neuroscience studies tend to show that the prefrontal brain regions (known to be involved in inhibitory control) are activated during the generation of creative ideas. In the present article, we discuss how a dual-process model of creativity--much like the ones proposed to account for decision making and reasoning--could…

  4. Supergravity actions with integral forms

    Science.gov (United States)

    Castellani, L.; Catenacci, R.; Grassi, P. A.

    2014-12-01

    Integral forms provide a natural and powerful tool for the construction of supergravity actions. They are generalizations of usual differential forms and are needed for a consistent theory of integration on supermanifolds. The group geometrical approach to supergravity and its variational principle are reformulated and clarified in this language. Central in our analysis is the Poincaré dual of a bosonic manifold embedded into a supermanifold. Finally, using integral forms we provide a proof of Gates' so-called "Ectoplasmic Integration Theorem", relating superfield actions to component actions.

  5. Supergravity Actions with Integral Forms

    CERN Document Server

    Castellani, L; Grassi, P A

    2014-01-01

    Integral forms provide a natural and powerful tool for the construction of supergravity actions. They are generalizations of usual differential forms and are needed for a consistent theory of integration on supermanifolds. The group geometrical approach to supergravity and its variational principle are reformulated and clarified in this language. Central in our analysis is the Poincare' dual of a bosonic manifold embedded into a supermanifold. Finally, using integral forms we provide a proof of Gates' so-called "Ectoplasmic Integration Theorem", relating superfield actions to component actions.

  6. Supergravity actions with integral forms

    Directory of Open Access Journals (Sweden)

    L. Castellani

    2014-12-01

    Full Text Available Integral forms provide a natural and powerful tool for the construction of supergravity actions. They are generalizations of usual differential forms and are needed for a consistent theory of integration on supermanifolds. The group geometrical approach to supergravity and its variational principle are reformulated and clarified in this language. Central in our analysis is the Poincaré dual of a bosonic manifold embedded into a supermanifold. Finally, using integral forms we provide a proof of Gates' so-called “Ectoplasmic Integration Theorem”, relating superfield actions to component actions.

  7. Supergravity actions with integral forms

    Energy Technology Data Exchange (ETDEWEB)

    Castellani, L., E-mail: leonardo.castellani@mfn.unipmn.it [Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. Michel, 11, 15121 Alessandria (Italy); INFN, Sezione di Torino, via P. Giuria 1, 10125 Torino (Italy); Catenacci, R., E-mail: roberto.catenacci@mfn.unipmn.it [Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. Michel, 11, 15121 Alessandria (Italy); Grassi, P.A., E-mail: pietro.grassi@mfn.unipmn.it [Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. Michel, 11, 15121 Alessandria (Italy); INFN, Sezione di Torino, via P. Giuria 1, 10125 Torino (Italy)

    2014-12-15

    Integral forms provide a natural and powerful tool for the construction of supergravity actions. They are generalizations of usual differential forms and are needed for a consistent theory of integration on supermanifolds. The group geometrical approach to supergravity and its variational principle are reformulated and clarified in this language. Central in our analysis is the Poincaré dual of a bosonic manifold embedded into a supermanifold. Finally, using integral forms we provide a proof of Gates' so-called “Ectoplasmic Integration Theorem”, relating superfield actions to component actions.

  8. Dual Income Taxes

    DEFF Research Database (Denmark)

    Sørensen, Peter Birch

    This paper discusses the principles and practices of dual income taxation in the Nordic countries. The first part of the paper explains the rationale and the historical background for the introduction of the dual income tax and describes the current Nordic tax practices. The second part...... of the paper focuses on the problems of taxing income from small businesses and the issue of corporate-personal tax integration under the dual income tax, considering alternative ways of dealing with these challenges. In the third and final part of the paper, I briefly discuss whether introducing a dual income...... tax could be relevant for New Zealand....

  9. Dual Income Taxes

    DEFF Research Database (Denmark)

    Sørensen, Peter Birch

    This paper discusses the principles and practices of dual income taxation in the Nordic countries. The first part of the paper explains the rationale and the historical background for the introduction of the dual income tax and describes the current Nordic tax practices. The second part...... of the paper focuses on the problems of taxing income from small businesses and the issue of corporate-personal tax integration under the dual income tax, considering alternative ways of dealing with these challenges. In the third and final part of the paper, I briefly discuss whether introducing a dual income...... tax could be relevant for New Zealand....

  10. Dual-fuel, dual-throat engine preliminary analysis

    Science.gov (United States)

    Obrien, C. J.

    1979-01-01

    A propulsion system analysis of the dual fuel, dual throat engine for launch vehicle applications was conducted. Basic dual throat engine characterization data were obtained to allow vehicle optimization studies to be conducted. A preliminary baseline engine system was defined.

  11. Holographic Complexity Equals Bulk Action?

    Science.gov (United States)

    Brown, Adam R.; Roberts, Daniel A.; Susskind, Leonard; Swingle, Brian; Zhao, Ying

    2016-05-01

    We conjecture that the quantum complexity of a holographic state is dual to the action of a certain spacetime region that we call a Wheeler-DeWitt patch. We illustrate and test the conjecture in the context of neutral, charged, and rotating black holes in anti-de Sitter spacetime, as well as black holes perturbed with static shells and with shock waves. This conjecture evolved from a previous conjecture that complexity is dual to spatial volume, but appears to be a major improvement over the original. In light of our results, we discuss the hypothesis that black holes are the fastest computers in nature.

  12. Action semantics modulate action prediction.

    Science.gov (United States)

    Springer, Anne; Prinz, Wolfgang

    2010-11-01

    Previous studies have demonstrated that action prediction involves an internal action simulation that runs time-locked to the real action. The present study replicates and extends these findings by indicating a real-time simulation process (Graf et al., 2007), which can be differentiated from a similarity-based evaluation of internal action representations. Moreover, results showed that action semantics modulate action prediction accuracy. The semantic effect was specified by the processing of action verbs and concrete nouns (Experiment 1) and, more specifically, by the dynamics described by action verbs (Experiment 2) and the speed described by the verbs (e.g., "to catch" vs. "to grasp" vs. "to stretch"; Experiment 3). These results propose a linkage between action simulation and action semantics as two yet unrelated domains, a view that coincides with a recent notion of a close link between motor processes and the understanding of action language.

  13. The Dual Career Family.

    Science.gov (United States)

    Gurtin, Lee

    1980-01-01

    The dual career couple is forced to make a series of choices and compromises that impact the realms of marriage and career. The dilemmas that confront dual career marriages can be overcome only by compromise, accommodation, and mutual understanding on the part of the individuals involved. A revamping of human resources and recruitment programs is…

  14. Dual Credit Report

    Science.gov (United States)

    Light, Noreen

    2016-01-01

    In 2015, legislation to improve access to dual-credit programs and to reduce disparities in access and completion--particularly for low income and underrepresented students--was enacted. The new law focused on expanding access to College in the High School but acknowledged issues in other dual-credit programs and reinforced the notion that cost…

  15. Dual Youla parameterization

    DEFF Research Database (Denmark)

    Niemann, Hans Henrik

    2003-01-01

    A different aspect of using the parameterisation of all systems stabilised by a given controller, i.e. the dual Youla parameterisation, is considered. The relation between system change and the dual Youla parameter is derived in explicit form. A number of standard uncertain model descriptions are...

  16. Self-Dual Gravity

    CERN Document Server

    Krasnov, Kirill

    2016-01-01

    Self-dual gravity is a diffeomorphism invariant theory in four dimensions that describes two propagating polarisations of the graviton and has a negative mass dimension coupling constant. Nevertheless, this theory is not only renormalisable but quantum finite, as we explain. We also collect various facts about self-dual gravity that are scattered across the literature.

  17. Optical dual self functions

    Institute of Scientific and Technical Information of China (English)

    华建文; 刘立人; 王宁

    1997-01-01

    A recipe to construct the exact dual self-Fourier-Fresnel-transform functions is shown, where the Dirac comb function and transformable even periodic function are used. The mathematical proof and examples are given Then this kind of self-transform function is extended to the feasible optical dual self-transform functions.

  18. Dual doubled geometry

    NARCIS (Netherlands)

    Bergshoeff, Eric A.; Riccioni, Fabio; Alvarez-Gaumé, L.

    2011-01-01

    We probe doubled geometry with dual fundamental branes. i.e. solitons. Restricting ourselves first to solitonic branes with more than two transverse directions we find that the doubled geometry requires an effective wrapping rule for the solitonic branes which is dual to the wrapping rule for fundam

  19. Research on Dual Control

    Institute of Scientific and Technical Information of China (English)

    Duan Li; Fucai Qian; Peilin Fu

    2005-01-01

    This paper summarizes recent progress by the authors in developing two solution frameworks for dual control. The first solution framework considers a class of dual control problems where there exists a parameter uncertainty in the observation equation of the LQG problem. An analytical active dual control law is derived by a variance minimization approach. The issue of how to determine an optimal degree of active learning is then addressed, thus achieving an optimality for this class of dual control problems. The second solution framework considers a general class of discrete-time LQG problems with unknown parameters in both state and observation equations. The best possible (partial) closed-loop feedback control law is derived by exploring the future nominal posterior probabilities, thus taking into account the effect of future learning when constructing the optimal nominal dual control.

  20. Remarks on 2+1 Self-dual Chern-Simons Gravity

    CERN Document Server

    García-Compéan, H; Ramírez, C; Sabido, M

    2000-01-01

    We study 2+1 Chern-Simons gravity at the classical level action. In particular we rederive the linear combinations of the ``standard'' and ``exotic'' Einstein actions, from the (anti)`self-duality' of the `internal' Lorentzian indices. The relation to a genuine four-dimensional (anti) self-dual topological theories greatly facilitates the analysis and its relation to hyperbolic three-dimensional geometry. Finally non-abelian vector field ``dual'' action is also obtained.

  1. Remarks on 2+1 Self-dual Chern-Simons Gravity

    OpenAIRE

    Garcia-Compean, H.; Obregon, O.; Ramirez, C.; Sabido, M.

    1999-01-01

    We study 2+1 Chern-Simons gravity at the classical action level. In particular we rederive the linear combinations of the ``standard'' and ``exotic'' Einstein actions, from the (anti) self-duality of the ``internal'' Lorentzian indices. The relation to a genuine four-dimensional (anti)self-dual topological theory greatly facilitates the analysis and its relation to hyperbolic three-dimensional geometry. Finally a non-abelian vector field ``dual'' action is also obtained.

  2. A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca(2+) channel blocker and endothelin A/B2 receptor antagonist.

    Science.gov (United States)

    Park, Byong-Gon; Shin, Woon-Seob; Oh, Sangtae; Park, Gab-Man; Kim, Nam Ik; Lee, Seokjoon

    2017-09-01

    We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK(+))-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63μM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9.8±0.6μM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca(2+) channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Estimating latency from inhibitory input

    DEFF Research Database (Denmark)

    Levakova, Marie; Ditlevsen, Susanne; Lansky, Petr

    2014-01-01

    to the stimulus by an increase in the firing rate. We focus on the estimation of the response latency in the case of inhibitory stimuli. Models used in this paper represent two different descriptions of response latency. We consider either the latency to be constant across trials or to be a random variable......Stimulus response latency is the time period between the presentation of a stimulus and the occurrence of a change in the neural firing evoked by the stimulation. The response latency has been explored and estimation methods proposed mostly for excitatory stimuli, which means that the neuron reacts....... In the case of random latency, special attention is given to models with selective interaction. The aim is to propose methods for estimation of the latency or the parameters of its distribution. Parameters are estimated by four different methods: method of moments, maximum-likelihood method, a method...

  4. Twisted Covariant Noncommutative Self-dual Gravity

    CERN Document Server

    Estrada-Jimenez, S; Obregón, O; Ramírez, C

    2008-01-01

    A twisted covariant formulation of noncommutative self-dual gravity is presented. The recent formulation introduced by J. Wess and coworkers for constructing twisted Yang-Mills fields is used. It is shown that the noncommutative torsion is solved at any order of the $\\theta$-expansion in terms of the tetrad and the extra fields of the theory. In the process the first order expansion in $\\theta$ for the Pleba\\'nski action is explicitly obtained.

  5. Length and coverage of inhibitory decision rules

    KAUST Repository

    Alsolami, Fawaz

    2012-01-01

    Authors present algorithms for optimization of inhibitory rules relative to the length and coverage. Inhibitory rules have a relation "attribute ≠ value" on the right-hand side. The considered algorithms are based on extensions of dynamic programming. Paper contains also comparison of length and coverage of inhibitory rules constructed by a greedy algorithm and by the dynamic programming algorithm. © 2012 Springer-Verlag.

  6. Monetary rewards modulate inhibitory control

    Directory of Open Access Journals (Sweden)

    Paula Marcela Herrera

    2014-05-01

    Full Text Available The ability to override a dominant response, often referred to as behavioural inhibiton, is considered a key element of executive cognition. Poor behavioural inhibition is a defining characteristic of several neurological and psychiatric populations. Recently, there has been increasing interest in the motivational dimension of behavioural inhibition, with some experiments incorporating emotional contingencies in classical inhibitory paradigms such as the Go/Nogo and Stop Signal Tasks. Several studies have reported a positive modulatory effect of reward on the performance of such tasks in pathological conditions such as substance abuse, pathological gambling, and ADHD. However, experiments that directly investigate the modulatory effects of reward magnitudes on the performance of inhibitory paradigms are rare and consequently, little is known about the finer grained relationship between motivation and self-control. Here, we probed the effect of reward and reward magnitude on behavioural inhibition using two modified version of the widely used Stop Signal Task. The first task compared no reward with reward, whilst the other compared two different reward magnitudes. The reward magnitude effect was confirmed by the second study, whereas it was less compelling in the first study, possibly due to the effect of having no reward in some conditions. In addition, our results showed a kick start effect over global performance measures. More specifically, there was a long lasting improvement in performance throughout the task, when participants received the highest reward magnitudes at the beginning of the protocol. These results demonstrate that individuals’ behavioural inhibition capacities are dynamic not static because they are modulated by the reward magnitude and initial reward history of the task at hand.

  7. Effects of a no-go Task 2 on Task 1 performance in dual - tasking: From benefits to costs.

    Science.gov (United States)

    Janczyk, Markus; Huestegge, Lynn

    2017-04-01

    When two tasks are combined in a dual-task experiment, characteristics of Task 2 can influence Task 1 performance, a phenomenon termed the backward crosstalk effect (BCE). Besides instances depending on the (spatial) compatibility of both responses, a particularly interesting example was introduced by Miller (2006): If Task 2 was a no-go task (i.e., one not requiring any action at all), responses were slowed in Task 1. Subsequent work, however, also reported the opposite result-that is, faster Task 1 responses in cases of no-go Task 2 trials. We report three experiments aiming to more precisely identify the conditions under which a no-go Task 2 facilitates or impedes Task 1 performance. The results suggest that an adverse no-go BCE is only observed when the Task 2 response(s) are sufficiently prepared in advance, yielding strong inhibitory control demands for Task 2 that eventually hamper Task 1 processing as well (i.e., inhibitory costs). If this is not the case, encountering a no-go Task 2 trial facilitates Task 1 performance, suggesting that the underlying task representation is reduced to a single - task. These results are discussed in the context of other recent work on BCEs and of recently suggested accounts of the no-go BCE.

  8. Alternative self-dual gravity in eight dimensions

    Science.gov (United States)

    Nieto, J. A.

    2016-07-01

    We develop an alternative Ashtekar formalism in eight dimensions. In fact, using a MacDowell-Mansouri physical framework and a self-dual curvature symmetry, we propose an action in eight dimensions in which the Levi-Civita tenor with eight indices plays a key role. We explicitly show that such an action contains number of linear, quadratic and cubic terms in the Riemann tensor, Ricci tensor and scalar curvature. In particular, the linear term is reduced to the Einstein-Hilbert action with cosmological constant in eight dimensions. We prove that such a reduced action is equivalent to the Lovelock action in eight dimensions.

  9. Alternative Self-dual Gravity in Eight Dimensions

    CERN Document Server

    Nieto, J A

    2016-01-01

    We develop an alternative Ashtekar formalism in eight dimensions. In fact, using a MacDowell-Mansouri physical framework and a self-dual curvature symmetry we propose an action in eight dimensions in which the Levi-Civita tenor with eight indices plays a key role. We explicitly show that such an action contains number of linear, quadratic and cubic terms in the Riemann tensor, Ricci tensor and scalar curvature. In particular, the linear term is reduced to the Einstein-Hilbert action with cosmological constant in eight dimensions. We prove that such a reduced action is equivalent to the Lovelock action in eight dimensions.

  10. Dual Credit/Dual Enrollment and Data Driven Policy Implementation

    Science.gov (United States)

    Lichtenberger, Eric; Witt, M. Allison; Blankenberger, Bob; Franklin, Doug

    2014-01-01

    The use of dual credit has been expanding rapidly. Dual credit is a college course taken by a high school student for which both college and high school credit is given. Previous studies provided limited quantitative evidence that dual credit/dual enrollment is directly connected to positive student outcomes. In this study, predictive statistics…

  11. Dual coil ignition system

    Energy Technology Data Exchange (ETDEWEB)

    Huberts, Garlan J.; Qu, Qiuping; Czekala, Michael Damian

    2017-03-28

    A dual coil ignition system is provided. The dual coil ignition system includes a first inductive ignition coil including a first primary winding and a first secondary winding, and a second inductive ignition coil including a second primary winding and a second secondary winding, the second secondary winding connected in series to the first secondary winding. The dual coil ignition system further includes a diode network including a first diode and a second diode connected between the first secondary winding and the second secondary winding.

  12. Dual energy CT

    DEFF Research Database (Denmark)

    Al-Najami, Issam; Drue, Henrik Christian; Steele, Robert

    2017-01-01

    and inaccurate with existing methods. Dual Energy Computed Tomography (DECT) enables qualitative tissue differentiation by simultaneous scanning with different levels of energy. We aimed to assess the feasibility of DECT in quantifying tumor response to neoadjuvant therapy in loco-advanced rectal cancer. METHODS...... to determine the average quantitative parameters; effective-Z, water- and iodine-concentration, Dual Energy Index (DEI), and Dual Energy Ratio (DER). These parameters were compared to the regression in the resection specimen as measured by the pathologist. RESULTS: Changes in the quantitative parameters...

  13. Action physics

    Science.gov (United States)

    McGinness, Lachlan P.; Savage, C. M.

    2016-09-01

    More than a decade ago, Edwin Taylor issued a "call to action" that presented the case for basing introductory university mechanics teaching around the principle of stationary action [E. F. Taylor, Am. J. Phys. 71, 423-425 (2003)]. We report on our response to that call in the form of an investigation of the teaching and learning of the stationary action formulation of physics in a first-year university course. Our action physics instruction proceeded from the many-paths approach to quantum physics to ray optics, classical mechanics, and relativity. Despite the challenges presented by action physics, students reported it to be accessible, interesting, motivational, and valuable.

  14. Exact self-dual skyrmions

    Science.gov (United States)

    Ferreira, L. A.; Shnir, Ya.

    2017-09-01

    We introduce a Skyrme type model with the target space being the sphere S3 and with an action possessing, as usual, quadratic and quartic terms in field derivatives. The novel character of the model is that the strength of the couplings of those two terms are allowed to depend upon the space-time coordinates. The model should therefore be interpreted as an effective theory, such that those couplings correspond in fact to low energy expectation values of fields belonging to a more fundamental theory at high energies. The theory possesses a self-dual sector that saturates the Bogomolny bound leading to an energy depending linearly on the topological charge. The self-duality equations are conformally invariant in three space dimensions leading to a toroidal ansatz and exact self-dual Skyrmion solutions. Those solutions are labelled by two integers and, despite their toroidal character, the energy density is spherically symmetric when those integers are equal and oblate or prolate otherwise.

  15. Complementary Actions

    Directory of Open Access Journals (Sweden)

    Luisa eSartori

    2015-05-01

    Full Text Available Complementary colors are color pairs which, when combined in the right proportions, produce white or black. Complementary actions refer here to forms of social interaction wherein individuals adapt their joint actions according to a common aim. Notably, complementary actions are incongruent actions. But being incongruent is not sufficient to be complementary (i.e., to complete the action of another person. Successful complementary interactions are founded on the abilities: (i to simulate another person’s movements, (ii to predict another person’s future action/s, (iii to produce an appropriate incongruent response which differ, while interacting, with observed ones, and (iv to complete the social interaction by integrating the predicted effects of one’s own action with those of another person. This definition clearly alludes to the functional importance of complementary actions in the perception–action cycle and prompts us to scrutinize what is taking place behind the scenes. Preliminary data on this topic have been provided by recent cutting-edge studies utilizing different research methods. This mini-review aims to provide an up-to-date overview of the processes and the specific activations underlying complementary actions.

  16. Walkable dual emissions

    National Research Council Canada - National Science Library

    Xu, Hai-Bing; Jiao, Peng-Chong; Kang, Bin; Deng, Jian-Guo; Zhang, Yan

    2013-01-01

    Walkable dual emissions, in which the emission bands of the walker reversibly cross or leave those of the stationary ones depending on temperature and concentration, have been demonstrated in cyclic...

  17. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape.

    Science.gov (United States)

    Woo, Seng-Ryong; Turnis, Meghan E; Goldberg, Monica V; Bankoti, Jaishree; Selby, Mark; Nirschl, Christopher J; Bettini, Matthew L; Gravano, David M; Vogel, Peter; Liu, Chih Long; Tangsombatvisit, Stephanie; Grosso, Joseph F; Netto, George; Smeltzer, Matthew P; Chaux, Alcides; Utz, Paul J; Workman, Creg J; Pardoll, Drew M; Korman, Alan J; Drake, Charles G; Vignali, Dario A A

    2012-02-15

    Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.

  18. Gauge theory of supergravity based only on a self-dual spin connection

    Energy Technology Data Exchange (ETDEWEB)

    Nieto, J.A.; Socorro, J.; Obregon, O. [Area of Superstrings, Escuela de Ciencias Fisico-Matematicas de la Universidad Michoacana de San Nicolas de Hidalgo, P.O. Box 749, 58000, Morelia, Michoacan (Mexico)]|[Instituto de Fisica de la Universidad de Guanajuato, P.O. Box E-143, 37150, Leon, Gto. (Mexico)]|[Depto. de Fisica, Universidad Autonoma Metropolitana-Iztapalapa, P.O. Box 55-534, 09340, D.F., Mexico (Mexico)

    1996-05-01

    A gauge theory of supergravity is constructed based only on the supersymmetric self-dual spin connection associated to the supergroup OSp(1{vert_bar}4). We show that Jacobson{close_quote}s supergravity action arises naturally from our proposed action. It is formulated by taking the self-dual part of the MacDowell-Mansouri gauge theory of supergravity. In this sense, our quadratic action in the supersymmetric self-dual curvature tensor provides a relation between these two important previous extensions of supergravity. {copyright} {ital 1996 The American Physical Society.}

  19. Transient inhibitory seizures mimicking crescendo TIAs.

    Science.gov (United States)

    Lee, H; Lerner, A

    1990-01-01

    Somatic inhibitory seizures are thought to occur rarely. We describe a patient with somatic inhibitory seizures who initially presented with a clinical picture of crescendo transient ischemic attacks. He did not improve with anticoagulation, but the episodes ceased promptly after the administration of an anticonvulsant.

  20. Inhibitory Effect of Furosemide on Carbonic Anhydrase

    Institute of Scientific and Technical Information of China (English)

    CUI Jianli; ZHAO Tongjin; JIANG Yan; ZHOU Haimeng

    2006-01-01

    This study investigated the inhibitory effect of a high efficiency diuretic, furosemide, on carbonic anhydrase (CA). First, comparing the inhibitory effect of acetazolamide, a low efficiency diuretic, on CA, shows that furosemide or acetazolamide can quickly make CA inactive when its concentration is close to the enzyme concentration, different from the usual inhibitory kinetics in which the concentration of the inhibitor is far higher than the enzyme concentration. Secondly, the reaction of the enzyme indicates that the inhibitory effect of furosemide or acetazolamide on carbonic anhydrase is quickly reversible. Finally, the degree of the inhibitory effect of furosemide and of acetazolamide on CA are compared. The results show that furosemide inhibits CA less than acetazolamide.

  1. Inhibitory control of linear and supralinear dendritic excitation in CA1 pyramidal neurons.

    Science.gov (United States)

    Müller, Christina; Beck, Heinz; Coulter, Douglas; Remy, Stefan

    2012-09-01

    The transformation of dendritic excitatory synaptic inputs to axonal action potential output is the fundamental computation performed by all principal neurons. We show that in the hippocampus this transformation is potently controlled by recurrent inhibitory microcircuits. However, excitatory input on highly excitable dendritic branches could resist inhibitory control by generating strong dendritic spikes and trigger precisely timed action potential output. Furthermore, we show that inhibition-sensitive branches can be transformed into inhibition-resistant, strongly spiking branches by intrinsic plasticity of branch excitability. In addition, we demonstrate that the inhibitory control of spatially defined dendritic excitation is strongly regulated by network activity patterns. Our findings suggest that dendritic spikes may serve to transform correlated branch input into reliable and temporally precise output even in the presence of inhibition.

  2. Dyon Condensation and Dual Superconductivity in Abelian Higgs Model of QCD

    Directory of Open Access Journals (Sweden)

    B. S. Rajput

    2010-01-01

    Full Text Available Constructing the effective action for dyonic field in Abelian projection of QCD, it has been demonstrated that any charge (electrical or magnetic of dyon screens its own direct potential to which it minimally couples and antiscreens the dual potential leading to dual superconductivity in accordance with generalized Meissner effect. Taking the Abelian projection of QCD, an Abelian Higgs model, incorporating dual superconductivity and confinement, has been constructed and its representation has been obtained in terms of average of Wilson loop.

  3. The political downside of dual identity : Group identifications and religious political mobilization of Muslim minorities

    NARCIS (Netherlands)

    Martinovic, Borja; Verkuijten, Maykel

    2014-01-01

    Research on the political mobilization of ethnic minorities has shown that dual ethno-national identification facilitates involvement in political action on behalf of the ethnic group. This study extends this research by proposing that a dual identity can impede political mobilization on behalf of a

  4. Dual Projection and Selfduality in Three Dimensions

    CERN Document Server

    Banerjee, R; Banerjee, Rabin; Wotzasek, Clovis

    2001-01-01

    We discuss the notion of duality and selfduality in the context of the dual projection operation that creates an internal space of potentials. Contrary to the prevailing algebraic or group theoretical methods, this technique is applicable to both even and odd dimensions. The role of parity in the kernel of the Gauss law to determine the dimensional dependence is clarified. We derive the appropriate invariant actions, discuss the symmetry groups and their proper generators. In particular, the novel concept of duality symmetry and selfduality in Maxwell theory in (2+1) dimensions is analysed in details. The corresponding action is a 3D version of the familiar duality symmetric electromagnetic theory in 4D. Finally, the duality symmetric actions in the different dimensions constructed here manifest both the SO(2) and $Z_2$ symmetries, contrary to conventional results.

  5. Studies on Pharmacodynamics in vitro o Florfenicol Dual Suspension Emulsion

    Institute of Scientific and Technical Information of China (English)

    Xiaowen LI; Hongjun ZHANG; Chengshu WU; Zigong WEI

    2012-01-01

    Abstract [Objective] The paper was to study in vitro pharmacodynamics character- istics of florfenicol dual suspension emulsion (DSEF). [Method] The florfenicol injec- tion (FI) was used as the control group, the minimal inhibitory concentration (MIC), minimal bactericide concentration (MBC) and mutant selection window (MSW) of florfenicol dual suspension emulsion on 5 kinds of bacteria were determined. The post-antibiotic effect (PAE) and post-antibiotic sub-MIC effect (PASME) of Salmonella typhimurium were also measured. [Result] Compared with the ordinary injection, the MIC and MBC of florfenicol dual suspension emulsion on 5 kinds of bacteria showed no obvious changes. However, florfenicol dual suspension emulsion obvious- ly narrowed MSW of 5 kinds of bacteria (P〈0.01), which also significantly extended PAE and PASME of S. typhimurium (P〈0.01). [Conclusion] The florfenicol dual sus- pension emulsion in vitro can reduce the probability of bacterial resistance, signifi- cantly prolong after effect time of antibiotics on bacteria, thereby effectively improving the antibacterial effect.

  6. INHIBITORY MOTOR SEIZURES: SEMIOLOGY AND THERAPY

    Directory of Open Access Journals (Sweden)

    K. Yu. Мukhin

    2013-01-01

    Full Text Available The article is devoted to rare and unique type of epileptic seizures – inhibitory motor seizures, characterized by the inability to execute a voluntary movement with preserved consciousness. The exact prevalence of this type of seizures is not known, but many cases are unrecognized or non-correctly diagnosed as Todd's paralysis. Therefore practical doctors should know the clinical and electroencephalographic characteristics of this type of seizures andtake them into account in the differential diagnoses . The authors presented a detailed review of the literature, including the historical data, etiology, pathogenesis and proposed mechanisms of formation of inhibitory motor seizures, clinical and EEG characteristics, therapeutic approaches. Antiepileptic drugs of choice used in the treatment of inhibitory motor seizures are valproic acid (preferably depakine chronosphere – original prolonged form of valproate. The authors also presented their observations of patients with inhibitory motor seizures.

  7. Dual phase evolution

    CERN Document Server

    Green, David G; Abbass, Hussein A

    2014-01-01

    This book explains how dual phase evolution operates in all these settings and provides a detailed treatment of the subject. The authors discuss the theoretical foundations for the theory, how it relates to other phase transition phenomena and its advantages in evolutionary computation and complex adaptive systems. The book provides methods and techniques to use this concept for problem solving. Dual phase evolution concerns systems that evolve via repeated phase shifts in the connectivity of their elements. It occurs in vast range of settings, including natural systems (species evolution, landscape ecology, geomorphology), socio-economic systems (social networks) and in artificial systems (annealing, evolutionary computing).

  8. The antifungal eugenol perturbs dual aromatic and branched-chain amino acid permeases in the cytoplasmic membrane of yeast.

    Science.gov (United States)

    Darvishi, Emad; Omidi, Mansoor; Bushehri, Ali Akbar Shahnejat; Golshani, Ashkan; Smith, Myron L

    2013-01-01

    Eugenol is an aromatic component of clove oil that has therapeutic potential as an antifungal drug, although its mode of action and precise cellular target(s) remain ambiguous. To address this knowledge gap, a chemical-genetic profile analysis of eugenol was done using ∼4700 haploid Saccharomyces cerevisiae gene deletion mutants to reveal 21 deletion mutants with the greatest degree of susceptibility. Cellular roles of deleted genes in the most susceptible mutants indicate that the main targets for eugenol include pathways involved in biosynthesis and transport of aromatic and branched-chain amino acids. Follow-up analyses showed inhibitory effects of eugenol on amino acid permeases in the yeast cytoplasmic membrane. Furthermore, phenotypic suppression analysis revealed that eugenol interferes with two permeases, Tat1p and Gap1p, which are both involved in dual transport of aromatic and branched-chain amino acids through the yeast cytoplasmic membrane. Perturbation of cytoplasmic permeases represents a novel antifungal target and may explain previous observations that exposure to eugenol results in leakage of cell contents. Eugenol exposure may also contribute to amino acid starvation and thus holds promise as an anticancer therapeutic drug. Finally, this study provides further evidence of the usefulness of the yeast Gene Deletion Array approach in uncovering the mode of action of natural health products.

  9. Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.

    Science.gov (United States)

    Xie, Qiong; Zheng, Zhaoxi; Shao, Biyun; Fu, Wei; Xia, Zheng; Li, Wei; Sun, Jian; Zheng, Wei; Zhang, Weiwei; Sheng, Wei; Zhang, Qihong; Chen, Hongzhuan; Wang, Hao; Qiu, Zhuibai

    2017-12-01

    Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ42) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

  10. Commuting Dual Toeplitz Operators on the Polydisk

    Institute of Scientific and Technical Information of China (English)

    Yu Feng LU; Shu Xia SHANG

    2007-01-01

    On the polydisk, the commutativity of dual Toeplitz operators is studied. We obtain characterizations of commuting dual Toeplitz operators, essentially commuting dual Toeplitz operators and essentially semi-commuting dual Toeplitz operators.

  11. Lipase inhibitory activity of chlorophyll a, isofucosterol and saringosterol isolated from chloroform fraction of Sargassum thunbergii.

    Science.gov (United States)

    Kim, Koth-Bong-Woo-Ri; Kim, Min-Ji; Ahn, Dong-Hyun

    2014-01-01

    Three compounds (chlorophyll a, isofucosterol and saringosterol) were isolated from chloroform fraction of Sargassum thunbergii extract. The three compounds had two- to fourfold lower lipase inhibitory activity than that of the CHCl3:MeOH (C:M) (100:1) fraction (fraction I, 83.78% at 1 mg/mL). These results suggested that the high lipase inhibitory activity of fraction I was attributable to the actions of the three compounds. Therefore, S. thunbergii has potential for application as an anti-obesity agent.

  12. Early Dual Language Learning

    Science.gov (United States)

    Genesee, Fred

    2008-01-01

    Parents and child care personnel in English-dominant parts of the world often express misgivings about raising children bilingually. Their concerns are based on the belief that dual language learning during the infant-toddler stage confuses children, delays their development, and perhaps even results in reduced language competence. In this…

  13. Scalar QED$_2$ with a topological term - a lattice study in a dual representation

    CERN Document Server

    Kloiber, Thomas

    2014-01-01

    We present a dual representation for the partition function of 2-dimensional scalar quantum electrodynamics with a topological term ($\\theta$-term). In the dual representation the complex action problem at non-zero $\\theta$ is absent, which is an obstacle for Monte Carlo simulations in the conventional form of the model. We discuss the technical aspects of the dual representation and show that a dual Monte Carlo simulation can be implemented. As a first application we demonstrate how the $2\\pi$-periodicity of physical observables is recovered in a suitable continuum limit.

  14. Investigating Potential Modes of Actions of Mimusops kummel Fruit Extract and Solvent Fractions for Their Antidiarrheal Activities in Mice.

    Science.gov (United States)

    Molla, Mulugeta; Gemeda, Negero; Abay, Solomon M

    2017-01-01

    Fruits of Mimusops kummel A. DC. (Sapotaceae) are traditionally used for the treatment of diarrhea. The present study aimed at investigating modes of actions of this fruits for antidiarrheal action to guide future drug development process. Fractions of chloroform, n-butanol, and water were obtained from 80% methanol extract, which was prepared by maceration. Antidiarrheal activities and the modes of actions were investigated in mice. In castor oil induced diarrheal model, the extract delayed onset of diarrhea and reduced number and weight of feces at all tested doses significantly. In this model all fractions significantly delayed onset of diarrhea at all tested doses. Charcoal meal test showed that the extract and all the fractions produced a significant antimotility effect at all tested doses. Enteropooling test showed that the extract as well as n-butanol and aqueous fractions at all tested doses produced a significant decline in volume and weight of intestinal contents, whereas chloroform fraction had substantial effect only at high dose. This study demonstrated that the extract and solvent fractions produced antidiarrheal activities due to dual inhibitory effect, intestinal motility, and fluid secretion, with the aqueous fraction being the most active among fractions in three models.

  15. Investigating Potential Modes of Actions of Mimusops kummel Fruit Extract and Solvent Fractions for Their Antidiarrheal Activities in Mice

    Directory of Open Access Journals (Sweden)

    Mulugeta Molla

    2017-01-01

    Full Text Available Background. Fruits of Mimusops kummel A. DC. (Sapotaceae are traditionally used for the treatment of diarrhea. The present study aimed at investigating modes of actions of this fruits for antidiarrheal action to guide future drug development process. Methods. Fractions of chloroform, n-butanol, and water were obtained from 80% methanol extract, which was prepared by maceration. Antidiarrheal activities and the modes of actions were investigated in mice. Results. In castor oil induced diarrheal model, the extract delayed onset of diarrhea and reduced number and weight of feces at all tested doses significantly. In this model all fractions significantly delayed onset of diarrhea at all tested doses. Charcoal meal test showed that the extract and all the fractions produced a significant antimotility effect at all tested doses. Enteropooling test showed that the extract as well as n-butanol and aqueous fractions at all tested doses produced a significant decline in volume and weight of intestinal contents, whereas chloroform fraction had substantial effect only at high dose. Conclusion. This study demonstrated that the extract and solvent fractions produced antidiarrheal activities due to dual inhibitory effect, intestinal motility, and fluid secretion, with the aqueous fraction being the most active among fractions in three models.

  16. Alcohol-induced impairment of inhibitory control is linked to attenuated brain responses in right fronto-temporal cortex

    Science.gov (United States)

    Gan, Gabriela; Guevara, Alvaro; Marxen, Michael; Neumann, Maike; Jünger, Elisabeth; Kobiella, Andrea; Mennigen, Eva; Pilhatsch, Maximilian; Schwarz, Daniel; Zimmermann, Ulrich S.; Smolka, Michael N.

    2014-01-01

    Background A self-enhancing loop between impaired inhibitory control under alcohol and alcohol consumption has been proposed as a possible mechanism underlying dysfunctional drinking in susceptible people. However, the neural underpinnings of alcohol-induced impairment of inhibitory control are widely unknown. Methods We measured inhibitory control in fifty young adults with a stop-signal task (SST) during functional magnetic resonance imaging (fMRI). In a single-blind placebo-controlled cross-over design, all participants performed the SST once under alcohol with a breath alcohol concentration (BrAC) of 0.6 g/kg, and once under placebo. In addition, alcohol consumption was assessed using a free-access alcohol self-administration (ASA) paradigm in the same participants. Results Inhibitory control was robustly decreased under alcohol compared to placebo indicated by longer stop-signal reaction times (SSRTs). On the neural level, impaired inhibitory control under alcohol was associated with attenuated brain responses in the right fronto-temporal portion of the inhibition network that supports the attentional capture of infrequent stop-signals, and subsequent updating of action plans from response execution to inhibition. Furthermore, the extent of alcohol-induced impairment of inhibitory control predicted free-access alcohol consumption. Conclusion We suggest that during inhibitory control alcohol affects cognitive processes preceding actual motor inhibition. Under alcohol, decreased brain responses in right fronto-temporal areas might slow down the attentional capture of infrequent stop-signals and subsequent updating of action plans which leads to impaired inhibitory control. In turn, pronounced alcohol-induced impairment of inhibitory control may enhance alcohol consumption in young adults which might promote future alcohol problems. PMID:24560581

  17. Alcohol-induced impairment of inhibitory control is linked to attenuated brain responses in right fronto-temporal cortex.

    Science.gov (United States)

    Gan, Gabriela; Guevara, Alvaro; Marxen, Michael; Neumann, Maike; Jünger, Elisabeth; Kobiella, Andrea; Mennigen, Eva; Pilhatsch, Maximilian; Schwarz, Daniel; Zimmermann, Ulrich S; Smolka, Michael N

    2014-11-01

    A self-enhancing loop between impaired inhibitory control under alcohol and alcohol consumption has been proposed as a possible mechanism underlying dysfunctional drinking in susceptible people. However, the neural underpinnings of alcohol-induced impairment of inhibitory control are widely unknown. We measured inhibitory control in 50 young adults with a stop-signal task during functional magnetic resonance imaging. In a single-blind placebo-controlled cross-over design, all participants performed the stop-signal task once under alcohol with a breath alcohol concentration of .6 g/kg and once under placebo. In addition, alcohol consumption was assessed with a free-access alcohol self-administration paradigm in the same participants. Inhibitory control was robustly decreased under alcohol compared with placebo, indicated by longer stop-signal reaction times. On the neural level, impaired inhibitory control under alcohol was associated with attenuated brain responses in the right fronto-temporal portion of the inhibition network that supports the attentional capture of infrequent stop-signals and subsequent updating of action plans from response execution to inhibition. Furthermore, the extent of alcohol-induced impairment of inhibitory control predicted free-access alcohol consumption. We suggest that during inhibitory control alcohol affects cognitive processes preceding actual motor inhibition. Under alcohol, decreased brain responses in right fronto-temporal areas might slow down the attentional capture of infrequent stop-signals and subsequent updating of action plans, which leads to impaired inhibitory control. In turn, pronounced alcohol-induced impairment of inhibitory control might enhance alcohol consumption in young adults, which might promote future alcohol problems. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Global optogenetic activation of inhibitory interneurons during epileptiform activity.

    Science.gov (United States)

    Ledri, Marco; Madsen, Marita Grønning; Nikitidou, Litsa; Kirik, Deniz; Kokaia, Merab

    2014-02-26

    Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. In particular, the possibility to specifically activate by light-determined interneuron populations expressing channelrhodopsin-2 provides an unprecedented opportunity of exploring their contribution to physiological and pathological network activity. There are several subclasses of interneurons in cortical areas with different functional connectivity to the principal neurons (e.g., targeting their perisomatic or dendritic compartments). Therefore, one could optogenetically activate specific or a mixed population of interneurons and dissect their selective or concerted inhibitory action on principal cells. We chose to explore a conceptually novel strategy involving simultaneous activation of mixed populations of interneurons by optogenetics and study their impact on ongoing epileptiform activity in mouse acute hippocampal slices. Here we demonstrate that such approach results in a brief initial action potential discharge in CA3 pyramidal neurons, followed by prolonged suppression of ongoing epileptiform activity during light exposure. Such sequence of events was caused by massive light-induced release of GABA from ChR2-expressing interneurons. The inhibition of epileptiform activity was less pronounced if only parvalbumin- or somatostatin-expressing interneurons were activated by light. Our data suggest that global optogenetic activation of mixed interneuron populations is a more effective approach for development of novel therapeutic strategies for epilepsy, but the initial action potential generation in principal neurons needs to be taken in consideration.

  19. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses

    Science.gov (United States)

    Trouche, Stéphanie; Sasaki, Jennifer M.; Tu, Tiffany; Reijmers, Leon G.

    2013-01-01

    SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. PMID:24183705

  20. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses.

    Science.gov (United States)

    Trouche, Stéphanie; Sasaki, Jennifer M; Tu, Tiffany; Reijmers, Leon G

    2013-11-20

    A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission

    Science.gov (United States)

    Accardi, Michael V.; Daniels, Bryan A.; Brown, Patricia M. G. E.; Fritschy, Jean-Marc; Tyagarajan, Shiva K.; Bowie, Derek

    2014-01-01

    Neuronal communication imposes a heavy metabolic burden in maintaining ionic gradients essential for action potential firing and synaptic signalling. Although cellular metabolism is known to regulate excitatory neurotransmission, it is still unclear whether the brain’s energy supply affects inhibitory signalling. Here we show that mitochondrial-derived reactive oxygen species (mROS) regulate the strength of postsynaptic GABAA receptors at inhibitory synapses of cerebellar stellate cells. Inhibition is strengthened through a mechanism that selectively recruits α3-containing GABAA receptors into synapses with no discernible effect on resident α1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly recruited α3-containing GABAA receptors are activated by neurotransmitter released onto discrete postsynaptic sites. Although traditionally associated with oxidative stress in neurodegenerative disease, our data identify mROS as a putative homeostatic signalling molecule coupling cellular metabolism to the strength of inhibitory transmission.

  2. Regulation of hematopoietic cell function by inhibitory immunoglobulin G receptors and their inositol lipid phosphatase effectors.

    Science.gov (United States)

    Cady, Carol T; Rice, Jeffrey S; Ott, Vanessa L; Cambier, John C

    2008-08-01

    Numerous autoimmune and inflammatory disorders stem from the dysregulation of hematopoietic cell activation. The activity of inositol lipid and protein tyrosine phosphatases, and the receptors that recruit them, is critical for prevention of these disorders. Balanced signaling by inhibitory and activating receptors is now recognized to be an important factor in tuning cell function and inflammatory potential. In this review, we provide an overview of current knowledge of membrane proximal events in signaling by inhibitory/regulatory receptors focusing on structural and functional characteristics of receptors and their effectors Src homology 2 (SH2) domain-containing tyrosine phosphatase 1 and SH2 domain-containing inositol 5-phosphatase-1. We review use of new strategies to identify novel regulatory receptors and effectors. Finally, we discuss complementary actions of paired inhibitory and activating receptors, using Fc gammaRIIA and Fc gammaRIIB regulation human basophil activation as a prototype.

  3. Toluene decreases Purkinje cell output by enhancing inhibitory synaptic transmission in the cerebellar cortex.

    Science.gov (United States)

    Gmaz, Jimmie M; McKay, Bruce E

    2014-02-07

    Toluene belongs to a class of psychoactive drugs known as inhalants. Found in common household products such as adhesives, paint products, and aerosols, toluene is inhaled for its intoxicating and euphoric properties. Additionally, exposure to toluene disrupts motor behaviors in a manner consistent with impairments to cerebellar function. Previous work has suggested a role of GABA in mediating toluene's neurobehavioral effects, but how this manifests in the cerebellar cortex is not yet understood. In the present study, we examined the effects of toluene on cerebellar Purkinje cell action potential output and inhibitory synaptic transmission onto Purkinje cells using patch clamp electrophysiology in acute rat cerebellar slices. Toluene (1mM) reduced the frequency of Purkinje cell action potential output without affecting input resistance. Furthermore, toluene dose-dependently enhanced inhibitory synaptic transmission onto Purkinje cells, increasing the amplitude and frequency of inhibitory postsynaptic currents; no change in the frequency of action potentials from molecular layer interneurons was noted. The observed decreases in Purkinje cell action potential output could contribute to toluene-evoked impairments in cerebellar and motor functions. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Supermembrane in D=5: component action

    Energy Technology Data Exchange (ETDEWEB)

    Bellucci, S. [INFN-Laboratori Nazionali di Frascati,Via E. Fermi 40, 00044 Frascati (Italy); Kozyrev, N.; Krivonos, S. [Bogoliubov Laboratory of Theoretical Physics, Joint Institute for Nuclear Research,Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Yeranyan, A. [Museo Storico della Fisica e Centro Studi e Ricerche “Enrico Fermi”,Via Panisperna 89A, 00184 Roma (Italy); INFN-Laboratori Nazionali di Frascati,Via E. Fermi 40, 00044 Frascati (Italy); Department of Physics, Yerevan State University,Alex Manoogian St. 1, Yerevan, 0025 (Armenia)

    2014-05-29

    Based on the connection between partial breaking of global supersymmetry, coset approach, which realized the given pattern of supersymmetry breaking, and the Nambu-Goto actions for the extended objects, we have constructed on-shell component action for N=1,D=5 supermembrane and its dual cousins. We demonstrate that the proper choice of the components and the use of the covariant (with respect to broken supersymmetry) derivatives drastically simplify the action: it can be represented as a sum of four terms each having an explicit geometric meaning.

  5. Complexity and Two Identities of Action Growth

    CERN Document Server

    Huang, Hyat; Lu, H

    2016-01-01

    The recently proposed complexity-action conjecture allows one to calculate how fast one can produce a quantum state from a reference state in terms of the on-shell action of the dual AdS black hole at the Wheeler-DeWitt patch. We show that the action growth rate is given by the difference of the generalized enthalpy between the two corresponding horizons. The proof relies on the second identity that the surface-term contribution on a horizon is given by the product of the associated temperature and entropy.

  6. Dual-readout Calorimetry

    CERN Document Server

    Akchurin, N; Cardini, A.; Cascella, M.; Cei, F.; De Pedis, D.; Fracchia, S.; Franchino, S.; Fraternali, M.; Gaudio, G.; Genova, P.; Hauptman, J.; La Rotonda, L.; Lee, S.; Livan, M.; Meoni, E.; Moggi, A.; Pinci, D.; Policicchio, A.; Saraiva, J.G.; Sill, A.; Venturelli, T.; Wigmans, R.

    2013-01-01

    The RD52 Project at CERN is a pure instrumentation experiment whose goal is to un- derstand the fundamental limitations to hadronic energy resolution, and other aspects of energy measurement, in high energy calorimeters. We have found that dual-readout calorimetry provides heretofore unprecedented information event-by-event for energy resolution, linearity of response, ease and robustness of calibration, fidelity of data, and particle identification, including energy lost to binding energy in nuclear break-up. We believe that hadronic energy resolutions of {\\sigma}/E $\\approx$ 1 - 2% are within reach for dual-readout calorimeters, enabling for the first time comparable measurement preci- sions on electrons, photons, muons, and quarks (jets). We briefly describe our current progress and near-term future plans. Complete information on all aspects of our work is available at the RD52 website http://highenergy.phys.ttu.edu/dream/.

  7. Higher Representations Duals

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2010-01-01

    We uncover novel solutions of the 't Hooft anomaly matching conditions for scalarless gauge theories with matter transforming according to higher dimensional representations of the underlying gauge group. We argue that, if the duals exist, they are gauge theories with fermions transforming...... according to the defining representation of the dual gauge group. The resulting conformal windows match the one stemming from the all-orders beta function results when taking the anomalous dimension of the fermion mass to be unity which are also very close to the ones obtained using the Schwinger......-Dyson approximation. We use the solutions to gain useful insight on the conformal window of the associated electric theory. A consistent picture emerges corroborating previous results obtained via different analytic methods and in agreement with first principle lattice explorations....

  8. Dual Campus High School

    Directory of Open Access Journals (Sweden)

    Carmen P. Mombourquette

    2013-04-01

    Full Text Available September 2010 witnessed the opening of the first complete dual campus high school in Alberta. Catholic Central High School, which had been in existence since 1967 in one building, now offered courses to students on two campuses. The “dual campus” philosophy was adopted so as to ensure maximum program flexibility for students. The philosophy, however, was destined to affect student engagement and staff efficacy as the change in organizational structure, campus locations, and course availability was dramatic. Changing school organizational structure also had the potential of affecting student achievement. A mixed-methods study utilizing engagement surveys, efficacy scales, and interviews with students and teachers was used to ascertain the degree of impact. The results of the study showed that minimal impact occurred to levels of student engagement, minor negative impact to staff efficacy, and a slight increase to student achievement results.

  9. Dual Double Field Theory

    CERN Document Server

    Bergshoeff, Eric A; Penas, Victor A; Riccioni, Fabio

    2016-01-01

    We present the dual formulation of double field theory at the linearized level. This is a classically equivalent theory describing the duals of the dilaton, the Kalb-Ramond field and the graviton in a T-duality or O(D,D) covariant way. In agreement with previous proposals, the resulting theory encodes fields in mixed Young-tableau representations, combining them into an antisymmetric 4-tensor under O(D,D). In contrast to previous proposals, the theory also requires an antisymmetric 2-tensor and a singlet, which are not all pure gauge. The need for these additional fields is analogous to a similar phenomenon for "exotic" dualizations, and we clarify this by comparing with the dualizations of the component fields. We close with some speculative remarks on the significance of these observations for the full non-linear theory yet to be constructed.

  10. Dual-comb MIXSEL

    Science.gov (United States)

    Link, S. M.; Zaugg, C. A.; Klenner, A.; Mangold, M.; Golling, M.; Tilma, B. W.; Keller, U.

    2015-03-01

    We present a single semiconductor disk laser simultaneously emitting two different gigahertz modelocked pulse trains. A birefringent crystal inside a modelocked integrated external-cavity surface-emitting laser (MIXSEL) separates the cavity beam into two spatially separated beams with perpendicular polarizations on the MIXSEL chip. This MIXSEL then generates two orthogonally polarized collinear modelocked pulse trains from one simple straight cavity. Superimposing the beams on a photo detector creates a microwave beat signal, representing a strikingly simple setup to down-convert the terahertz optical frequencies into the electronically accessible microwave regime. This makes the dual-comb MIXSEL scheme an ultra-compact and cost-efficient candidate for dual-comb spectroscopy applications.

  11. Action Emulation

    NARCIS (Netherlands)

    D.J.N. van Eijck (Jan); J. Ruan; T. Sadzik

    2012-01-01

    textabstractThe effects of public announcements, private communications, deceptive messages to groups, and so on, can all be captured by a general mechanism of updating multi-agent models with update action models, now in widespread use. There is a natural extension of the definition of

  12. China's Actions

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    @@ China's National Development and Reform Commission publicized the country's policies and actions for addressing climate change in a report released on November 26,2009.The report highlighted China's efforts in cutting greenhouse gas emissions in 2009 by: (1)Rigorously checking the blind expansion of its energy-and pollution-intensive industries.

  13. Dual-readout Calorimetry

    OpenAIRE

    Akchurin, N.; Bedeschi, F.; Cardini, A.; Cascella, M.; Cei, F.; Pedis, D.; Fracchia, S.; Franchino, S.; Fraternali, M.; Gaudio, G.; P. Genova; Hauptman, J.; La Rotonda, L.; Lee, S.; Livan, M.(INFN Sezione di Pavia, Pavia, Italy)

    2013-01-01

    The RD52 Project at CERN is a pure instrumentation experiment whose goal is to understand the fundamental limitations to hadronic energy resolution, and other aspects of energy measurement, in high energy calorimeters. We have found that dual-readout calorimetry provides heretofore unprecedented information event-by-event for energy resolution, linearity of response, ease and robustness of calibration, fidelity of data, and particle identification, including energy lost to binding energy in n...

  14. Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus.

    Science.gov (United States)

    Khazipov, Roustem; Khalilov, Ilgam; Tyzio, Roman; Morozova, Elena; Ben-Ari, Yezekiel; Holmes, Gregory L

    2004-02-01

    The immature brain is prone to seizures but the underlying mechanisms are poorly understood. We explored the hypothesis that increased seizure susceptibility during early development is due to the excitatory action of GABA. Using noninvasive extracellular field potential and cell-attached recordings in CA3 of Sprague-Dawley rat hippocampal slices, we compared the developmental alterations in three parameters: excitatory actions of GABA, presence of the immature pattern of giant depolarizing potentials (GDPs) and severity of epileptiform activity generated by high potassium. The GABA(A) receptor agonist isoguvacine increased firing of CA3 pyramidal cells in neonatal slices while inhibiting activity in adults. A switch in the GABA(A) signalling from excitation to inhibition occurred at postnatal day (P) 13.5 +/- 0.4. Field GDPs were present in the form of spontaneous population bursts until P12.7 +/- 0.3. High potassium (8.5 mm) induced seizure-like events (SLEs) in 35% of slices at P7-16 (peak at P11.3 +/- 0.4), but only interictal activity before and after that age. The GABA(A) receptor antagonist bicuculline reduced the frequency or completely blocked SLEs and induced interictal clonic-like activity accompanied by a reduction in the frequency but an increase in the amplitude of the population spikes. In slices with interictal activity, bicuculline typically caused a large amplitude interictal clonic-like activity at all ages; in slices from P5-16 rats it was often preceded by one SLE at the beginning of bicuculline application. These results suggest that, in the immature hippocampus, GABA exerts dual (both excitatory and inhibitory) actions and that the excitatory component in the action of GABA may contribute to increased excitability during early development.

  15. The dual action of ozone on the skin.

    Science.gov (United States)

    Valacchi, G; Fortino, V; Bocci, V

    2005-12-01

    The aim of this brief review is to summarize the recent literature on the effect of ozone (O3) on cutaneous tissues. Recently it has been reported that a chronic contact with O3 can be deleterious for the skin. Our group and others have shown a progressive depletion of antioxidant content in the stratum corneum and this can then lead to a cascade of effects resulting in an active cellular response in the deeper layers of the skin. Using an in vivo model we have shown an increase of proliferative, adaptive and proinflammatory cutaneous tissue responses. On the other hand the well known activity of O3 as a potent disinfectant and oxygen (O2) donor has been also studied for therapeutic use. Two approaches have been described. The first consists of a quasi-total body exposure in a thermostatically controlled cabin. This treatment has proved to be useful in patients with chronic limb ischaemia. The second approach is based on the topical application of ozonated olive oil in several kinds of skin infection (from soreness to diabetic ulcers, burns, traumatic and surgical wounds, abscesses and skin reactions after radiotherapy). We and other authors have observed a striking cleansing effect with improved oxygenation and enhanced healing of these conditions. It is now clear that, on the skin, O3, like other drugs, poisons and radiation, can display either a damaging effect from a long exposure or a beneficial effect after a brief exposure to O2 and O3 or to the application of ozonated oil to chronic wounds.

  16. Structure-Activity Relationships of the Antimicrobial Peptide Arasin 1 — And Mode of Action Studies of the N-Terminal, Proline-Rich Region

    Science.gov (United States)

    Paulsen, Victoria S.; Blencke, Hans-Matti; Benincasa, Monica; Haug, Tor; Eksteen, Jacobus J.; Styrvold, Olaf B.; Scocchi, Marco; Stensvåg, Klara

    2013-01-01

    Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH2 terminus of the peptide and the fragment arasin 1(1–23) was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1–23) were shown to be non-toxic to human red blood cells and arasin 1(1–23) was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1–23) was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC), arasin 1(1–23) was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1–23) has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1–23) involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC. PMID:23326415

  17. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Directory of Open Access Journals (Sweden)

    Victoria S Paulsen

    Full Text Available Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2 terminus of the peptide and the fragment arasin 1(1-23 was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23 were shown to be non-toxic to human red blood cells and arasin 1(1-23 was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23 was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC, arasin 1(1-23 was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23 has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23 involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  18. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Science.gov (United States)

    Paulsen, Victoria S; Blencke, Hans-Matti; Benincasa, Monica; Haug, Tor; Eksteen, Jacobus J; Styrvold, Olaf B; Scocchi, Marco; Stensvåg, Klara

    2013-01-01

    Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2) terminus of the peptide and the fragment arasin 1(1-23) was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23) were shown to be non-toxic to human red blood cells and arasin 1(1-23) was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23) was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC), arasin 1(1-23) was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23) has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23) involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  19. Dual-Schemata Model

    Science.gov (United States)

    Taniguchi, Tadahiro; Sawaragi, Tetsuo

    In this paper, a new machine-learning method, called Dual-Schemata model, is presented. Dual-Schemata model is a kind of self-organizational machine learning methods for an autonomous robot interacting with an unknown dynamical environment. This is based on Piaget's Schema model, that is a classical psychological model to explain memory and cognitive development of human beings. Our Dual-Schemata model is developed as a computational model of Piaget's Schema model, especially focusing on sensori-motor developing period. This developmental process is characterized by a couple of two mutually-interacting dynamics; one is a dynamics formed by assimilation and accommodation, and the other dynamics is formed by equilibration and differentiation. By these dynamics schema system enables an agent to act well in a real world. This schema's differentiation process corresponds to a symbol formation process occurring within an autonomous agent when it interacts with an unknown, dynamically changing environment. Experiment results obtained from an autonomous facial robot in which our model is embedded are presented; an autonomous facial robot becomes able to chase a ball moving in various ways without any rewards nor teaching signals from outside. Moreover, emergence of concepts on the target movements within a robot is shown and discussed in terms of fuzzy logics on set-subset inclusive relationships.

  20. COX, LOX and platelet aggregation inhibitory properties of Lauraceae neolignans.

    Science.gov (United States)

    Coy, Ericsson David; Cuca, Luis Enrique; Sefkow, Michael

    2009-12-15

    The anti-inflammatory potential of 26 neolignans (14 of the bicyclooctane-type and 12 of the benzofuran-type), isolated from three Lauraceae species (Pleurothyrium cinereum, Ocotea macrophylla and Nectandra amazonum), was evaluated in vitro through inhibition of COX-1, COX-2, 5-LOX and agonist-induced aggregation of rabbit platelets. Benzofuran neolignans were found to be selective COX-2 inhibitors, whereas bicyclooctane neolignans inhibit selectively the PAF-action as well as COX-1 and 5-LOX. The neolignan 9-nor-7,8-dehydro-isolicarin B 15 and cinerin C 7 were found to be the most potent COX-2 inhibitor and PAF-antagonist, respectively. Nectamazin C 10 exhibited dual 5-LOX/COX-2 inhibition.

  1. Inhibitory effect and mechanism of acarbose combined with gymnemic acidon maltose absorption in rat intestine

    Institute of Scientific and Technical Information of China (English)

    Hong Luo; Le Feng Wang; Toshiaki Imoto; Yasutaka Hiji

    2000-01-01

    AIM The control of diet regimen and nutrient intake, aiming to avoid the evaggerated levels of glucose andanabolic hormone is broadly accepted as basic treatment of diabetes mellitus. Maltose is an importanthydrolysate of starch, main source of nutrition. Acarbose is an alpha-D-glucosidase inhibitor but with a shortinhibitory duration. Gymnemic acid (GA), a group of triterpene glucuronides, inhibits glucose absorptionwith a longer effective duration but it needs a longer time to achieve its maximum effect. To determinewhether nutrient control in diabetic care can be improved by combination of them, we compared thecombinative and individual effect of acarbose and GA on maltose absorption and hydrolysis in smallintestine.METHODS The absorption and hydrolysis of maltose were studied by re-cyclic perfusion of intestinal loopsin situ and motility of the intestine was recorded with the intestinal loop in vitro, of Wistar rat.RESULTS The total inhibitory rate of maltose absorption was improved by the combination of GA (0.1 -1.0 mg/mL) and acarbose (0.1- 2.0 mmol/L) throughout their effective duration (P<0.05, U test ofMann-Whitney), although the improvement only could be seen in the low dosages during the first hour. Withthe combination, inhibitory duration of acarbose on maltose absorption was prolonged to 3 hours and theonset of GA inhibitory effect was fastened to 15 minutes. GAsuppressed the intestinal mobility with a goodcorrelation (r = 0.98) to the inhibitory effect of GA on maltose absorption and the inhibitory effect of2 mmol/L (higher dose) acarbose on maltose hydrolysis was dual modulated by 1 mg/mL GA in vivoindicating that the combined effects involved the functional alteration of intestinal barriers.CONCLUSION There are augmented effects of acarbose and GA, which involve pre-cellular andparacellular barriers. Furthermore, diabetic care can be improved by employing this combination.

  2. Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter targeting potential agents for Alzheimer's disease.

    Science.gov (United States)

    Kogen, Hiroshi; Toda, Narihiro; Tago, Keiko; Marumoto, Shinji; Takami, Kazuko; Ori, Mayuko; Yamada, Naho; Koyama, Kazuo; Naruto, Shunji; Abe, Kazumi; Yamazaki, Reina; Hara, Takao; Aoyagi, Atsushi; Abe, Yasuyuki; Kaneko, Tsugio

    2002-10-03

    Highly efficient acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitors, (S)-4 and (R)-13 were designed and synthesized on the basis of the hypothetical model of AChE active site. Both compounds showed potent inhibitory activities against AChE and SERT. [structure: see text

  3. Inhibitory ability of children with developmental dyscalculia.

    Science.gov (United States)

    Zhang, Huaiying; Wu, Hanrong

    2011-02-01

    Inhibitory ability of children with developmental dyscalculia (DD) was investigated to explore the cognitive mechanism underlying DD. According to the definition of developmental dyscalculia, 19 children with DD-only and 10 children with DD&RD (DD combined with reading disability) were selected step by step, children in two control groups were matched with children in case groups by gender and age, and the match ratio was 1:1. Psychological testing software named DMDX was used to measure inhibitory ability of the subjects. The differences of reaction time in number Stroop tasks and differences of accuracy in incongruent condition of color-word Stroop tasks and object inhibition tasks between DD-only children and their controls reached significant levels (P<0.05), and the differences of reaction time in number Stroop tasks between dyscalculic and normal children did not disappear after controlling the non-executive components. The difference of accuracy in color-word incongruent tasks between children with DD&RD and normal children reached significant levels (P<0.05). Children with DD-only confronted with general inhibitory deficits, while children with DD&RD confronted with word inhibitory deficits only.

  4. Macrophage Migration Inhibitory Factor in Protozoan Infections

    Directory of Open Access Journals (Sweden)

    Marcelo T. Bozza

    2012-01-01

    Full Text Available Macrophage migration inhibitory factor (MIF is a cytokine that plays a central role in immune and inflammatory responses. In the present paper, we discussed the participation of MIF in the immune response to protozoan parasite infections. As a general trend, MIF participates in the control of parasite burden at the expense of promoting tissue damage due to increased inflammation.

  5. Neuraminidase inhibitory terpenes from endophytic Cochliobolus sp.

    Science.gov (United States)

    Zhang, Gao-Fei; Guo, Zhi-Kai; Wang, Wei; Cui, Jiang-Tao; Tan, Ren-Xiang; Ge, Hui-Ming

    2011-08-01

    The chemical study of endophytic fungus of Cochliobolus led to the isolation of 10 terpenes (1-10), including one new compound named isocochlioquinone B (1). Their structures were elucidated on the basis of spectroscopic methods, including 2D NMR techniques. Compounds 5-7 showed significant neuraminidase inhibitory activity with IC(50) values of 0.79-1.75 μM.

  6. Dual lattice representations for O(N and CP(N−1 models with a chemical potential

    Directory of Open Access Journals (Sweden)

    Falk Bruckmann

    2015-10-01

    Full Text Available We derive dual representations for O(N and CP(N−1 models on the lattice. In terms of the dual variables the partition sums have only real and positive contributions also at finite chemical potential. Thus the complex action problem of the conventional formulation is overcome and using the dual variables Monte Carlo simulations are possible at arbitrary chemical potential.

  7. Protesters as "passionate economists" : A dynamic dual pathway model of approach coping with collective disadvantage

    NARCIS (Netherlands)

    van Zomeren, Martijn; Leach, Colin Wayne; Spears, Russell

    To explain the psychology behind individuals' motivation to participate in collective action against collective disadvantage (e.g., protest marches), the authors introduce a dynamic dual pathway model of approach coping that integrates many common explanations of collective action (i.e., group

  8. Alexander Duals of Multipermutohedron Ideals

    Indian Academy of Sciences (India)

    Ajay Kumar; Chanchal Kumar

    2014-02-01

    An Alexander dual of a multipermutohedron ideal has many combinatorial properties. The standard monomials of an Artinian quotient of such a dual correspond bijectively to some -parking functions, and many interesting properties of these Artinian quotients are obtained by Postnikov and Shapiro (Trans. Am. Math. Soc. 356 (2004) 3109–3142). Using the multigraded Hilbert series of an Artinian quotient of an Alexander dual of multipermutohedron ideals, we obtained a simple proof of Steck determinant formula for enumeration of -parking functions. A combinatorial formula for all the multigraded Betti numbers of an Alexander dual of multipermutohedron ideals are also obtained.

  9. Towards a Dual Approach

    DEFF Research Database (Denmark)

    Holli, Anne Maria; Harder, Mette Marie Stæhr

    2016-01-01

    countries acknowledged as forerunners in gender equality, which also have ‘fairly strong’ parliamentary standing committees. The results show that both committees on gender equality can be regarded as ‘feminist’ in character and both interact with relevant civil society organisations. Their impact......Drawing on insights from state feminism and legislative studies on parliamentary committees, this article develops a dual approach for the comparative analysis of committees on gender equality. Empirically, it compares the standing committees on gender equality in Denmark and Finland, two Nordic...

  10. Dual cure photocatalyst systems

    Energy Technology Data Exchange (ETDEWEB)

    DeVoe, R.J.; Brown-Wensley, K.A.; Holmes, G.L.; Mathis, M.D.; McCormick, F.B.; Palazzotto, M.C.; Spurgeon, K.M. (Minnesota Mining and Mfg. Co., St. Paul, MN (USA). Corporate Research Labs.)

    1990-01-01

    A family of dual cure photocatalyst systems is being developed to be used in the solventless processing of organic coatings. The photocatalyst systems consist of organometallic compounds often in combination with other agents. Upon photolysis, the photocatalyst system generates a Lewis acid and a free radical. The Lewis acid can initiate the polymerization of epoxies or the addition of isocyanates and polyols to form polyurethanes while the free radical can initiate the polymerization of acrylates. The performance of the various photocatalyst systems will be compared on the basis of the physical properties of the cured compositions they produce. 17 figs.

  11. Infants' understanding of everyday social interactions: a dual process account.

    Science.gov (United States)

    Gredebäck, Gustaf; Melinder, Annika

    2010-02-01

    Six- and 12-month-old infant's eye movements were recorded as they observed feeding actions being performed in a rational or non-rational manner. Twelve-month-olds fixated the goal of these actions before the food arrived (anticipation); the latency of these gaze shifts being dependent (r=.69) on infants life experience being feed. In addition, 6- and 12-month-olds dilated their pupil during observation of non-rational feeding actions. This effect could not be attributed to light differences or differences in familiarity, but was interpreted to reflect sympathetic-like activity and arousal caused by a violation of infant's expectations about rationality. We argue that evaluation of rationality requires less experience than anticipations of action goals, suggesting a dual process account of preverbal infants' everyday action understanding.

  12. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery.

    Science.gov (United States)

    Tyzio, Roman; Cossart, Rosa; Khalilov, Ilgam; Minlebaev, Marat; Hübner, Christian A; Represa, Alfonso; Ben-Ari, Yehezkel; Khazipov, Rustem

    2006-12-15

    We report a signaling mechanism in rats between mother and fetus aimed at preparing fetal neurons for delivery. In immature neurons, gamma-aminobutyric acid (GABA) is the primary excitatory neurotransmitter. We found that, shortly before delivery, there is a transient reduction in the intracellular chloride concentration and an excitatory-to-inhibitory switch of GABA actions. These events were triggered by oxytocin, an essential maternal hormone for labor. In vivo administration of an oxytocin receptor antagonist before delivery prevented the switch of GABA actions in fetal neurons and aggravated the severity of anoxic episodes. Thus, maternal oxytocin inhibits fetal neurons and increases their resistance to insults during delivery.

  13. Optical Force and Torque on Dipolar Dual Chiral Particles

    CERN Document Server

    Rahimzadegan, Aso; Alaee, Rasoul; Fernandez-Corbaton, Ivan; Rockstuhl, Carsten

    2016-01-01

    On the one hand, electromagnetic dual particles preserve the helicity of light upon interaction. On the other hand, chiral particles respond differently to light of opposite helicity. These two properties on their own constitute a source of fascination. Their combined action, however, is less explored. Here, we study on analytical grounds the force and torque as well as the optical cross sections of dual chiral particles in dipolar approximation exerted by a wave of well-defined helicity, i.e. a circularly polarized plane wave. We put emphasis on particles that possess a maximally electromagnetic chiral and hence dual response. Besides the analytical insights, we also investigate the exerted optical force and torque on a real particle at the example of a metallic helix that is designed to approach the maximal electromagnetic chirality condition. Various applications in the context of optical sorting but also nanorobotics can be perceived considering the particles studied in this contribution.

  14. Exotic dual of type II double field theory

    Science.gov (United States)

    Bergshoeff, Eric A.; Hohm, Olaf; Riccioni, Fabio

    2017-04-01

    We perform an exotic dualization of the Ramond-Ramond fields in type II double field theory, in which they are encoded in a Majorana-Weyl spinor of O (D , D). Starting from a first-order master action, the dual theory in terms of a tensor-spinor of O (D , D) is determined. This tensor-spinor is subject to an exotic version of the (self-)duality constraint needed for a democratic formulation. We show that in components, reducing O (D , D) to GL (D), one obtains the expected exotically dual theory in terms of mixed Young tableaux fields. To this end, we generalize exotic dualizations to self-dual fields, such as the 4-form in type IIB string theory.

  15. Exotic dual of type II double field theory

    Directory of Open Access Journals (Sweden)

    Eric A. Bergshoeff

    2017-04-01

    Full Text Available We perform an exotic dualization of the Ramond–Ramond fields in type II double field theory, in which they are encoded in a Majorana–Weyl spinor of O(D,D. Starting from a first-order master action, the dual theory in terms of a tensor–spinor of O(D,D is determined. This tensor–spinor is subject to an exotic version of the (self-duality constraint needed for a democratic formulation. We show that in components, reducing O(D,D to GL(D, one obtains the expected exotically dual theory in terms of mixed Young tableaux fields. To this end, we generalize exotic dualizations to self-dual fields, such as the 4-form in type IIB string theory.

  16. Action potential broadening in a presynaptic channelopathy

    OpenAIRE

    R. Begum; Bakiri, Y.; Volynski, K. E.; Kullmann, D M

    2016-01-01

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for...

  17. Controlled versus automatic processes: which is dominant to safety? The moderating effect of inhibitory control.

    Directory of Open Access Journals (Sweden)

    Yaoshan Xu

    Full Text Available This study explores the precursors of employees' safety behaviors based on a dual-process model, which suggests that human behaviors are determined by both controlled and automatic cognitive processes. Employees' responses to a self-reported survey on safety attitudes capture their controlled cognitive process, while the automatic association concerning safety measured by an Implicit Association Test (IAT reflects employees' automatic cognitive processes about safety. In addition, this study investigates the moderating effects of inhibition on the relationship between self-reported safety attitude and safety behavior, and that between automatic associations towards safety and safety behavior. The results suggest significant main effects of self-reported safety attitude and automatic association on safety behaviors. Further, the interaction between self-reported safety attitude and inhibition and that between automatic association and inhibition each predict unique variances in safety behavior. Specifically, the safety behaviors of employees with lower level of inhibitory control are influenced more by automatic association, whereas those of employees with higher level of inhibitory control are guided more by self-reported safety attitudes. These results suggest that safety behavior is the joint outcome of both controlled and automatic cognitive processes, and the relative importance of these cognitive processes depends on employees' individual differences in inhibitory control. The implications of these findings for theoretical and practical issues are discussed at the end.

  18. Controlled versus automatic processes: which is dominant to safety? The moderating effect of inhibitory control.

    Science.gov (United States)

    Xu, Yaoshan; Li, Yongjuan; Ding, Weidong; Lu, Fan

    2014-01-01

    This study explores the precursors of employees' safety behaviors based on a dual-process model, which suggests that human behaviors are determined by both controlled and automatic cognitive processes. Employees' responses to a self-reported survey on safety attitudes capture their controlled cognitive process, while the automatic association concerning safety measured by an Implicit Association Test (IAT) reflects employees' automatic cognitive processes about safety. In addition, this study investigates the moderating effects of inhibition on the relationship between self-reported safety attitude and safety behavior, and that between automatic associations towards safety and safety behavior. The results suggest significant main effects of self-reported safety attitude and automatic association on safety behaviors. Further, the interaction between self-reported safety attitude and inhibition and that between automatic association and inhibition each predict unique variances in safety behavior. Specifically, the safety behaviors of employees with lower level of inhibitory control are influenced more by automatic association, whereas those of employees with higher level of inhibitory control are guided more by self-reported safety attitudes. These results suggest that safety behavior is the joint outcome of both controlled and automatic cognitive processes, and the relative importance of these cognitive processes depends on employees' individual differences in inhibitory control. The implications of these findings for theoretical and practical issues are discussed at the end.

  19. Action Learning: Avoiding Conflict or Enabling Action

    Science.gov (United States)

    Corley, Aileen; Thorne, Ann

    2006-01-01

    Action learning is based on the premise that action and learning are inextricably entwined and it is this potential, to enable action, which has contributed to the growth of action learning within education and management development programmes. However has this growth in action learning lead to an evolution or a dilution of Revan's classical…

  20. Hamilton principle for the dual electrodynamics; Principio de Hamilton para a eletrodinamica dual

    Energy Technology Data Exchange (ETDEWEB)

    Souza Silva, Saulo Carneiro de

    1995-12-31

    The present work discusses the classical electromagnetic theory in the presence of magnetic monopoles. We review the connection between such objects and the long standing problem of charge quantization and the main theoretical difficulties in formulating the classical dual electromagnetic theory in terms of an action principle. We show that a deeper understanding of the source of such difficulties leads naturally to the construction of a variational principle for a non-local Lagrangian from which all the (local) dynamical equations for electric, magnetic charges and fields can be obtained. (author) 53 refs.

  1. Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors.

    Science.gov (United States)

    Zhang, Zhimin; Hou, Shaohua; Chen, Hongli; Ran, Ting; Jiang, Fei; Bian, Yuanyuan; Zhang, Dewei; Zhi, Yanle; Wang, Lu; Zhang, Li; Li, Hongmei; Zhang, Yanmin; Tang, Weifang; Lu, Tao; Chen, Yadong

    2016-06-15

    The bromodomain protein module and histone deacetylase (HDAC), which recognize and remove acetylated lysine, respectively, have emerged as important epigenetic therapeutic targets in cancer treatments. Herein we presented a novel design approach for cancer drug development by combination of bromodomain and HDAC inhibitory activity in one molecule. The designed compounds were synthesized which showed inhibitory activity against bromodomain 4 and HDAC1. The representative dual bromodomain/HDAC inhibitors, compound 11 and 12, showed potent antiproliferative activities against human leukaemia cell line K562 and MV4-11 in cellular assays. This work may lay the foundation for developing dual bromodomain/HDAC inhibitors as potential anticancer therapeutics.

  2. Robust dual-response optimization

    NARCIS (Netherlands)

    Yanikoglu, Ihsan; den Hertog, Dick; Kleijnen, J.P.C.

    2016-01-01

    This article presents a robust optimization reformulation of the dual-response problem developed in response surface methodology. The dual-response approach fits separate models for the mean and the variance and analyzes these two models in a mathematical optimization setting. We use metamodels esti

  3. Dual-Credit in Kentucky

    Science.gov (United States)

    Stephenson, Lisa G.

    2013-01-01

    Credit-based transition programs provide high school students with opportunities to jump start their college education. The Kentucky Community and Technical College System (KCTCS) offers college credit through dual-credit programs. While KCTCS dual-credit offerings have been successful in helping high school students start their college education…

  4. Dual-core Itanium Processor

    CERN Multimedia

    2006-01-01

    Intel’s first dual-core Itanium processor, code-named "Montecito" is a major release of Intel's Itanium 2 Processor Family, which implements the Intel Itanium architecture on a dual-core processor with two cores per die (integrated circuit). Itanium 2 is much more powerful than its predecessor. It has lower power consumption and thermal dissipation.

  5. Dual Card,Double Happiness

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    As Christmas Day and New Year Day draw near, why not treat yourself with a smart digital gizmo. Then, the Samsung Dual-card Cellphone is what you are longing for. Samsung B5712C, the first dual-card model released by Samsung,

  6. Asymmetry in Dual Language Practice

    Directory of Open Access Journals (Sweden)

    Audrey Amrein

    2000-01-01

    Full Text Available The capacity for dual-language programs to deliver specific benefits to students with different primary and secondary language skills continues to be debated. Individuals favoring dual language assert that as it relies upon a reciprocal approach, dual language students acquire dual language proficiency without the need for teachers to translate from one language to another. By utilizing and conserving the language skills that students bring, dual language students also gain cross-cultural understandings and an expanded opportunity to realize academic success in the future. Research that explores whether these programs meet the needs of monolingual and bilingual students is limited. The intent of this study is not to criticize dual language practice. Instead, it is to describe a newly implemented dual language immersion program that exists and operates in Phoenix, Arizona. In particular, this study examines the practices of dual language teachers at Leigh Elementary School and the challenges encountered as school personnel worked to provide students with different primary and secondary language skills increased opportunities to learn.

  7. Benefits of Dual Language Education

    Science.gov (United States)

    Wallstrum, Kiara

    2009-01-01

    The focus of this paper examines how dual language education (DLE) programs are valuable. The literature shows that children do much more than just thrive in a dual language environment. According to research, children who are bilingual are cognitively, academically, intellectually, socially and verbally more advantaged than their monolingual…

  8. Interactions between Autophagy and Inhibitory Cytokines

    Science.gov (United States)

    Wu, Tian-tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy. PMID:27313501

  9. Mast Cell and Immune Inhibitory Receptors

    Institute of Scientific and Technical Information of China (English)

    LixinLi; ZhengbinYao

    2004-01-01

    Modulation by balancing activating and inhibitory receptors constitutes an important mechanism for regulating immune responses. Cells that are activated following ligation of receptors bearing immunoreceptor tyrosine-based activation motifs (ITAMs) can be negatively regulated by other receptors bearing immunoreceptor tyrosine-based inhibition motifs (ITIMs). Human mast cells (MCs) are the major effector cells of type I hypersensitivity and important participants in a number of disease processes. Antigen-mediated aggregation of IgE bound to its high-affinity receptor on MCs initiates a complex series of biochemical events leading to MC activation. With great detailed description and analysis of several inhibitory receptors on human MCs, a central paradigm of negative regulation of human MC activation by these receptors has emerged. Cellular & Molecular Immunology. 2004;1(6):408-415.

  10. Interactions between Autophagy and Inhibitory Cytokines.

    Science.gov (United States)

    Wu, Tian-Tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy.

  11. Valproic acid mediates the synaptic excitatory/inhibitory balance through astrocytes--a preliminary study.

    Science.gov (United States)

    Wang, Chao-Chuan; Chen, Po See; Hsu, Chien-Wen; Wu, Shou-Jung; Lin, Chieh-Ting; Gean, Po Wu

    2012-04-27

    Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for the treatment of epilepsy and bipolar disorder. However, the underlying therapeutic mechanisms of the treatment of each disease remain unclear. Recently, the anti-epileptic effect of VPA has been found to lead to modulation of the synaptic excitatory/inhibitory balance. In addition, the therapeutic action of VPA has been linked to its effect on astrocytes by regulating gene expression at the molecular level, perhaps through an epigenetic mechanism as a histone deacetylase (HDAC) inhibitor. To provide insight into the mechanisms underlying the actions of VPA, this study investigated whether the synaptic excitatory/inhibitory (E/I) balance could be mediated by VPA through astrocytes. First, using the primary rat neuronal, astroglial, and neuro-glial mixed culture systems, we demonstrated that VPA treatment could regulate the mRNA levels of two post-synaptic cell adhesion molecules(neuroligin-1 and neuregulin-1) and two extracellular matrices (neuronal pentraxin-1and thrombospondin-3) in primary rat astrocyte cultures in a time- and concentration-dependent manner. Moreover, the up-regulation effect of VPA was noted in astrocytes, but not in neurons. In addition, these regulatory effects could be mimicked by sodium butyrate, a HDAC inhibitor, but not by lithium or two other glycogen synthase kinase-3 beta inhibitors. With the known role of these four proteins in regulating the synaptic E/I balance, we further demonstrated that VPA increased excitatory post-synaptic protein (postsynaptic density 95) and inhibitory post-synaptic protein (Gephyrin) in cortical neuro-glial mixed cultures. Our results suggested that VPA might affect the synaptic excitatory/inhibitory balance through its effect on astrocytes. This work provides the basis for future evaluation of the role of astroglial cell adhesion molecules and the extracellular matrix on the control of excitatory and

  12. Modulation of an inhibitory reflex in single motor units in human masseter by tonic painful stimulation.

    Science.gov (United States)

    Svensson, P; McMillan, A S; Graven-Nielsen, T; Wang, K; Arendt-Nielsen, L

    1999-12-01

    Perioral electrical stimuli cause inhibitory reflex responses in single motor-units (SMU) and surface electromyographic (EMG) recordings from voluntary contracted human jaw-closing muscles. Tonic experimental masseter pain has recently been shown to reduce the inhibitory reflex response in surface EMG recordings but the effect on SMU activity has not been described. In this study, motor-unit action potentials were recorded with wire electrodes inserted into the left masseter in eleven subjects. The subjects kept the SMU firing rate around 10 Hz by feedback. Ninety-nine electrical stimuli were applied sequentially to the left mental nerve with increasing stimulus delays in steps of 1 ms after the preceding motor unit action potential. The inhibitory reflex in SMU was recorded before, during and after infusion of hypertonic saline (5%) into the ipsilateral masseter muscle. Spike train data were used to calculate (1) the mean pre- and post-stimulus inter-spike-intervals (ISI) in all of the 99 trials, (2) cumulative changes in firing probability, and (3) estimation of the compound inhibitory post-synaptic potential (IPSP) in the masseter motoneuron. Tonic masseter pain did not change pre-stimulus SMU firing characteristics but the mean ISI for the first post-stimulus discharge (158.2+/-9.2 ms) was significantly decreased compared to the pre-pain (175.8+/-11.3 ms, Pmasseter pain compared to pre-pain and post-pain conditions. In conclusion, this study indicates that tonic masseter pain has a net excitatory effect on the inhibitory jaw-reflexes, which could be mediated by presynaptic mechanisms on the involved motoneurons.

  13. Two networks of electrically coupled inhibitory neurons in neocortex

    Science.gov (United States)

    Gibson, Jay R.; Beierlein, Michael; Connors, Barry W.

    1999-11-01

    Inhibitory interneurons are critical to sensory transformations, plasticity and synchronous activity in the neocortex. There are many types of inhibitory neurons, but their synaptic organization is poorly understood. Here we describe two functionally distinct inhibitory networks comprising either fast-spiking (FS) or low-threshold spiking (LTS) neurons. Paired-cell recordings showed that inhibitory neurons of the same type were strongly interconnected by electrical synapses, but electrical synapses between different inhibitory cell types were rare. The electrical synapses were strong enough to synchronize spikes in coupled interneurons. Inhibitory chemical synapses were also common between FS cells, and between FS and LTS cells, but LTS cells rarely inhibited one another. Thalamocortical synapses, which convey sensory information to the cortex, specifically and strongly excited only the FS cell network. The electrical and chemical synaptic connections of different types of inhibitory neurons are specific, and may allow each inhibitory network to function independently.

  14. Inhibitory mechanisms of glabridin on tyrosinase

    Science.gov (United States)

    Chen, Jianmin; Yu, Xiaojing; Huang, Yufeng

    2016-11-01

    Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin could lead to a variety of skin disorders. Glabridin, an isoflavan, isolated from the root of Glycyrrhiza glabra Linn, has exhibited several pharmacological activities, including excellent inhibitory effects on tyrosinase. In this paper, the inhibitory kinetics of glabridin on tyrosinase and their binding mechanisms were determined using spectroscopic, zebrafish model and molecular docking techniques. The results indicate that glabridin reversibly inhibits tyrosinase in a noncompetitive manner through a multiphase kinetic process with the IC50 of 0.43 μmol/L. It has been shown that glabridin had a strong ability to quench the intrinsic fluorescence of tyrosinase mainly through a static quenching procedure, suggesting a stable glabridin-tyrosinase complex may be generated. The results of molecular docking suggest that glabridin did not directly bind to the active site of tyrosinase. Moreover, according to the results of zebrafish model system, glabridin shows no effects on melanin synthesis in zebrafish but presents toxicity to zebrafish embryo. The possible inhibitory mechanisms, which will help to design and search for tyrosinase inhibitors especially for glabridin analogues, were proposed.

  15. MODULATING EXCITATION THROUGH PLASTICITY AT INHIBITORY SYNAPSES

    Directory of Open Access Journals (Sweden)

    Vivien eChevaleyre

    2014-03-01

    Full Text Available Learning is believed to depend on lasting changes in synaptic efficacy such as long-term potentiation and long-term depression. As a result, a profusion of studies has tried to elucidate the mechanisms underlying these forms of plasticity. Traditionally, experience-dependent changes at excitatory synapses were assumed to underlie learning and memory formation. However, with the relatively more recent investigation of inhibitory transmission, it had become evident that inhibitory synapses are not only plastic, but also provide an additional way to modulate excitatory transmission and the induction of plasticity at excitatory synapses.Thanks to recent technological advances, progress has been made in understanding synaptic transmission and plasticity from particular interneuron subtypes. In this review article, we will describe various forms of synaptic plasticity that have been ascribed to two fairly well characterized populations of interneurons in the hippocampus, those expressing cholecystokinin (CCK and parvalbumin (PV. We will discuss the resulting changes in the strength and plasticity of excitatory transmission that occur in the local circuit as a result of the modulation of inhibitory transmission. We will focus on the hippocampus because this region has a relatively well-understood circuitry, numerous forms of activity-dependent plasticity and a multitude of identified interneuron subclasses.

  16. Spatial patterning of excitatory and inhibitory neuropil territories during spinal circuit development.

    Science.gov (United States)

    Yan, Qing; Zhai, Lu; Zhang, Bo; Dallman, Julia E

    2017-05-01

    To generate rhythmic motor behaviors, both single neurons and neural circuits require a balance between excitatory inputs that trigger action potentials and inhibitory inputs that promote a stable resting potential (E/I balance). Previous studies have focused on individual neurons and have shown that, over a short spatial scale, excitatory and inhibitory (E/I) synapses tend to form structured territories with inhibitory inputs enriched on cell bodies and proximal dendrites and excitatory inputs on distal dendrites. However, systems-level E/I patterns, at spatial scales larger than single neurons, are largely uncharted. We used immunostaining for PSD-95 and gephyrin postsynaptic scaffolding proteins as proxies for excitatory and inhibitory synapses, respectively, to quantify the numbers and map the distributions of E/I synapses in zebrafish spinal cord at both an embryonic stage and a larval stage. At the embryonic stage, we found that PSD-95 puncta outnumber gephyrin puncta, with the number of gephyrin puncta increasing to match that of PSD-95 puncta at the larval stage. At both stages, PSD-95 puncta are enriched in the most lateral neuropil corresponding to distal dendrites while gephyrin puncta are enriched on neuronal somata and in the medial neuropil. Significantly, similar to synaptic puncta, neuronal processes also exhibit medial-lateral territories at both developmental stages with enrichment of glutamatergic (excitatory) processes laterally and glycinergic (inhibitory) processes medially. This establishment of neuropil excitatory-inhibitory structure largely precedes dendritic arborization of primary motor neurons, suggesting that the structured neuropil could provide a framework for the development of E/I balance at the cellular level. J. Comp. Neurol. 525:1649-1667, 2017. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  17. Developmental changes in inhibitory processing: Evidence from psychophysiological measures.

    NARCIS (Netherlands)

    van der Molen, M.W.

    2000-01-01

    Two major theories of the development of inhibitory functioning are discussed that assume a close relation between inhibitory ability and the maturation of the frontal lobes. It is argued that a psychophysiological approach may add considerably to the study of developmental change in inhibitory proc

  18. The Dual Role of Media Internalization in Adolescent Sexual Behavior.

    Science.gov (United States)

    Rousseau, Ann; Beyens, Ine; Eggermont, Steven; Vandenbosch, Laura

    2017-08-01

    Sexualizing media content is prevalent in various media types. Sexualizing media messages and portrayals emphasize unattainable body and appearance ideals as the primary components of sexual desirability. The internalization of these ideals is positively related to self-objectification and sexual body consciousness. In turn, self-objectification and sexual body consciousness affect adolescents' sexual behavior, albeit in opposing directions. While objectifying self-perceptions are linked to higher levels of sexual behavior, body consciousness during physical intimacy is linked to lower levels of sexual behavior. Based on this knowledge, the present three-wave panel study of 824 Belgian, predominant heterosexual adolescents (M age = 15.33; SD = 1.45) proposes a dual-pathway model that investigates two different pathways through which the internalization of media ideals may impact adolescents' sexual behavior. An inhibitory pathway links media internalization to lower levels of sexual behavior through sexual body consciousness, and a supportive pathway links media internalization to higher levels of sexual behavior through self-objectification. Structural equation analyses supported the proposed dual-pathway, showing that the impact of media internalization on adolescents' sexual behavior proceeds through an inhibitory pathway and a supportive pathway. Regarding the supportive pathway, media internalization (W1) positively predicted sexual behavior (W3), through valuing appearance over competence (W2). Regarding the inhibitory pathway, media internalization (W1) positively predicted body surveillance, which, in turn, positively predicted sexual body consciousness (all W2). Sexual body consciousness (W2) is negatively related to sexual behavior (W3). From a sexual developmental perspective, these findings emphasize the importance of guiding adolescents in interpreting and processing sexualizing media messages.

  19. New self-dual $k$-generalized Abelian-Higgs models

    CERN Document Server

    Casana, R; Santos, A C

    2015-01-01

    We have shown the existence of self-dual solutions in new Maxwell-Higgs scenarios whose gauge field possess $k$-generalized dynamics, i.e., the kinetic part of the gauge action being highly nonlinear. We have implemented the BPS formalism providing highly nonlinear generalized self-dual equations whose solutions possess a total energy proportional to the magnetic flux. However, there is a key condition which allows to express the self-dual equations in a form mathematically similar those arising in the Maxwell-Higgs model. Under such a key condition, we have analyzed the general properties of the self-dual axially symmetric vortices. We have observed the generalization modifies the vortex core, the magnetic field amplitude and the bosonic masses but the total energy remains proportional to the quantized magnetic flux. Finally, we have established a prescription which allows to obtain different $k$-generalized Abelian Higgs models providing self-dual configurations.

  20. Vortex dynamics in self-dual Chern-Simons Higgs systems

    CERN Document Server

    Kim, Y; Kim, Yoonbai; Lee, Kimyeong

    1994-01-01

    We consider vortex dynamics in self-dual Chern-Simons Higgs systems. We show that the naive Aharanov-Bohm phase is the inverse of the statistical phase expected from the vortex spin, and that the self-dual configurations of vortices are degenerate in energy but not in angular momentum. We also use the path integral formalism to derive the dual formulation of Chern-Simons Higgs systems in which vortices appear as charged particles. We argue that besides the electromagnetic interaction, there is an additional interaction between vortices, the so-called Magnus force, and that these forces can be put together into a single `dual electromagnetic' interaction. This dual electromagnetic interaction leads to the right Aharanov-Bohm phase. We also derive and study the effective action for slowly moving vortices, which contains terms both linear and quadratic in the vortex velocity.

  1. Dual-horizon Peridynamics

    CERN Document Server

    Ren, Huilong; Cai, Yongchang; Rabczuk, Timon

    2015-01-01

    In this paper we develop a new Peridynamic approach that naturally includes varying horizon sizes and completely solves the "ghost force" issue. Therefore, the concept of dual-horizon is introduced to consider the unbalanced interactions between the particles with different horizon sizes. The present formulation is proved to fulfill both the balances of linear momentum and angular momentum. Neither the "partial stress tensor" nor the "`slice" technique are needed to ameliorate the ghost force issue in \\cite{Silling2014}. The consistency of reaction forces is naturally fulfilled by a unified simple formulation. The method can be easily implemented to any existing peridynamics code with minimal changes. A simple adaptive refinement procedure is proposed minimizing the computational cost. The method is applied here to the three Peridynamic formulations, namely bond based, ordinary state based and non-ordinary state based Peridynamics. Both two- and three- dimensional examples including the Kalthof-Winkler experi...

  2. Dual Criteria Decisions

    DEFF Research Database (Denmark)

    Andersen, Steffen; Harrison, Glenn W.; Lau, Morten Igel;

    2014-01-01

    The most popular models of decision making use a single criterion to evaluate projects or lotteries. However, decision makers may actually consider multiple criteria when evaluating projects. We consider a dual criteria model from psychology. This model integrates the familiar tradeoffs between...... risk and utility that economists traditionally assume, allowance for rank-dependent decision weights, and consideration of income thresholds. We examine the issues involved in full maximum likelihood estimation of the model using observed choice data. We propose a general method for integrating...... the multiple criteria, using the logic of mixture models, which we believe is attractive from a decision-theoretic and statistical perspective. The model is applied to observed choices from a major natural experiment involving intrinsically dynamic choices over highly skewed outcomes. The evidence points...

  3. Dual-enzyme natural motors incorporating decontamination and propulsion capabilities

    OpenAIRE

    Sattayasamitsathit, S; Kaufmann, K; Galarnyk, M; Vazquez-Duhalt, R.; Wang, J

    2014-01-01

    Self-propelled dual-function biocatalytic motors, consisting of unmodified natural tissue and capable of in-motion bioremediation, are described. These enzyme-rich tissue motors rely on the catalase and peroxidase activities of their Raphanus sativus radish body for their propulsion and remediation actions, respectively. The continuous movement of the biocatalytic tissue motors through the contaminated sample facilitates the dynamic removal of phenolic pollutants. Hydrogen peroxide plays a du...

  4. Inhibitory properties underlying non-monotonic input-output relationship in low-frequency spherical bushy neurons of the gerbil.

    Science.gov (United States)

    Kuenzel, Thomas; Nerlich, Jana; Wagner, Hermann; Rübsamen, Rudolf; Milenkovic, Ivan

    2015-01-01

    Spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive input from large excitatory auditory nerve (AN) terminals, the endbulbs of Held, and mixed glycinergic/GABAergic inhibitory inputs. The latter have sufficient potency to block action potential firing in vivo and in slice recordings. However, it is not clear how well the data from slice recordings match the inhibition in the intact brain and how it contributes to complex phenomena such as non-monotonic rate-level functions (RLF). Therefore, we determined the input-output relationship of a model SBC with simulated endbulb inputs and a dynamic inhibitory conductance constrained by recordings in brain slice preparations of hearing gerbils. Event arrival times from in vivo single-unit recordings in gerbils, where 70% of SBC showed non-monotonic RLF, were used as input for the model. Model output RLFs systematically changed from monotonic to non-monotonic shape with increasing strength of tonic inhibition. A limited range of inhibitory synaptic properties consistent with the slice data generated a good match between the model and recorded RLF. Moreover, tonic inhibition elevated the action potentials (AP) threshold and improved the temporal precision of output functions in a SBC model with phase-dependent input conductance. We conclude that activity-dependent, summating inhibition contributes to high temporal precision of SBC spiking by filtering out weak and poorly timed EPSP. Moreover, inhibitory parameters determined in slice recordings provide a good estimate of inhibitory mechanisms apparently active in vivo.

  5. Inhibitory action of compound phyllanthus urinaria(CPU Ⅱ ) on the growth of transplant hepatoma(H22) in mice.%叶下珠复方Ⅱ号对小鼠H22肝癌移植瘤生长的抑制作用

    Institute of Scientific and Technical Information of China (English)

    李常青; 申建柯; 李小翚

    2011-01-01

    目的 观察叶下珠复方Ⅱ号对小鼠H22肝癌移植瘤生长的抑制作用,并探讨其可能的作用机制.方法 取昆明小鼠40只,建立小鼠H22肝癌移植瘤模型,分为模型组、叶下珠复方Ⅱ号高剂量组(37.5g/kg)、低剂量组(18.75g/kg)和环磷酰胺(20mg/kg)治疗组.叶下珠复方Ⅱ号高、低剂量组均灌胃给药,环磷酰胺组采用腹腔注射,每日1次,连续8d.末次给药24h后,测定瘤体质量,计算抑瘤率;检测血清IL-2和TNF-a含量.结果 叶下珠复方Ⅱ号高、低剂量组瘤重明显低于模型组,差异均有显著性意义(P<0.01),但与环磷酰胺组比较,差异均无显著性意义(P>0.05).叶下珠复方Ⅱ号高、低剂量组的抑瘤率分别为67%和58%,与环磷酰胺组接近.叶下珠复方Ⅱ号高剂量组血清IL-2水平明显高于模型组(P<0.05).叶下珠复方Ⅱ号高、低剂量组血清TNF-a水平明显低于模型组,差异有显著性意义(P<0.05).结论 叶下珠复方Ⅱ号有较好的抑制小鼠H22肝癌移植瘤生长作用,作用机制与调节免疫,升高IL-2水平和抑制TNF-a水平有关.%Objective To observe the inhibitory effects of CPU II on the growth of transplant Hepatoma 22 (H22) in mice. Methods Forty NIH mice were established for transplation tumour model of H22,then they were randomly divided into four groups: model group (group A), high and low dosage group of CPU II (group B, group C), and cyclophosphamidum as the positive control (group D).Mice in group B and group C were administrated orally with CPU II at dosage of 37.5 g/kg and 18.75 g/kg daily respectively. Mice in group D were injected with cyclophosphamidum intraperitoneal at dosage of 20mg/kg daily. Eith days after treatment,the tumour-inhibition rate were calculated according to the tumour mass weight in mice,the serum levels of IL-2 and TNF-a were determined. Results It showed that tumour mass weight in group B and group C were obviously lower than that of group A (P0

  6. Is 1 Hz rTMS Always Inhibitory in Healthy Individuals?

    Science.gov (United States)

    Caparelli, EC; Backus, W; Telang, F; Wang, GJ; Maloney, T; Goldstein, RZ; Henn, F

    2012-01-01

    1 Hz repetitive Transcranial Magnetic Stimulation (rTMS) is considered to have an inhibitory effect in healthy people because it suppresses the excitability of the motor or visual cortex that is expressed as an increase in the motor or the phosphene threshold (PT), respectively. However, the underlying mechanisms and the brain structures involved in the action of rTMS are still unknown. In this study we used two sessions of simultaneous TMS-functional magnetic resonance imaging (fMRI), one before and one after, 15 minutes of 1Hz rTMS to map changes in brain function associated with the reduction in cortical excitability of the primary visual cortex induced by 1 Hz rTMS, when TMS was applied on the occipital area of healthy volunteers. Two groups were evaluated, one group composed of people that can see phosphenes, and another of those lacking this perception. The inhibitory effect, induced by the 1 Hz rTMS, was observed through the increase of the PT, in the first group, but did not lead to a global reduction in brain activation, instead, showed change in the activation pattern before and after rTMS. Conversely, for the second group, changes in brain activation were observed just in few brain areas, suggesting that the effect of 1 Hz rTMS might not be inhibitory for everyone and that the concept of inhibitory/excitatory effect of rTMS may need to be revised. PMID:22930669

  7. Inhibitory Activity of (+-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility.

    Directory of Open Access Journals (Sweden)

    Yi Yang

    Full Text Available Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+-usnic acid and cetuximab. These results implied that (+-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action.

  8. Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen

    Energy Technology Data Exchange (ETDEWEB)

    Khan, S.H.; Sorof, S. (Fox Chase Cancer Center, Philadelphia, PA (United States))

    1990-12-01

    Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ{sub 2}, and {Delta}{sup 12}-PGJ{sub 2}, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA{sub 2} and {Delta}{sup 12}-PGJ{sub 2} in primary cultures of purified rat hepatocytes. As a model ligand, ({sup 3}H)PGA{sub 1} bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 {mu}M (low affinity). The high-affinity finding of ({sup 3}H)PGA{sup 1} correlated with their growth inhibitory activities reported previously and here. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.

  9. Solving the sign problems of the massless lattice Schwinger model with a dual formulation

    Directory of Open Access Journals (Sweden)

    Christof Gattringer

    2015-08-01

    Full Text Available We derive an exact representation of the massless Schwinger model on the lattice in terms of dual variables which are configurations of loops, dimers and plaquette occupation numbers. When expressed with the dual variables the partition sum has only real and positive terms also when a chemical potential or a topological term are added – situations where the conventional representation has a complex action problem. The dual representation allows for Monte Carlo simulations without restrictions on the values of the chemical potential or the vacuum angle.

  10. Solving the sign problems of the massless lattice Schwinger model with a dual formulation

    CERN Document Server

    Gattringer, Christof; Sazonov, Vasily

    2015-01-01

    We derive an exact representation of the massless Schwinger model on the lattice in terms of dual variables which are configurations of loops, dimers and plaquette occupation numbers. When expressed with the dual variables the partition sum has only real and positive terms also when a chemical potential or a topological term are added -- situations where the conventional representation has a complex action problem. The dual representation allows for Monte Carlo simulations without restrictions on the values of the chemical potential or the vacuum angle.

  11. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders.

    Science.gov (United States)

    Ben-Ari, Yehezkel; Khalilov, Ilgam; Kahle, Kristopher T; Cherubini, Enrico

    2012-10-01

    Ionic currents and the network-driven patterns they generate differ in immature and adult neurons: The developing brain is not a "small adult brain." One of the most investigated examples is the developmentally regulated shift of actions of the transmitter GABA that inhibit adult neurons but excite immature ones because of an initially higher intracellular chloride concentration [Cl(-)](i), leading to depolarizing and often excitatory actions of GABA instead of hyperpolarizing and inhibitory actions. The levels of [Cl(-)](i) are also highly labile, being readily altered transiently or persistently by enhanced episodes of activity in relation to synaptic plasticity or a variety of pathological conditions, including seizures and brain insults. Among the plethora of channels, transporters, and other devices involved in controlling [Cl(-)](i), two have emerged as playing a particularly important role: the chloride importer NKCC1 and the chloride exporter KCC2. Here, the authors stress the importance of determining how [Cl(-)](i) is dynamically regulated and how this affects brain operation in health and disease. In a clinical perspective, agents that control [Cl(-)](i) and reinstate inhibitory actions of GABA open novel therapeutic perspectives in many neurological disorders, including infantile epilepsies, autism spectrum disorders, and other developmental disorders.

  12. Dimensional reduction as a method to obtain dual theories for massive spin two in arbitrary dimensions

    Science.gov (United States)

    Khoudeir, A.; Montemayor, R.; Urrutia, Luis F.

    2008-09-01

    Using the parent Lagrangian method together with a dimensional reduction from D to (D-1) dimensions, we construct dual theories for massive spin two fields in arbitrary dimensions in terms of a mixed symmetry tensor TA[A1A2…AD-2]. Our starting point is the well-studied massless parent action in dimension D. The resulting massive Stueckelberg-like parent actions in (D-1) dimensions inherit all the gauge symmetries of the original massless action and can be gauge fixed in two alternative ways, yielding the possibility of having a parent action with either a symmetric or a nonsymmetric Fierz-Pauli field eAB. Even though the dual sector in terms of the standard spin two field includes only the symmetrical part e{AB} in both cases, these two possibilities yield different results in terms of the alternative dual field TA[A1A2…AD-2]. In particular, the nonsymmetric case reproduces the Freund-Curtright action as the dual to the massive spin two field action in four dimensions.

  13. Dimensional reduction as a method to obtain dual theories for massive spin two in arbitray dimensions

    CERN Document Server

    Khoudeir, A; Urrutia, Luis F

    2008-01-01

    Using the parent Lagrangian method together with a dimensional reduction from D to (D-1) dimensions we constuct dual theories for massive spin two fields in arbitray dimensions in terms of a mixed symmetry tensor T_{A[A_1...A_{D-2}]}. Our starting point is the well studied massless parent action in dimension D. The resulting massive Stueckelberg-like parent actions in (D-1) dimensions inherits all the gauge symmetries of the original masless action and can be gauge fixed in two alternative ways, yielding the possibility of having either a parent action with a symmetric or a non-symmetric Fierz-Pauli field e_{AB}. Even though the dual sector in terms of the standard spin two field includes only the symmetrical part e_{{AB}} in both cases, these two alternatives yield different results in terms of the alternative dual field T_{A[A_1...A_{D-2}]}. In particular, the non-symmetric case reproduces the Freund-Curtright action as the dual to the massive spin two field action in four dimensions.

  14. Romantic love is associated with enhanced inhibitory control in an emotional stop-signal task

    Directory of Open Access Journals (Sweden)

    Sensen Song

    2016-10-01

    Full Text Available Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG, and half were single and had never been in a romantic relationship (single group, SG. Based on duration of romantic relationship (i.e., love duration, the LG were further divided into two subgroups: early stage love and longer periods of love. All participants completed an emotional Stop Signal Task (eSST, which consisted of a variety of human face stimuli representing sadness (a negative emotion, as well as neutral emotions. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in longer periods of love or SG individuals, with no significant differences between the latter two groups. Conclusions: Compared with individuals who were single, early-stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness.

  15. Inhibitory effect of strychnine on acetylcholine receptor activation in bovine adrenal medullary chromaffin cells.

    Science.gov (United States)

    Kuijpers, G A; Vergara, L A; Calvo, S; Yadid, G

    1994-01-01

    1. Strychnine, which is known as a potent and selective antagonist of the inhibitory glycine receptor in the central nervous system, inhibits the nicotinic stimulation of catecholamine release from bovine cultured adrenal chromaffin cells in a concentration-dependent (1-100 microM) manner. At 10 microM nicotine, the IC50 value for strychnine is approximately 30 microM. Strychnine also inhibits the nicotine-induced membrane depolarization and increase in intracellular Ca2+ concentration. 2. The inhibitory action of strychnine is reversible and is selective for nicotinic stimulation, with no effect observed on secretion elicited by a high external K+ concentration, histamine or angiotensin II. 3. Strychnine competes with nicotine in its effect, but not modify the apparent positive cooperatively of the nicotine binding sites. In the absence of nicotine, strychnine has no effect on catecholamine release. Glycine does not affect catecholamine release nor the inhibitory action of strychnine on this release. 4. These results suggest that strychnine interacts with the agonist binding site of the nicotinic acetylcholine receptor in chromaffin cells, thus exerting a pharmacological effect independently of the glycine receptor. PMID:7834198

  16. Romantic Love Is Associated with Enhanced Inhibitory Control in an Emotional Stop-Signal Task.

    Science.gov (United States)

    Song, Sensen; Zou, Zhiling; Song, Hongwen; Wang, Yongming; d'Oleire Uquillas, Federico; Wang, Huijun; Chen, Hong

    2016-01-01

    Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG), and half were single and had never been in a romantic relationship (single group, SG). Based on duration of romantic relationship (i.e., love duration), the LG were further divided into two subgroups: "early stage love" and "longer periods of love". All participants completed an emotional Stop Signal Task, consisting of a variety of human face stimuli displaying either sad or neutral affect. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT)] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in "longer periods of love" or SG individuals, with no significant differences between the two latter groups. Conclusion: Compared with individuals who were single, early stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness.

  17. Atomic-position Localization Via Dual Measurement

    CERN Document Server

    Nha, H; Chang, J S; An, K; Nha, Hyunchul; Lee, Jai-Hyung; Chang, Joon-Sung; An, Kyungwon

    2002-01-01

    We study localization of atomic position when a three-level atom interacts with a quantized standing-wave field in the Ramsey interferometer setup. Both the field quadrature amplitude and the atomic internal state are measured to obtain the atomic position information. It is found that this dual measurement scheme produces an interference pattern superimposed on a diffraction-like pattern in the atomic position distribution, where the former pattern originates from the state-selective measurement and the latter from the field measurement. The present scheme results in a better resolution in the position localization than the field-alone measurement schemes. We also discuss the measurement-correlated mechanical action of the standing-wave field on the atom in the light of Popper's test.

  18. Dual of QCD with One Adjoint Fermion

    DEFF Research Database (Denmark)

    Mojaza, Matin; Nardecchia, Marco; Pica, Claudio;

    2011-01-01

    We construct the magnetic dual of QCD with one adjoint Weyl fermion. The dual is a consistent solution of the 't Hooft anomaly matching conditions, allows for flavor decoupling and remarkably constitutes the first nonsupersymmetric dual valid for any number of colors. The dual allows to bound the...

  19. 内源性大麻素物质对家兔窦房结自律细胞动作电位的抑制作用%Inhibitory effects of endocannabinoid on the action potential of pace-maker cells in sinoatrial nodes of rabbits

    Institute of Scientific and Technical Information of China (English)

    张娇; 王三怡; 周京京; 魏燕; 李茜; 杨晶; 张翼

    2013-01-01

    内源性大麻素物质(endocannabinoid anandamde,AEA)可对抗缺血/再灌注所致心脏损伤和心律失常,但其电生理机制尚未完全明了.本文旨在利用细胞内微电极记录方法观察AEA对家兔窦房结自律细胞动作电位的影响,并探讨其机制.采用新西兰大白兔制备离体窦房结标本并记录动作电位,通过累计给药法给予窦房结标本不同浓度(1、10、100、200和500nmol/L)的AEA处理,部分标本在AEA (200 nmol/L)处理前,分别给予大麻素l型(CBl)受体阻断剂AM251、大麻素2型(CB2)受体阻断剂AM630、非特异性K+通道阻滞剂tetraethylammonium (TEA)和NO合酶抑制剂L-nitro-arginine methylester (L-NAME)预处理.结果显示:(1) AEA(100、200和500 nmol/L)可缩短家兔窦房结自律细胞的动作电位时程,降低动作电位幅度(P<0.05); (2) AM251可消除AEA缩短动作电位时程的作用,而AM630对此无影响;(3) TEA和L-NAME对AEA的作用无影响.结果提示,AEA可通过CB1受体降低家兔窦房结自律细胞动作电位幅度、缩短动作电位时程,此作用可能通过阻断Ca2+通道所实现,与K+通道及NO无关.%Endocannabinoid anandamide (AEA) has protective effect on the heart against ischemia/reperfusion injury and arrhythmia,but the electrophysiological mechanism is unclear yet.In this study,the sinoatrial node (SAN) samples from New Zealand rabbits were prepared,and intracellular recording technique was used to elucidate the effect of AEA on the action potential (AP) of SAN pacemaker cells of rabbits and the mechanism.Different concentrations of AEA (1,10,100,200,500 nmol/L) were applied cumulatively.For some SAN samples,cannabinoid type 1 (CB1) receptor antagonist AM251,cannabinoid type 2 (CB2) receptor antagonist AM630,potassium channel blocker tetraethylammonium (TEA) and nitric oxide (NO) synthase inhibitor L-nitro-arginine methylester(L-NAME) were used before AEA treatment,respectively.We found that:(1) AEA (100,200 and 500 nmol

  20. The Man of Dual Nationality.

    Science.gov (United States)

    Abe, Yoshio

    1985-01-01

    Presents an English translation of the first few pages, set in a Japanese internment camp in the U.S. during World War II, of a Japanese novel about the problems of dual nationality and personal identity. (KH)

  1. Lp-dual Quermassintegral sums

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In this paper,we first introduce a concept of L_p-dual Quermassintegral sum function of convex bodies and establish the polar projection Minkowski inequality and the polar projection Aleksandrov-Fenchel inequality for L_p-dual Quermassintegral sums.Moreover,by using Lutwak’s width-integral of index i,we establish the L_p-Brunn-Minkowski inequality for the polar mixed projec- tion bodies.As applications,we prove some interrelated results.

  2. Dual pairs in fluid dynamics

    CERN Document Server

    Gay-Balmaz, François

    2010-01-01

    This paper is a rigorous study of the dual pair structure of the ideal fluid and the dual pair structure for the $n$-dimensional Camassa-Holm (EPDiff) equation, including the proofs of the necessary transitivity results. In the case of the ideal fluid, we show that a careful definition of the momentum maps leads naturally to central extensions of diffeomorphism groups such as the group of quantomorphisms and the Ismagilov central extension.

  3. DESIGN OF A DUAL KEYBOARD

    OpenAIRE

    V. Ragavi; G. Geetha

    2013-01-01

    The design of a computer keyboard with dual function is proposed. This computer keyboard called Dual Keyboard can function both as a normal keyboard and as a pressure sensitive keyboard. The proposed device has a switch that decides the function. The keyboard makes use of sensors placed beneath the keys to measure the pressure applied on the key by the user. This device has many applications. In this study, it is applied to mitigate Denial of Service (DoS) attack.

  4. Fast dual tomography

    Science.gov (United States)

    Carrion, Philip M.

    1990-09-01

    This paper can be considered as a continuation of the work by Carrion and Carneiro (1989), where a generalized approach to linearized inversion of geophysical data was developed. Their method allows one to incorporate virtually any constraints in the inversion and reformulate the problem in the dual space of Langrangian multipliers (see also Carrion, 1989a). The constrained tomography makes traveltime inversion robust: it automatically rejects “bad data” which correspond to solutions beyond the chosen constraints and allows one to start inversion with an arbitrary chosen initial model.In this paper, I will derive basic formulas for constrained tomographic imaging that can be used in such areas of geophysics as global mapping of the earth interior, exploration geophysics, etc. The method is fast: an example that will be shown in the paper took only 6 min. of VAX CPU time. Had the conventional least-squares matrix inversion been used it would have taken more than 10 hours of the CPU time to solve the same problem.

  5. Fast dual tomography

    Energy Technology Data Exchange (ETDEWEB)

    Carrion, P.M. (PPPG/UFBA - Campus Universitario da Federacao, Salvador-Bahia (Brazil))

    1990-09-01

    This paper can be considered as a continuation of the work by Carrion and Carneiro (1989), where a generalized approach to linearized inversion of geophysical data was developed. Their method allows one to incorporate virtually any constraints in the inversion and reformulate the problem in the dual space of Langrangian multipliers (see also Carrion, 1989a). The constrained tomography makes traveltime inversion robust: it automatically rejects bad data which correspond to solutions beyond the chosen constraints and allows one to start inversion with an arbitrary chosen initial model. In this paper, the author derives basic formulas for constrained tomographic imaging that can be used in such areas of geophysics as global mapping of the earth interior, exploration geophysics, etc. The method is fast: an example that will be shown in the paper took only 6 min. of VAX CPU time. Had the conventional least-squares matrix inversion been used it would have taken more than 10 hours of the CPU time to solve the same problem.

  6. Comparison of Heuristics for Inhibitory Rule Optimization

    KAUST Repository

    Alsolami, Fawaz

    2014-09-13

    Knowledge representation and extraction are very important tasks in data mining. In this work, we proposed a variety of rule-based greedy algorithms that able to obtain knowledge contained in a given dataset as a series of inhibitory rules containing an expression “attribute ≠ value” on the right-hand side. The main goal of this paper is to determine based on rule characteristics, rule length and coverage, whether the proposed rule heuristics are statistically significantly different or not; if so, we aim to identify the best performing rule heuristics for minimization of rule length and maximization of rule coverage. Friedman test with Nemenyi post-hoc are used to compare the greedy algorithms statistically against each other for length and coverage. The experiments are carried out on real datasets from UCI Machine Learning Repository. For leading heuristics, the constructed rules are compared with optimal ones obtained based on dynamic programming approach. The results seem to be promising for the best heuristics: the average relative difference between length (coverage) of constructed and optimal rules is at most 2.27% (7%, respectively). Furthermore, the quality of classifiers based on sets of inhibitory rules constructed by the considered heuristics are compared against each other, and the results show that the three best heuristics from the point of view classification accuracy coincides with the three well-performed heuristics from the point of view of rule length minimization.

  7. New cholinesterase inhibitory constituents from Lonicera quinquelocularis.

    Directory of Open Access Journals (Sweden)

    Dilfaraz Khan

    Full Text Available A phytochemical investigation on the ethyl acetate soluble fraction of Lonicera quinquelocularis (whole plant led to the first time isolation of one new phthalate; bis(7-acetoxy-2-ethyl-5-methylheptyl phthalate (3 and two new benzoates; neopentyl-4-ethoxy-3, 5-bis (3-methyl-2-butenyl benzoate (4 and neopentyl-4-hydroxy-3, 5-bis (3-methyl-2-butenyl benzoate (5 along with two known compounds bis (2-ethylhexyl phthalate (1 and dioctyl phthalate (2. Their structures were established on the basis of spectroscopic analysis and by comparison with available data in the literature. All the compounds (1-5 were tested for their acetylcholinesterase (AChE and butyrylcholinesterase (BChE inhibitory activities in dose dependent manner. The IC50 (50% inhibitory effect values of compounds 3 and 5 against AChE were 1.65 and 3.43 µM while the values obtained against BChE were 5.98 and 9.84 µM respectively. Compounds 2 and 4 showed weak inhibition profile.

  8. Pancreatic Lipase Inhibitory Effects of Mangosteen Pericarps

    Directory of Open Access Journals (Sweden)

    Xinjie Lin

    2014-03-01

    Full Text Available Pancreatic lipase plays a key role in the digestion and absorption of lipids, inhibition of Pancreatic Lipase (PL is considered as a new approach to obesity treatment. The objective of the present study was to find PL inhibitors from natural food sources. Eighteen natural food products sampled from local supermarkets in Zhuhai were tested for PL inhibitory activity using a copper-soap photometric method. Among the samples tested, the crude extracts from mangosteen pericarp, lemon pulp, celery, cucumber and dry longan were found to be able to suppress the PL activity to different extents, while dry red chili, fresh green chili and dry clove exhibited a promotion effect on the PL. Shiitake mushroom, green bell pepper, lemon peel and spices (ginger, oregano leaf, bay leaf, cinnamon and dry tangerine showed no significant influence either on the inhibition or promotion. The crude extract of mangosteen pericarp was further fractioned to trace active fractions. It was found that the n-butanol fraction was the major contributor to the PL-inhibitory effect of mangosteen pericarp and the inhibition rate was 43.9% at the concentration of 1 mg/mL, the IC50 value was 0.918 mg/mL. Mangosteen pericarp is worthy of utilization as functional food constituents for the prevention and treatment of obesity.

  9. [Experimental study on inhibitory effect of ganlu xiaodu Dan on coxackie virus in vitro].

    Science.gov (United States)

    He, Y; Wu, C; Zhao, G

    1998-12-01

    To observe the Coxackie virus inhibitory effect of Ganlu Xiaodu Dan (GLXDD), including complete recipe, incomplete recipe and supplemented recipe of it. Using tissue culture technique, the maximal non-toxic concentration of drug on cultured cells, the influence of drug on proliferation of virus in cultured cells and the virus inhibitory effect in different time of action were observed. The maximal non-toxic concentration of GLXDD was 1:40 (25 g/L), no matter whether the recipe was complete, incomplete or supplementary. CLXDD in that concentration could inhibit significantly the proliferation of Coxackie virus B2, B3 and B4 strains, the inhibition index being over 2 and the output of these strains treated with complete recipe of GLXDD was lower significantly than that of the control group (P Coxackie virus in cultured cells.

  10. [Substrate-inhibitory analysis of monoamine oxidase from hepatopancreas of the octopus Bathypolypus arcticus].

    Science.gov (United States)

    Basova, I N; Iagodina, O V

    2012-01-01

    Study of the substrate-inhibitory specificity of mitochondrial monoamine oxidase (MAO) of hepatopancreas of the octopus Bathypolypus arcticus revealed distinctive peculiarities of catalytic properties of this enzyme. The studied enzyme, on one hand, like the classic MAO of homoiothermal animals, is able to deaminate tyramine, serotonin, benzylamine, tryptamine, beta-phenylethylamine, while, on the other hand, deaminates histamine and does not deaminate putrescine--classic substrates of diamine oxidase (DAO). Results of the substrate-inhibitory analysis with use of chlorgiline and deprenyl are indirect proofs of the existence in the octopus hepatopancreas of one molecular MAO form. Semicarbazide and pyronine G turned out to be weak irreversible inhibitors, four derivatives of acridine--irreversible inhibitors of the intermediate effectiveness with respect to the octopus hepatopancreas MAO; specificity of action of inhibitors at deamination of different substrates was equal.

  11. Inhibitory effects of pepstatin A and mefloquine on the growth of Babesia parasites.

    Science.gov (United States)

    Munkhjargal, Tserendorj; AbouLaila, Mahmoud; Terkawi, Mohamad Alaa; Sivakumar, Thillaiampalam; Ichikawa, Madoka; Davaasuren, Batdorj; Nyamjargal, Tserendorj; Yokoyama, Naoaki; Igarashi, Ikuo

    2012-10-01

    We evaluated the inhibitory effects of pepstatin A and mefloquine on the in vitro and in vivo growths of Babesia parasites. The in vitro growth of Babesia bovis, B. bigemina, B. caballi, and B. equi was significantly inhibited (P mefloquine (50% inhibitory concentrations = 59.7, 56.7, 20.7, and 4 μM, respectively). Furthermore, both reagents either alone at a concentration of 5 mg/kg or in combinations (2.5/2.5 and 5/5 mg/kg) for 10 days significantly inhibited the in vivo growth of B. microti in mice. Mefloquine treatment was highly effective and the combination treatments were less effective than other treatments. Therefore, mefloquine may antagonize the actions of pepstatin A against babesiosis and aspartic proteases may play an important role in the asexual growth cycle of Babesia parasites.

  12. Chemical Constituents of Jacaranda oxyphylla and their Acetylcholinesterase Inhibitory and Antimicrobial Activities

    Directory of Open Access Journals (Sweden)

    Vinicius Viana Pereira

    2016-05-01

    Full Text Available This study evaluated chemical composition of Jacaranda oxyphylla, acetylcholinesterase inhibitory and antimicrobial activities of the isolated compounds. Phytochemical investigation of leaves extract yielded three classes of substances: fatty compounds, sterols and triterpenes. Butyl hexadecanoate (1, fatty alcohol (2, 2-(4-hydroxyphenylethyl triacontanoate (3, β -sitosterol (4, sitosterol-3-O- β- D -glucoside (5, 6'-palmitoyl-sitosterol-3-O- β- D -glucoside (6, oleanolic acid (7, ursolic acid (8 and corosolic acid (9 were obtained from n-hexane, CHCl 3 and EtOH extracts of J. oxyphylla. It was found a pronounced acetylcholinesterase inhibitory activity for the fatty compounds 1-3 and sterols 5 and 6, with values between 60 to 77%. Substances 7-9 presented a high antibacterial action against Bacillus cereus and Salmonella typhimurium, with values of growth inhibition in the range of 84 to 90%.

  13. Ação inibitória da Interleucina - 1ß sobre a proliferação de células musculares lisas cultivadas a partir de veias safenas humanas Inhibitory action of the Interleukin 1ß over the cellular proliferation of smooth muscle cells cultivated from human saphenous veins

    Directory of Open Access Journals (Sweden)

    Luís A.O. Dallan

    2005-06-01

    conditions (AHC. The Interleukin - 1ß expression was also elevated in these veins slices. The aim of this study is to evaluate the influence of the interleukin - 1ß in the precocious proliferation of the cultures of primary smooth muscle cells (PSMC. METHOD: PSMC of six different human SVs were cultivated in Dulbecco's Modified Eagle Method associated with bovine fetal serum. The control group was not treated with Interleukin - 1ß but treated groups were. Cellular proliferation (CP was evaluated by measuring triple thymidine [³H], incorporated into the proliferated cells. RESULTS: The treatment with Interleukin - 1ß decreases cellular proliferation. The control group presented 100 ± 4.5% of CP. In the treated groups the quantity of Interleukin - 1ß administered and the respective levels of CP observed were: 0.1 ng/ml - 112 ± 0.7%; 1 ng/mL - 83 ± 4.7%; 10 ng/mL - 69.1 ± 3.8% and 100 ng/mL - 76.3 ± 10.9% (p < 0.01. CONCLUSION: We can conclude that the administration of increasing quantities of Interleukin - 1ß inhibits the proliferation of PSMC cultivated from human SVs. This suggests that the precocious process of apoptosis observed in the SV grafts exposed to AHC can be related to the action of this interleukin.

  14. Allosteric Inhibition of Macrophage Migration Inhibitory Factor Revealed by Ibudilast

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Y.; Crichlow, G; Vermeire, J; Leng, L; Du, X; Hodsdon, M; Bucala, R; Cappello, M; Gross, M; et al.

    2010-01-01

    AV411 (ibudilast; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) is an antiinflammatory drug that was initially developed for the treatment of bronchial asthma but which also has been used for cerebrovascular and ocular indications. It is a nonselective inhibitor of various phosphodiesterases (PDEs) and has varied antiinflammatory activity. More recently, AV411 has been studied as a possible therapeutic for the treatment of neuropathic pain and opioid withdrawal through its actions on glial cells. As described herein, the PDE inhibitor AV411 and its PDE-inhibition-compromised analog AV1013 inhibit the catalytic and chemotactic functions of the proinflammatory protein, macrophage migration inhibitory factor (MIF). Enzymatic analysis indicates that these compounds are noncompetitive inhibitors of the p-hydroxyphenylpyruvate (HPP) tautomerase activity of MIF and an allosteric binding site of AV411 and AV1013 is detected by NMR. The allosteric inhibition mechanism is further elucidated by X-ray crystallography based on the MIF/AV1013 binary and MIF/AV1013/HPP ternary complexes. In addition, our antibody experiments directed against MIF receptors indicate that CXCR2 is the major receptor for MIF-mediated chemotaxis of peripheral blood mononuclear cells.

  15. Steve Woods's contribution to research on amylin's eating inhibitory effect.

    Science.gov (United States)

    Lutz, Thomas Alexander

    2011-04-18

    Amylin is secreted by pancreatic beta-cells and seems to function as a physiological signal of satiation and possibly also as an adiposity signal. Amylin's satiating effect is mediated via a direct action at area postrema (AP) neurons. The central pathways mediating amylin's effects rely on connections from the AP to the nucleus of the solitary tract and lateral parabrachial nucleus. Amylin was shown to interact, probably at the brainstem, with other satiating signals, namely cholecystokinin, glucagon-like peptide 1 and peptide YY, and other adiposity signals, namely leptin and insulin. The interaction with leptin, which is thought to involve the hypothalamus, may have important implications for the development of new and improved hormonal anti-obesity treatments. Steve Woods has contributed to the recent literature on amylin's eating inhibitory effect by some frequently cited publications. Steve's work concentrated more on the central administration of amylin and on amylin's potential role as an adiposity signal. His work will be reviewed here and discussed in the context of other important findings on amylin's role in the control of energy homeostasis.

  16. Raf-1 kinase inhibitory protein expression in thyroid carcinomas.

    Science.gov (United States)

    Kim, Hyun-Soo; Kim, Gou Young; Lim, Sung-Jig; Kim, Youn Wha

    2010-12-01

    Raf-1 kinase inhibitory protein (RKIP) has been implicated in several fundamental signal transduction pathways that control cellular growth, differentiation, apoptosis and migration. RKIP is reduced in a variety of human carcinomas, but RKIP expression in thyroid carcinomas has not been analyzed at the protein level. In this study, we examined the immunohistochemical expression of RKIP in various subtypes of thyroid carcinoma. Immunostaining for RKIP was performed on 104 cases of primary thyroid carcinoma (40 papillary, 29 follicular, 11 medullary, 11 poorly differentiated, and 13 anaplastic carcinomas) and 26 cases of nodal metastatic tumor (17 papillary, 4 medullary, and 5 anaplastic carcinomas). Normal thyroid tissue and all cases of follicular, papillary, and medullary carcinomas showed uniform, strong cytoplasmic immunoreactivity for RKIP. With the exception of one case, poorly differentiated carcinomas also revealed strong RKIP expression. In contrast, RKIP expression was completely absent in all anaplastic carcinomas. The transition zone from the differentiated carcinoma component (strong RKIP expression) to the anaplastic carcinoma component (no RKIP expression) demonstrated a completely opposite pattern of RKIP immunoreactivity. This reduction of RKIP expression in anaplastic carcinoma was statistically significant (P carcinomas showed uniform, strong cytoplasmic RKIP immunoreactivity, in contrast, in metastatic anaplastic carcinomas, RKIP expression was completely absent. RKIP expression is significantly reduced in anaplastic thyroid carcinoma as compared to other subtypes of thyroid carcinoma. Further studies are necessary to elucidate the precise mechanism of RKIP action in anaplastic thyroid carcinoma.

  17. Evaluation of Traditional Indian Antidiabetic Medicinal Plants for Human Pancreatic Amylase Inhibitory Effect In Vitro

    Directory of Open Access Journals (Sweden)

    Sudha Ponnusamy

    2011-01-01

    Full Text Available Pancreatic α-amylase inhibitors offer an effective strategy to lower the levels of post prandial hyperglycemia via control of starch breakdown. Eleven Ayurvedic Indian medicinal plants with known hypoglycemic properties were subjected to sequential solvent extraction and tested for α-amylase inhibition, in order to assess and evaluate their inhibitory potential on pancreatic α-amylase. Analysis of 91 extracts, showed that 10 exhibited strong Human Pancreatic Amylase (HPA inhibitory potential. Of these, 6 extracts showed concentration dependent inhibition with IC50 values, namely, cold and hot water extracts from Ficus bengalensis bark (4.4 and 125 μgmL-1, Syzygium cumini seeds (42.1 and 4.1 μgmL-1, isopropanol extracts of Cinnamomum verum leaves (1.0 μgmL-1 and Curcuma longa rhizome (0.16 μgmL-1. The other 4 extracts exhibited concentration independent inhibition, namely, methanol extract of Bixa orellana leaves (49 μgmL-1, isopropanol extract from Murraya koenigii leaves (127 μgmL-1, acetone extracts from C. longa rhizome (7.4 μgmL-1 and Tribulus terrestris seeds (511 μgmL-1. Thus, the probable mechanism of action of the above fractions is due to their inhibitory action on HPA, thereby reducing the rate of starch hydrolysis leading to lowered glucose levels. Phytochemical analysis revealed the presence of alkaloids, proteins, tannins, cardiac glycosides, flavonoids, saponins and steroids as probable inhibitory compounds.

  18. Unusual target selectivity of perisomatic inhibitory cells in the hilar region of the rat hippocampus.

    Science.gov (United States)

    Acsády, L; Katona, I; Martínez-Guijarro, F J; Buzsáki, G; Freund, T F

    2000-09-15

    Perisomatic inhibitory innervation of all neuron types profoundly affects their firing characteristics and vulnerability. In this study we examined the postsynaptic targets of perisomatic inhibitory cells in the hilar region of the dentate gyrus where the proportion of potential target cells (excitatory mossy cells and inhibitory interneurons) is approximately equal. Both cholecystokinin (CCK)- and parvalbumin-immunoreactive basket cells formed multiple contacts on the somata and proximal dendrites of mossy cells. Unexpectedly, however, perisomatic inhibitory terminals arriving from these cell types largely ignored hilar GABAergic cell populations. Eighty-ninety percent of various GABAergic neurons including other CCK-containing basket cells received no input from CCK-positive terminals. Parvalbumin-containing cells sometimes innervated each other but avoided 75% of other GABAergic cells. Overall, a single mossy cell received 40 times more CCK-immunoreactive terminals and 15 times more parvalbumin-positive terminals onto its soma than the cell body of an average hilar GABAergic cell. In contrast to the pronounced target selectivity in the hilar region, CCK- and parvalbumin-positive neurons innervated each other via collaterals in stratum granulosum and moleculare. Our observations indicate that the inhibitory control in the hilar region is qualitatively different from other cortical areas at both the network level and the level of single neurons. The paucity of perisomatic innervation of hilar interneurons should have profound consequences on their action potential generation and on their ensemble behavior. These findings may help explain the unique physiological patterns observed in the hilus and the selective vulnerability of the hilar cell population in various pathophysiological conditions.

  19. Reciprocal inhibitory connections within a neural network for rotational optic-flow processing

    Directory of Open Access Journals (Sweden)

    Juergen Haag

    2007-10-01

    Full Text Available Neurons in the visual system of the blowfly have large receptive fields that are selective for specific optic flow fields. Here, we studied the neural mechanisms underlying flow-field selectivity in proximal Vertical System (VS-cells, a particular subset of tangential cells in the fly. These cells have local preferred directions that are distributed such as to match the flow field occurring during a rotation of the fly. However, the neural circuitry leading to this selectivity is not fully understood. Through dual intracellular recordings from proximal VS cells and other tangential cells, we characterized the specific wiring between VS cells themselves and between proximal VS cells and horizontal sensitive tangential cells. We discovered a spiking neuron (Vi involved in this circuitry that has not been described before. This neuron turned out to be connected to proximal VS cells via gap junctions and, in addition, it was found to be inhibitory onto VS1.

  20. Concentration-dependent inhibitory and stimulating effects of amphiphilic ammonium salts upon photosynthetic activity of spinach chloroplasts.

    Science.gov (United States)

    Sersen, F; Král'ová, K

    1996-02-01

    The effects of piperidinopropylesters of 2-, 3- and 4-alkoxy substituted phenylcarbamic acids (PPACs) on oxygen evolution rate (OER) in spinach chloroplasts were investigated. PPAGs show concentration-dependent effects, namely OER inhibition at higher effector concentrations and OER stimulation at lower concentrations, i.e. below the inhibitory concentration range. The inhibitory efficiency of PPACs showed dependence on the alkyl chain length of the alkoxy substituent as well as on the position of this substituent on the benzene ring. Using EPR spectroscopy and fluorescence measurements it was confirmed that the site of PPAC inhibitory action is the donor side of photosystem 2, where D1 and D2 proteins are situated, namely the intermediates Z+/Y+, and the manganese cluster containing protein as well. The stimulating effects of PPACs on OER in spinach chloroplasts at relatively low effector concentrations are caused by photophosphorylation uncoupling due to protonophore properties of the effectors.

  1. Asymmetry between excitatory and inhibitory learning.

    Science.gov (United States)

    Harris, Justin A; Patterson, Angela E; Andrew, Benjamin J; Kwok, Dorothy W S; Loy, Ignacio

    2016-10-01

    Five experiments investigated how learning about the added feature in a feature-positive discrimination or feature-negative discrimination is related to the change in reinforcement rate that the feature signals. Rats were trained in a magazine-approach paradigm with 2 concurrent discriminations between A versus AX and B versus BY. In 2 experiments (1 and 3), X and Y signaled an increase of 0.3 in the probability of reinforcement, from 0.1 to 0.4 (A vs. AX), or from 0.6 to 0.9 (B vs. BY). After extended training, each session included probe test trials in which X and Y were presented alone (Experiment 1) or in compound with another excitatory conditional stimulus (CS), C (Experiment 3). There was no difference in response rate between the 2 types of test trial (X vs. Y; XC vs. YC), consistent with the fact that X and Y signaled the same absolute change in reinforcement. In Experiments 2 and 4, X and Y signaled a decrease of 0.3 in the probability of reinforcement, from 0.4 to 0.1 (A vs. AX) or from 0.9 to 0.6 (B vs. BY). Test trials in which X or Y was presented with C showed that X had greater inhibitory strength than Y, consistent with the fact that X signaled a larger relative change in reinforcement. This was confirmed in Experiment 5, in which X and Y had the same inhibitory strength on test after training in which they signaled the same relative change in reinforcement but different absolute changes (0.3 to 0.1 for A vs. AX; 0.9 to 0.3 for B vs. BY). The results show that excitatory conditioning is linearly related to the increase in reinforcement rate, whereas inhibitory learning is not linearly related to the decrease in reinforcement rate. Implications of this for theories of associative learning are discussed. (PsycINFO Database Record

  2. d-Amino acid mutation of PMI as potent dual peptide inhibitors of p53-MDM2/MDMX interactions.

    Science.gov (United States)

    Li, Xiang; Liu, Chao; Chen, Si; Hu, Honggang; Su, Jiacan; Zou, Yan

    2017-09-07

    According to the previously reported potent dual l-peptide PMI of p53-MDM2/MDMX interactions, a series of d-amino acid mutational PMI analogues, PMI-1-4, with enhanced proteolytic resistence and in vitro tumor cell inhibitory activities were reported, of which Liposome-PMI-1 showed a stronger inhibitory activity against the U87 cell lines than Nutlin-3. This d-amino acid mutation strategy may give a hand for enhancing the potential of peptide drugs. Copyright © 2017. Published by Elsevier Ltd.

  3. A Common Representation of Spatial Features Drives Action and Perception

    DEFF Research Database (Denmark)

    Christiansen, Jens H; Christensen, Jeppe Høy; Grünbaum, Thor;

    2014-01-01

    Spatial features of an object can be specified using two different response types: either by use of symbols or motorically by directly acting upon the object. Is this response dichotomy reflected in a dual representation of the visual world: one for perception and one for action? Previously...

  4. A Common Representation of Spatial Features Drives Action and Perception

    DEFF Research Database (Denmark)

    Christiansen, Jens H; Christensen, Jeppe Høy; Grünbaum, Thor

    2014-01-01

    Spatial features of an object can be specified using two different response types: either by use of symbols or motorically by directly acting upon the object. Is this response dichotomy reflected in a dual representation of the visual world: one for perception and one for action? Previously...

  5. The species-specific mode of action of the antimicrobial peptide subtilosin against Listeria monocytogenes Scott A

    NARCIS (Netherlands)

    Kuijk, van S.J.A.; Noll, K.S.; Chikindas, M.L.

    2012-01-01

    Aims: To elucidate the molecular mechanism of action of the antimicrobial peptide subtilosin against the foodborne pathogen Listeria monocytogenes Scott A. Methods and Results: Subtilosin was purified from a culture of Bacillus amylliquefaciens. The minimal inhibitory concentration of subtilosin aga

  6. Two functional inhibitory circuits are comprised of a heterogeneous population of fast-spiking cortical interneurons.

    Science.gov (United States)

    Li, P; Huntsman, M M

    2014-04-18

    Cortical fast spiking (FS) interneurons possess autaptic, synaptic, and electrical synapses that serve to mediate a fast, coordinated response to their postsynaptic targets. While FS interneurons are known to participate in numerous and diverse actions, functional subgroupings within this multi-functional interneuron class remain to be identified. In the present study, we examined parvalbumin-positive FS interneurons in layer 4 of the primary somatosensory (barrel) cortex - a brain region well-known for specialized inhibitory function. Here we show that FS interneurons fall into two broad categories identified by the onset of the first action potential in a depolarizing train as: "delayed firing FS interneurons (FSD) and early onset firing FS interneurons (FSE). Subtle variations in action potential firing reveal six subtypes within these two categories: delayed non-accommodating (FSD-NAC), delayed stuttering (FSD-STUT), early onset stuttering (FSE-STUT), early onset-late spiking (FSE-LS), early onset early-spiking (FSE-ES), and early onset accommodating (FSE-AC). Using biophysical criteria previously employed to distinguish neuronal cell types, the FSD and FSE categories exhibit several shared biophysical and synaptic properties that coincide with the notion of specificity of inhibitory function within the cortical FS interneuron class.

  7. Timing control by redundant inhibitory neuronal circuits

    Science.gov (United States)

    Tristan, I.; Rulkov, N. F.; Huerta, R.; Rabinovich, M.

    2014-03-01

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model.

  8. Controlling Synfire Chain by Inhibitory Synaptic Input

    Science.gov (United States)

    Shinozaki, Takashi; Câteau, Hideyuki; Urakubo, Hidetoshi; Okada, Masato

    2007-04-01

    The propagation of highly synchronous firings across neuronal networks, called the synfire chain, has been actively studied both theoretically and experimentally. The temporal accuracy and remarkable stability of the propagation have been repeatedly examined in previous studies. However, for such a mode of signal transduction to play a major role in processing information in the brain, the propagation should also be controlled dynamically and flexibly. Here, we show that inhibitory but not excitatory input can bidirectionally modulate the propagation, i.e., enhance or suppress the synchronous firings depending on the timing of the input. Our simulations based on the Hodgkin-Huxley neuron model demonstrate this bidirectional modulation and suggest that it should be achieved with any biologically inspired modeling. Our finding may help describe a concrete scenario of how multiple synfire chains lying in a neuronal network are appropriately controlled to perform significant information processing.

  9. Impaired inhibitory control in recreational cocaine users.

    Directory of Open Access Journals (Sweden)

    Lorenza S Colzato

    Full Text Available Chronic use of cocaine is associated with impairment in response inhibition but it is an open question whether and to which degree findings from chronic users generalize to the upcoming type of recreational users. This study compared the ability to inhibit and execute behavioral responses in adult recreational users and in a cocaine-free-matched sample controlled for age, race, gender distribution, level of intelligence, and alcohol consumption. Response inhibition and response execution were measured by a stop-signal paradigm. Results show that users and non users are comparable in terms of response execution but users need significantly more time to inhibit responses to stop-signals than non users. Interestingly, the magnitude of the inhibitory deficit was positively correlated with the individuals lifetime cocaine exposure suggesting that the magnitude of the impairment is proportional to the degree of cocaine consumed.

  10. Differential actions of fipronil and dieldrin insecticides on GABA-gated chloride channels in cockroach neurons.

    Science.gov (United States)

    Zhao, Xilong; Salgado, Vincent L; Yeh, Jay Z; Narahashi, Toshio

    2003-09-01

    Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABAA receptors to fipronil and dieldrin. We examined differential actions of fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABAA receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC50 value of 4 nM followed by inhibition with an IC50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABAA receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABAA receptors. It was concluded that the higher toxicity of fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.

  11. Nootropic dipeptide noopept enhances inhibitory synaptic transmission in the hippocampus.

    Science.gov (United States)

    Povarov, I S; Kondratenko, R V; Derevyagin, V I; Ostrovskaya, R U; Skrebitskii, V G

    2015-01-01

    Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons.

  12. Training-induced behavioral and brain plasticity in inhibitory control

    OpenAIRE

    Lucas eSpierer; Camille eChavan; Aurelie Lynn Manuel

    2013-01-01

    Deficits in inhibitory control, the ability to suppress ongoing or planned motor or cognitive processes, contribute to many psychiatric and neurological disorders. The rehabilitation of inhibition-related disorders may therefore benefit from neuroplasticity-based training protocols aiming at normalizing inhibitory control proficiency and the underlying brain networks. Current literature on training-induced behavioral and brain plasticity in inhibitory control suggests that improvements may fo...

  13. Recruitment of activation receptors at inhibitory NK cell immune synapses.

    Directory of Open Access Journals (Sweden)

    Nicolas Schleinitz

    Full Text Available Natural killer (NK cell activation receptors accumulate by an actin-dependent process at cytotoxic immune synapses where they provide synergistic signals that trigger NK cell effector functions. In contrast, NK cell inhibitory receptors, including members of the MHC class I-specific killer cell Ig-like receptor (KIR family, accumulate at inhibitory immune synapses, block actin dynamics, and prevent actin-dependent phosphorylation of activation receptors. Therefore, one would predict inhibition of actin-dependent accumulation of activation receptors when inhibitory receptors are engaged. By confocal imaging of primary human NK cells in contact with target cells expressing physiological ligands of NK cell receptors, we show here that this prediction is incorrect. Target cells included a human cell line and transfected Drosophila insect cells that expressed ligands of NK cell activation receptors in combination with an MHC class I ligand of inhibitory KIR. The two NK cell activation receptors CD2 and 2B4 accumulated and co-localized with KIR at inhibitory immune synapses. In fact, KIR promoted CD2 and 2B4 clustering, as CD2 and 2B4 accumulated more efficiently at inhibitory synapses. In contrast, accumulation of KIR and of activation receptors at inhibitory synapses correlated with reduced density of the integrin LFA-1. These results imply that inhibitory KIR does not prevent CD2 and 2B4 signaling by blocking their accumulation at NK cell immune synapses, but by blocking their ability to signal within inhibitory synapses.

  14. The political downside of dual identity: group identifications and religious political mobilization of Muslim minorities.

    Science.gov (United States)

    Martinovic, Borja; Verkuyten, Maykel

    2014-12-01

    Research on the political mobilization of ethnic minorities has shown that dual ethno-national identification facilitates involvement in political action on behalf of the ethnic group. This study extends this research by proposing that a dual identity can impede political mobilization on behalf of another relevant in-group--the religious community - especially if this in-group is not accepted by the wider society. Using a sample of 641 Muslims of Turkish origin living in Germany and the Netherlands, dual ethno-national identity (Turkish-German/Turkish-Dutch) was examined in relation to religious Muslim identification and religious political mobilization. Dual identity was expected to be indirectly related to lower mobilization via decreased religious group identification. Further, this mediating process was predicted to be stronger for Turkish Muslims who perceived relatively high religious group discrimination. In both countries we found support for the mediating hypothesis, however, the moderating role of discrimination was confirmed only for the Netherlands. Turkish-Dutch identification was associated with lower support for religious political mobilization because of lower Muslim identification only for Turkish-Dutch participants who perceived high levels of discrimination. These findings indicate that a strong dual (ethno-national) identity can undermine minority members' support for political rights and actions on behalf of a third relevant in-group, and therefore qualify the social psychological benefits of the dual identity model.

  15. Inhibitory activity of monoacylglycerols on biofilm formation in Aeromonas hydrophila, Streptococcus mutans, Xanthomonas oryzae, and Yersinia enterocolitica.

    Science.gov (United States)

    Ham, Youngseok; Kim, Tae-Jong

    2016-01-01

    Biofilm provides a bacterial hiding place by forming a physical barrier and causing physiological changes in cells. The elimination of biofilm is the main goal of hygiene. Chemicals that are inhibitory to biofilm formation have been developed for use in food, personal hygiene products, and medical instruments. Monoacylglycerols are recognized as safe and are used in food as emulsifiers. In this study, the inhibitory activity of monoacylglycerols on bacterial biofilm formation was evaluated systematically with four bacterial strains, Aeromonas hydrophila, Streptococcus mutans, Xanthomonas oryzae, and Yersinia enterocolitica. Monoacylglycerols with two specific lengths of fatty acid moiety, monolaurin and monobehenin, were found to have strong inhibitory activity toward bacterial biofilm formation of S. mutans, X. oryzae, and Y. enterocolitica in a strain specific manner. First, this result suggested that biofilm formation was not inhibited by the detergent characteristics of monoacylglycerols. This suggestion was supported by the inhibitory action of monolaurin on biofilm development but not on the initial cell attachment of Y. enterocolitica in flow cytometric observation. Second, it was also suggested that two distinct response mechanisms to monoacylglycerols existed in bacteria. The existence of these two inhibitory response mechanisms was bacterial strain specific.

  16. Some characteristics of a raw starch digestion inhibitory factor from Aspergillus niger

    Energy Technology Data Exchange (ETDEWEB)

    Towprayoon, S.; Saha, B.C.; Fujio, Yusaku; Ueda, Seinosuke

    1988-09-01

    The effect of an inhibitory factor (IF) from Aspergillus niger 19 on raw starch digestion by pure glucoamylase I of black Aspergillus, pure glucoamylase of Rhizopus niveus, bacterial ..cap alpha..-amylase, fungal ..cap alpha..-amylase and various combination was investigated. The IF caused higher inhibition of raw starch hydrolysis by the combined action of glucoamylase and fungal ..cap alpha..-amylase than of hydrolysis by the individual enzymes. A protein moiety of IF might play an active part in this inhibition phenomenon. The IF was found to starch granules, preventing hydrolysis by the enzymes, and caused decreased raw starch hydrolysis yields.

  17. Thoracic applications of dual energy.

    Science.gov (United States)

    Remy-Jardin, Martine; Faivre, Jean-Baptiste; Pontana, Francois; Hachulla, Anne-Lise; Tacelli, Nunzia; Santangelo, Teresa; Remy, Jacques

    2010-01-01

    Recent technological advances in multidetector computed tomography (CT) have led to the introduction of dual-source CT, which allows acquisition of CT data at the same energy or at 2 distinct tube voltage settings during a single acquisition. The advantage of the former is improvement of temporal resolution, whereas the latter offers new options for CT imaging, allowing tissue characterization and functional analysis with morphologic evaluation. The most investigated application has been iodine mapping at pulmonary CT angiography. The material decomposition achievable opens up new options for recognizing substances poorly characterized by single-energy CT. Although it is too early to draw definitive conclusions on dual-energy CT applications, this article reviews the results already reported with the first generation of dual-source CT systems.

  18. Prostaglandin inhibitory and antioxidant components of Cistus laurifolius, a Turkish medicinal plant.

    Science.gov (United States)

    Sadhu, Samir Kumar; Okuyama, Emi; Fujimoto, Haruhiro; Ishibashi, Masami; Yesilada, Erdem

    2006-12-06

    As Cistus laurifolius has been used traditionally to treat inflammatory and rheumatic disorders, its leaves were tested for prostaglandin (PG) inhibitory and antioxidant activities. The leaf extract showed both activities, i.e., inhibitory effect at 300 microg/ml on PGE1- and E2-induced contractions in guinea pig ileum and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect. The separation guided by the activities shown by these dual assays provided sixteen compounds, 1-16. Known compounds 1-12 and 15 were identified as 3-O-methyl quercetin (1), 3,7-O-dimethyl quercetin (2), genkwanin (3), 3,7-O-dimethyl kaempferol (4), 3,4'-O-dimethyl quercetin (5), apigenin (6), 3,4'-O-dimethyl kaempferol (7), ellagic acid (8), beta-sitosterol-3-O-beta-glucoside (9), quercetin 3-O-alpha-rhamnoside (10), 5-O-p-coumaroyl quinic acid methyl ester (11), 1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-alpha-l-rhamnopyranoxypropyl)-2-methoxyphenoxy]-1,3-propanediol (12) and 2,3-dihydro-2-(4'-alpha-l-rhamnopyranosyloxy-3'-methoxyphenyl)-3-hydroxymethyl-7-methoxy-5-benzofuranpropanol (15). New lignan glycosides 13 and 14 were determined to be olivil 9-O-beta-D-xyloside and berchemol 9-O-rhamnoside, respectively. Compound 16 was isolated as a 2:1 mixture of two diastereomers, the major one of which was determined to be (7S,8R)-dihydrodehydrodiconiferyl alcohol 9'-O-alpha-L-rhamnoside. The structures were determined by detailed 2D NMR analysis together with NOEDF and CD. PG inhibitory effect was observed in 1, 5, 10, 12 and 16 at 30 microg/ml and antioxidant activity, in 1, 2, 8, 10, 12-14 and 16.

  19. An investigation of hierachical protein recruitment to the inhibitory platelet receptor, G6B-b.

    Science.gov (United States)

    Coxon, Carmen H; Sadler, Amanda J; Huo, Jiandong; Campbell, R Duncan

    2012-01-01

    Platelet activation is regulated by both positive and negative signals. G6B-b is an inhibitory platelet receptor with an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). The molecular basis of inhibition by G6B-b is currently unknown but thought to involve the SH2 domain-containing tyrosine phosphatase SHP-1. Here we show that G6B-b also associates with SHP-2, as well as SHP-1, in human platelets. Using a number of biochemical approaches, we found these interactions to be direct and that the tandem SH2 domains of SHP-2 demonstrated a binding affinity for G6B-b 100-fold higher than that of SHP-1. It was also observed that while SHP-1 has an absolute requirement for phosphorylation at both motifs to bind, SHP-2 can associate with G6B-b when only one motif is phosphorylated, with the N-terminal SH2 domain and the ITIM being most important for the interaction. A number of other previously unreported SH2 domain-containing proteins, including Syk and PLCγ2, also demonstrated specificity for G6B-b phosphomotifs and may serve to explain the observation that G6B-b remains inhibitory in the absence of both SHP-1 and SHP-2. In addition, the presence of dual phosphorylated G6B-b in washed human platelets can reduce the EC(50) for both CRP and collagen.

  20. An investigation of hierachical protein recruitment to the inhibitory platelet receptor, G6B-b.

    Directory of Open Access Journals (Sweden)

    Carmen H Coxon

    Full Text Available Platelet activation is regulated by both positive and negative signals. G6B-b is an inhibitory platelet receptor with an immunoreceptor tyrosine-based inhibitory motif (ITIM and an immunoreceptor tyrosine-based switch motif (ITSM. The molecular basis of inhibition by G6B-b is currently unknown but thought to involve the SH2 domain-containing tyrosine phosphatase SHP-1. Here we show that G6B-b also associates with SHP-2, as well as SHP-1, in human platelets. Using a number of biochemical approaches, we found these interactions to be direct and that the tandem SH2 domains of SHP-2 demonstrated a binding affinity for G6B-b 100-fold higher than that of SHP-1. It was also observed that while SHP-1 has an absolute requirement for phosphorylation at both motifs to bind, SHP-2 can associate with G6B-b when only one motif is phosphorylated, with the N-terminal SH2 domain and the ITIM being most important for the interaction. A number of other previously unreported SH2 domain-containing proteins, including Syk and PLCγ2, also demonstrated specificity for G6B-b phosphomotifs and may serve to explain the observation that G6B-b remains inhibitory in the absence of both SHP-1 and SHP-2. In addition, the presence of dual phosphorylated G6B-b in washed human platelets can reduce the EC(50 for both CRP and collagen.

  1. A novel role of dendritic gap junction and mechanisms underlying its interaction with thalamocortical conductance in fast spiking inhibitory neurons

    Directory of Open Access Journals (Sweden)

    Sun Qian-Quan

    2009-10-01

    Full Text Available Abstract Background Little is known about the roles of dendritic gap junctions (GJs of inhibitory interneurons in modulating temporal properties of sensory induced responses in sensory cortices. Electrophysiological dual patch-clamp recording and computational simulation methods were used in combination to examine a novel role of GJs in sensory mediated feed-forward inhibitory responses in barrel cortex layer IV and its underlying mechanisms. Results Under physiological conditions, excitatory post-junctional potentials (EPJPs interact with thalamocortical (TC inputs within an unprecedented few milliseconds (i.e. over 200 Hz to enhance the firing probability and synchrony of coupled fast-spiking (FS cells. Dendritic GJ coupling allows fourfold increase in synchrony and a significant enhancement in spike transmission efficacy in excitatory spiny stellate cells. The model revealed the following novel mechanisms: 1 rapid capacitive current (Icap underlies the activation of voltage-gated sodium channels; 2 there was less than 2 milliseconds in which the Icap underlying TC input and EPJP was coupled effectively; 3 cells with dendritic GJs had larger input conductance and smaller membrane response to weaker inputs; 4 synchrony in inhibitory networks by GJ coupling leads to reduced sporadic lateral inhibition and increased TC transmission efficacy. Conclusion Dendritic GJs of neocortical inhibitory networks can have very powerful effects in modulating the strength and the temporal properties of sensory induced feed-forward inhibitory and excitatory responses at a very high frequency band (>200 Hz. Rapid capacitive currents are identified as main mechanisms underlying interaction between two transient synaptic conductances.

  2. Inhibitory Action of Ethanolic Extract of Seeds of Moringa oleifera Lam. On Systemic and Local Anaphylaxis.

    Science.gov (United States)

    Mahajan, Shailaja G; Mehta, Anita A

    2007-10-01

    The current study characterizes the mechanism by which the seed extract of Moringa oleifera Lam (Moringaceae) decreases the mast cell-mediated immediate type hypersensitivity reaction. The immediate type hypersensitivity reaction is involved in many allergic diseases such as asthma and allergic rhinitis. Moringa oleifera, a shrub widely used in the traditional medicine in India, has been reported to possess anti-cancer, hypotensive, anti-arthritic, and anti-inflammatory activities. In the present study, the effects of the ethanolic extract of seeds of Moringa oleifera (MOEE-herbal remedy) on systemic and local anaphylaxis were investigated. The potential anti-anaphylactic effect of MOEE was studied in a mouse model of Compound 48/80-induced systemic anaphylactic shock. Passive cutaneous anaphylaxis activated by anti IgE-antibody was also used to assess the effect of MOEE. In addition, rat peritoneal mast cells (RPMC) were used to investigate the effect of MOEE on histamine release induced by compound 48/80. When administered 1 hr before 48/80 injection, MOEE at doses of 0.001-1.000 g/kg completely inhibited the inducible induced anaphylactic shock. MOEE significantly inhibited passive cutaneous anaphylaxis activated by anti-IgE antibody at a dose of 1 g/kg. When MOEE extract was given as pretreatment at concentrations ranging 0.1-100 mg/ml, the histamine release from the mast cells that was induced by the 48/80 was reduced in a dose-dependent manner. These results suggest a potential role for MOEE as a source of anti-anaphylactic agents for use in allergic disorders.

  3. Selective inhibitory action of Biginelli-type dihydropyrimidines on depolarization-induced arterial smooth muscle contraction

    NARCIS (Netherlands)

    Cernecka, Hana; Veizerova, Lucia; Mensikova, Lucia; Svetlik, Jan; Krenek, Peter

    2012-01-01

    OBJECTIVES: Dihydropyridine calcium channel blockers have some disadvantages such as light sensitivity and relatively short plasma half-lives. Stability of dihydropyrimidines analogues could be of advantage, yet they remain less well characterized. We aimed to test four newly synthesized Biginelli-t

  4. Inhibitory effect of boron against Botrytis cinerea on table grapes and its possible mechanisms of action.

    Science.gov (United States)

    Qin, Guozheng; Zong, Yuanyuan; Chen, Qiling; Hua, Donglai; Tian, Shiping

    2010-03-31

    Boron, an essential plant micronutrient, was effective in the form of potassium tetraborate for control of postharvest gray mold caused by Botrytis cinerea on table grapes stored at room temperature or at 0 degrees C. The inhibition of fruit decay was closely correlated with boron concentrations and partially influenced by pH value of the solution. Boron strongly inhibited spore germination, germ tube elongation, and mycelial spread of B. cinerea in the culture medium. Application of boron at 1% caused the appearance of abnormal spores (disrupted) in some cases. By using propidium iodide fluorescent staining, loss of membrane integrity in B. cinerea was observed after boron treatment. Furthermore, boron led to the leakage of cellular constituents (soluble proteins and carbohydrates) from hyphae of B. cinerea. These data suggest that the mechanisms by which boron decreased gray mold decay of table grapes may be directly related to the disruption effect of boron on cell membrane of the fungal pathogen that resulted in the breakdown of the cell membrane and loss of cytoplasmic materials from the hyphae.

  5. Significant NRC Enforcement Actions

    Data.gov (United States)

    Nuclear Regulatory Commission — This dataset provides a list of Nuclear Regulartory Commission (NRC) issued significant enforcement actions. These actions, referred to as "escalated", are issued by...

  6. Towards a big crunch dual

    Energy Technology Data Exchange (ETDEWEB)

    Hertog, Thomas E-mail: hertog@vulcan2.physics.ucsb.edu; Horowitz, Gary T

    2004-07-01

    We show there exist smooth asymptotically anti-de Sitter initial data which evolve to a big crunch singularity in a low energy supergravity limit of string theory. This opens up the possibility of using the dual conformal field theory to obtain a fully quantum description of the cosmological singularity. A preliminary study of this dual theory suggests that the big crunch is an endpoint of evolution even in the full string theory. We also show that any theory with scalar solitons must have negative energy solutions. The results presented here clarify our earlier work on cosmic censorship violation in N=8 supergravity. (author)

  7. DUAL BAND MONOPOLE ANTENNA DESIGN

    Directory of Open Access Journals (Sweden)

    P. Jithu

    2013-06-01

    Full Text Available The WLAN and Bluetooth applications become popular in mobile devices, integrating GSM and ISM bands operation in one compact antenna, can reduce the size of mobile devices. Recently, lot many investigations are carried out in designing a dual band antennas with operating frequencies in GSM band and in ISM band for mobile devices. Printed monopoles are under this investigation. In this paper, dual-band printed monopoles are presented to operate at GSM band i.e. 900 MHz and ISM band i.e. 2.4 GHz. We intend to observe the antenna characteristics on the network analyzer and verify the theoretical results with the practical ones.

  8. DESIGN OF A DUAL KEYBOARD

    Directory of Open Access Journals (Sweden)

    V. Ragavi

    2013-01-01

    Full Text Available The design of a computer keyboard with dual function is proposed. This computer keyboard called Dual Keyboard can function both as a normal keyboard and as a pressure sensitive keyboard. The proposed device has a switch that decides the function. The keyboard makes use of sensors placed beneath the keys to measure the pressure applied on the key by the user. This device has many applications. In this study, it is applied to mitigate Denial of Service (DoS attack.

  9. Nuclearity for Dual Operator Spaces

    Indian Academy of Sciences (India)

    Zhe Dong; Jicheng Tao

    2010-02-01

    In this short paper, we study the nuclearity for the dual operator space $V^∗$ of an operator space . We show that $V^∗$ is nuclear if and only if $V^{∗∗∗}$ is injective, where $V^{∗∗∗}$ is the third dual of . This is in striking contrast to the situation for general operator spaces. This result is used to prove that $V^{∗∗}$ is nuclear if and only if is nuclear and $V^{∗∗}$ is exact.

  10. Dual-Functional Antifogging/Antimicrobial Polymer Coating.

    Science.gov (United States)

    Zhao, Jie; Ma, Li; Millians, William; Wu, Tiehang; Ming, Weihua

    2016-04-06

    Dual-functional antifogging/antimicrobial polymer coatings were prepared by forming a semi-interpenetrating polymer network (SIPN) of partially quaternized poly(2-(dimethylamino)ethyl methacrylate-co-methyl methacrylate) and polymerized ethylene glycol dimethacrylate network. The excellent antifogging behavior of the smooth coating was mainly attributed to the hydrophilic/hydrophobic balance of the partially quaternized copolymer, while the covalently bonded, hydrophobic quaternary ammonium compound (5 mol % in the copolymer) rendered the coating strongly antimicrobial, as demonstrated by the total kill against both Gram-positive Staphylococcus epidermidis and Gram-negative Escherichia coli. The antimicrobial action of the SIPN coating was based on contact killing, without leaching of bactericidal species, as revealed by a zone-of-inhibition test. This type of dual-functional coating may find unique applications where both antimicrobial and antifogging properties are desired.

  11. Physiological Synchronization in a Vigilance Dual Task.

    Science.gov (United States)

    Guastello, Stephen J

    2016-01-01

    The synchronization of autonomic arousal levels and other physio-logical responses between people is a potentially important component of work team performance, client-therapist relationships, and other types of human interaction. This study addressed several problems: What statistical models are viable for identifying synchronization for loosely coupled human systems? How is the level of synchronization related to psychosocial variables such as empathy, subjective ratings of workload, and actual performance? Participants were 70 undergraduates who worked in pairs on a vigilance dual task in which they watched a virtual reality security camera, rang a bell when they saw the target intruder, and completed a jig-saw puzzle. Event rates either increased or decreased during the 90 min work period. The average R2 values for each person were .66, .66, .62, and .53 for the linear autoregressive model, linear autoregressive model with a synchronization component, the nonlinear autoregressive model, and the nonlinear autoregressive model with a synchronization component, respectively. All models were more accurate at a lag of 20 sec compared to 50 sec or customized lag lengths. Although the linear models were more accurate overall, the nonlinear synchronization parameters were more often related to psychological variables and performance. In particular, greater synchronization was observed with the nonlinear model when the target event rate increased, compared to when it decreased, which was expected from the general theory of synchronization. Nonlinear models were also more effective for uncovering inhibitory or dampening relationships between the co-workers as well as mutually excitatory relationships. Future research should explore the comparative model results for tasks that induce higher levels of synchronization and involve different types of internal group coordination.

  12. CARDIOVASCULAR ENDOCRINOLOGY Dual RAAS blockade has dual effects on outcome

    NARCIS (Netherlands)

    Heerspink, Hiddo J. Lambers; de Zeeuw, Dick

    Makani and colleagues report that dual blockade of the renin-angiotensin-aldosterone system is associated with harm despite previous studies showing that this approach decreases blood pressure and albuminuria. Do these results imply that we should abandon surrogate markers? Or should we become more

  13. Dual-band dual-polarized array for WLAN applications

    CSIR Research Space (South Africa)

    Steyn, JM

    2009-01-01

    Full Text Available ) simultaneously. The two linear polarizations have separate ports. The presented design is characterized by dual-band operation, reasonably good front-to-back ratios, average gains of 5.2 dBi and 6.2 dBi over the 2.4 and 5.2 GHz bands respectively, stable end...

  14. A dual method for maximum entropy restoration

    Science.gov (United States)

    Smith, C. B.

    1979-01-01

    A simple iterative dual algorithm for maximum entropy image restoration is presented. The dual algorithm involves fewer parameters than conventional minimization in the image space. Minicomputer test results for Fourier synthesis with inadequate phantom data are given.

  15. Sparsity and spectral properties of dual frames

    CERN Document Server

    Krahmer, Felix; Lemvig, Jakob

    2012-01-01

    We study sparsity and spectral properties of dual frames of a given finite frame. We show that any finite frame has a dual with no more than $n^2$ non-vanishing entries, where $n$ denotes the ambient dimension, and that for most frames no sparser dual is possible. Moreover, we derive an expression for the exact sparsity level of the sparsest dual for any given finite frame using a generalized notion of spark. We then study the spectral properties of dual frames in terms of singular values of the synthesis operator. We provide a complete characterization for which spectral patterns of dual frames are possible for a fixed frame. For many cases, we provide simple explicit constructions for dual frames with a given spectrum, in particular, if the constraint on the dual is that it be tight.

  16. Dual-Doppler Feasibility Study

    Science.gov (United States)

    Huddleston, Lisa L.

    2012-01-01

    When two or more Doppler weather radar systems are monitoring the same region, the Doppler velocities can be combined to form a three-dimensional (3-D) wind vector field thus providing for a more intuitive analysis of the wind field. A real-time display of the 3-D winds can assist forecasters in predicting the onset of convection and severe weather. The data can also be used to initialize local numerical weather prediction models. Two operational Doppler Radar systems are in the vicinity of Kennedy Space Center (KSC) and Cape Canaveral Air Force Station (CCAFS); these systems are operated by the 45th Space Wing (45 SW) and the National Weather Service Melbourne, Fla. (NWS MLB). Dual-Doppler applications were considered by the 45 SW in choosing the site for the new radar. Accordingly, the 45th Weather Squadron (45 WS), NWS MLB and the National Aeronautics and Space Administration tasked the Applied Meteorology Unit (AMU) to investigate the feasibility of establishing dual-Doppler capability using the two existing systems. This study investigated technical, hardware, and software requirements necessary to enable the establishment of a dual-Doppler capability. Review of the available literature pertaining to the dual-Doppler technique and consultation with experts revealed that the physical locations and resulting beam crossing angles of the 45 SW and NWS MLB radars make them ideally suited for a dual-Doppler capability. The dual-Doppler equations were derived to facilitate complete understanding of dual-Doppler synthesis; to determine the technical information requirements; and to determine the components of wind velocity from the equation of continuity and radial velocity data collected by the two Doppler radars. Analysis confirmed the suitability of the existing systems to provide the desired capability. In addition, it is possible that both 45 SW radar data and Terminal Doppler Weather Radar data from Orlando International Airport could be used to alleviate any

  17. A competitive inhibitory circuit for selection of active and passive fear responses.

    Science.gov (United States)

    Fadok, Jonathan P; Krabbe, Sabine; Markovic, Milica; Courtin, Julien; Xu, Chun; Massi, Lema; Botta, Paolo; Bylund, Kristine; Müller, Christian; Kovacevic, Aleksandar; Tovote, Philip; Lüthi, Andreas

    2017-02-02

    When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses. Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents. However, rodents also exhibit active responses such as flight under natural conditions. The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established. Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF(+)) mediate conditioned flight, and activation of somatostatin-positive (SOM(+)) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF(+) and SOM(+) neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection.

  18. Inhibitory effect against pathogenic and spoilage bacteria of Pseudomonas strains isolated from spoiled and fresh fish.

    Science.gov (United States)

    Gram, L

    1993-01-01

    The antibacterial effects of 209 Pseudomonas strains isolated from spoiled iced fish and newly caught fish were assessed by screening target organisms in agar diffusion assays. One-third (67 strains) inhibited the growth of one or several of six target organisms (Escherichia coli, Shewanella putrefaciens, Aeromonas sobria, Pseudomonas fluorescens, Listeria monocytogenes, and Staphylococcus aureus), of which S. aureus and A. sobria were the most sensitive. The inhibitory action was most pronounced among the strains producing siderophores, and the presence of iron eliminated the antibacterial effect of two-thirds of the inhibitory strains. Siderophore-mediated competition for iron may explain the inhibitory activity of these strains. All but nine of the inhibiting strains were found to inhibit the growth of 38 psychrotrophic S. putrefaciens strains isolated from spoiling fish and fish products. Siderophore-containing Pseudomonas culture supernatants inhibited growth of S. putrefaciens, as did the addition of iron chelators (ethylenediamine dihydroxyphenylacetic acid [EDDHA]). In particular, Pseudomonas strains isolated from newly caught and spoiled Nile perch (Lates niloticus) inhibited S. putrefaciens. This suggests that microbial interaction (e.g., competition or antagonism) may influence the selection of a microflora for some chilled food products. PMID:8357253

  19. Inhibitory effects of chickpea and Tribulus terrestris on lipase, α-amylase and α-glucosidase.

    Science.gov (United States)

    Ercan, Pınar; El, Sedef Nehir

    2016-08-15

    The total saponin content and its in vitro bioaccessibilities in Tribulus terrestris and chickpea were determined by a static in vitro digestion method (COST FA1005 Action INFOGEST). Also, in vitro inhibitory effects of the chosen food samples on lipid and starch digestive enzymes were determined by evaluating the lipase, α-amylase and α-glucosidase activities. The tested T. terrestris and chickpea showed inhibitory activity against α-glucosidase (IC50 6967 ± 343 and 2885 ± 85.4 μg/ml, respectively) and α-amylase (IC50 343 ± 26.2 and 167 ± 6.12 μg/ml, respectively). The inhibitory activities of T. terrestris and chickpea against lipase were 15.3 ± 2.03 and 9.74 ± 1.09 μg/ml, respectively. The present study provides the first evidence that these food samples (T. terrestris, chickpea) are potent inhibitors of key enzymes in digestion of carbohydrates and lipids in vitro.

  20. Effect of toothpaste on the plaque inhibitory properties of a cetylpyridinium chloride mouth rinse.

    Science.gov (United States)

    Sheen, S; Eisenburger, M; Addy, M

    2003-03-01

    Cetylpyridinium chloride (CPC) mouth rinses have moderate plaque inhibitory activity when used alone but rarely have shown adjunctive benefits to tooth brushing with toothpaste. Several explanations for this apparent anomaly can be proferred, including loss of antiseptic activity due to interactions with toothpaste ingredients. The aim of this study was to measure the effect of toothpaste on the plaque inhibitory properties of a CPC mouth rinse using paired rinses of CPC, toothpaste slurry (TP) and water (W). The study was a single blind, randomised, seven-treatment, cross over design balanced for residual effects, involving 21 healthy, dentate subjects. The paired rinses were: W-CPC, CPC-W, TP-CPC, CPC-TP, W-TP, TP-W and W-W. Rinsing with solutions or slurries was done for 60 s twice per day. On day 1, subjects were rendered plaque free, suspended tooth cleaning and commenced the allocated rinse regimen. On day 5, plaque was scored by index. A 2(1/2) day wash out of normal oral hygiene was allowed between each regimen. The order from lowest to highest plaque scores was as follows: W-CPC = CPC-W mouth rinse adversely affected the plaque inhibitory action of this antiseptic. This in part may explain the reported lack of adjunctive benefits of CPC rinses to normal oral hygiene practices and supports the suggestion, made for chlorhexidine rinses, that their use should follow toothpaste by at least 60 min.

  1. Effect of subinihibitory and inhibitory concentrations of Plectranthus amboinicus (Lour.) Spreng essential oil on Klebsiella pneumoniae.

    Science.gov (United States)

    Gonçalves, Thially Braga; Braga, Milena Aguiar; de Oliveira, Francisco F M; Santiago, Gilvandete M P; Carvalho, Cibele B M; Brito e Cabral, Paula; de Melo Santiago, Thiago; Sousa, Jeanlex S; Barros, Eduardo Bedê; do Nascimento, Ronaldo Ferreira; Nagao-Dias, Aparecida T

    2012-08-15

    We evaluated the antimicrobial activity and some mechanisms used by subinhibitory and inhibitory concentrations of the essential oil, obtained from leaves of Plectranthus amboinicus, against a standard strain of Klebsiella pneumoniae and 5 multiresistant clinical isolates of the bacteria. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC), the rate of kill and the pH sensitivity of the essential oil were determined by microdilution tests performed in 96-well plates. Subinhibitory and inhibitory concentrations of the essential oil were tested in order to check its action on K. pneumoniae membrane permeability, capsule expression, urease activity and cell morphology. The MIC and MBC of the essential oil were 0.09±0.01%. A complete inhibition of the bacterial growth was observed after 2 h of incubation with twice the MIC of the essential oil. A better MIC was found when neutral or alkaline pH broth was used. Alteration in membrane permeability was found by the increase of crystal violet uptake when the bacteria were incubated with twice the MIC levels of the essential oil. The urease activity could be prevented when all the subinhibitory concentrations were tested in comparison to the untreated group (pamboinicus can be a good candidate for future research.

  2. Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task.

    Science.gov (United States)

    Lhullier, F L R; Nicolaidis, R; Riera, N G; Cipriani, F; Junqueira, D; Dahm, K C S; Brusque, A M; Souza, D O

    2004-03-01

    Dehydroepiandrosterone (DHEA) exerts multiple effects in the rodent central nervous system (CNS), mediated through its nongenomic actions on several neurotransmitter systems, increasing neuronal excitability, modulating neuronal plasticity and presenting neuroprotective properties. It has been demonstrated that DHEA is a potent modulator of GABA(A), NMDA and Sigma receptors. In the present study, we investigated the effect of DHEA on (i) basal- and K(+)-stimulated l-[(3)H]glutamate release from synaptosomes (both in vitro and ex vivo), (ii) synaptosomal l-[(3)H]glutamate uptake (in vitro), and (iii) an inhibitory avoidance task (in vivo). The results indicated that DHEA in vitro increased glutamate release by 57%, and its intracerebroventricular infusion increased the basal-[(3)H]glutamate release by 15%. After 30 min of intraperitoneal administration, DHEA levels in the serum or CSF increased 33 and 21 times, respectively. Additionally, DHEA, intraperitoneally administrated 30 min before training, improved memory for inhibitory avoidance task. Concluding, DHEA could improve memory on an inhibitory avoidance task, perhaps due to its ability to physiologically strength the glutamatergic tonus by increasing glutamate release.

  3. Residential Mobility, Inhibitory Control, and Academic Achievement in Preschool

    Science.gov (United States)

    Schmitt, Sara A.; Finders, Jennifer K.; McClelland, Megan M.

    2015-01-01

    Research Findings: The present study investigated the direct effects of residential mobility on children's inhibitory control and academic achievement during the preschool year. It also explored fall inhibitory control and academic skills as mediators linking residential mobility and spring achievement. Participants included 359 preschool…

  4. Inhibitory Control Predicts Language Switching Performance in Trilingual Speech Production

    Science.gov (United States)

    Linck, Jared A.; Schwieter, John W.; Sunderman, Gretchen

    2012-01-01

    This study investigated the role of domain-general inhibitory control in trilingual speech production. Taking an individual differences approach, we examined the relationship between performance on a non-linguistic measure of inhibitory control (the Simon task) and a multilingual language switching task for a group of fifty-six native English (L1)…

  5. Remodeling of inhibitory synaptic connections in developing ferret visual cortex

    Directory of Open Access Journals (Sweden)

    Dalva Matthew B

    2010-02-01

    Full Text Available Abstract Background In the visual cortex, as in many other regions of the developing brain, excitatory synaptic connections undergo substantial remodeling during development. While evidence suggests that local inhibitory synapses may behave similarly, the extent and mechanisms that mediate remodeling of inhibitory connections are not well understood. Results Using scanning laser photostimulation in slices of developing ferret visual cortex, we assessed the overall patterns of developing inhibitory and excitatory synaptic connections converging onto individual neurons. Inhibitory synaptic inputs onto pyramidal neurons in cortical layers 2 and 3 were already present as early as postnatal day 20, well before eye opening, and originated from regions close to the recorded neurons. During the ensuing 2 weeks, the numbers of synaptic inputs increased, with the numbers of inhibitory (and excitatory synaptic inputs peaking near the time of eye opening. The pattern of inhibitory inputs refined rapidly prior to the refinement of excitatory inputs. By uncaging the neurotransmtter GABA in brain slices from animals of different ages, we find that this rapid refinement correlated with a loss of excitatory activity by GABA. Conclusion Inhibitory synapses, like excitatory synapses, undergo significant postnatal remodeling. The time course of the remodeling of inhibitory connections correlates with the emergence of orientation tuning in the visual cortex, implicating these rearrangements in the genesis of adult cortical response properties.

  6. [Preliminary study on the pharmacological action spicatus].

    Science.gov (United States)

    Gai, H; Shou, Y; Wang, J; Li, L

    1997-01-01

    In this report the pharmacological action of Spicatus was studied. The results insicated that it had diureric, antibiotic and anti-inflammatory effects, yet had Iittle toxic side-effect. It had significant inhibitory effect on crofon oil-caused mice ear swell. It also had marked diuretic effect in orcinary rats, but had Iittie effect on uric pH the rats. It exhibited certain inhibition of Staphycoloccus aureus, Eschrichia coli and Pseudomonas aeruginosa in vitro. The maximum tolerable dose test in mice showed no marked toxic effect, LD50 > 80 g/kg.

  7. Dual symmetry in a generalized Maxwell theory

    CERN Document Server

    Brandt, F T; McKeon, D G C

    2016-01-01

    We examine Podolsky's electrodynamics, which is noninvariant under the usual duality transformation. We deduce a generalization of Hodge's star duality, which leads to a dual gauge field and restores to a certain extent the dual symmetry. The model becomes fully dual symmetric asymptotically when it reduces to the Maxwell theory. We argue that this strict dual symmetry directly implies the existence of the basic invariants of the electromagnetic fields.

  8. Dual of QCD with One Adjoint Fermion

    CERN Document Server

    Mojaza, Matin; Pica, Claudio; Sannino, Francesco

    2011-01-01

    We construct the magnetic dual of QCD with one adjoint Weyl fermion. The dual is a consistent solution of the 't Hooft anomaly matching conditions, allows for flavor decoupling and remarkably constitutes the first nonsupersymmetric dual valid for any number of colors. The dual allows to bound the anomalous dimension of the Dirac fermion mass operator to be less than one in the conformal window.

  9. Holographic complexity and two identities of action growth

    Science.gov (United States)

    Huang, Hyat; Feng, Xing-Hui; Lü, H.

    2017-06-01

    The recently proposed complexity-action conjecture allows one to calculate how fast one can produce a quantum state from a reference state in terms of the on-shell action of the dual AdS black hole at the Wheeler-DeWitt patch. We show that the action growth rate is given by the difference of the generalized enthalpy between the two corresponding horizons. The proof relies on the second identity that the surface-term contribution on a horizon is given by the product of the associated temperature and entropy.

  10. Experimental evidence for a dual pathway model analysis of coping with the climate crisis

    NARCIS (Netherlands)

    van Zomeren, Martijn; Spears, Russell; Leach, Colinn Wayne

    2010-01-01

    Two experiments examined the psychological power of fear and group efficacy beliefs to increase environmental action intentions against the climate crisis Extending a dual pathway model of coping with collective disadvantage results showed evidence for emotion-focused approach coping Environmental a

  11. Cognitive and Neural Determinants of Response Strategy in the Dual-Solution Plus-Maze Task

    Science.gov (United States)

    De Leonibus, Elvira; Costantini, Vivian J. A.; Massaro, Antonio; Mandolesi, Georgia; Vanni, Valentina; Luvisetto, Siro; Pavone, Flaminia; Oliverio, Alberto; Mele, Andrea

    2011-01-01

    Response strategy in the dual-solution plus maze is regarded as a form of stimulus-response learning. In this study, by using an outcome devaluation procedure, we show that it can be based on both action-outcome and stimulus-response habit learning, depending on the amount of training that the animals receive. Furthermore, we show that…

  12. Executive functioning in preschoolers: reducing the inhibitory demands of the dimensional change card sort task.

    Science.gov (United States)

    Rennie, David A C; Bull, Rebecca; Diamond, Adele

    2004-01-01

    To investigate the role of inhibitory control in preschoolers' ability to switch sets, 3 conditions of the Dimensional Change Card Sort task ( Zelazo, Reznick, & Pinon, 1995) were tested. In Condition B (novel response options, standard stimuli) action inhibition was reduced, but the need for attentional inhibition was maintained. In Condition C (novel stimuli, standard response options) demands on both action and attentional inhibition were reduced. Performance in these was compared to that in the standard condition (A). Rule complexity was comparable across conditions. All 21 children who passed preswitch (average age 37 months) were tested on all postswitch conditions, order counterbalanced. Although reducing demands on action inhibition (Condition B) did not significantly improve performance, when demands on both action and attentional inhibition were reduced (Condition C) almost all children (95%) successfully switched sets (even children only 2 1/2 years old). Inadequate inhibition (of attention alone or both attention and action) appears sufficient to account for virtually all errors by preschoolers on this card sorting task.

  13. Inhibitory effect of cyanide on wastewater nitrification ...

    Science.gov (United States)

    The effect of CN- (CN-) on nitrification was examined with samples from nitrifying wastewater enrichments using two different approaches: by measuring substrate (ammonia) specific oxygen uptake rates (SOUR), and by using RT-qPCR to quantify the transcripts of functional genes involved in nitrification. The nitrifying bioreactor was operated as a continuous reactor with a 24 h hydraulic retention time. The samples were exposed in batch vessels to cyanide for a period of 12 h. The concentrations of CN- used in the batch assays were 0.03, 0.06, 0.1 and 1.0 mg/L. There was considerable decrease in SOUR with increasing dosages of CN-. A decrease of more than 50% in nitrification activity was observed at 0.1 mg/L CN-. Based on the RT-qPCR data, there was notable reduction in the transcript levels of amoA and hao for increasing CN- dosage, which corresponded well with the ammonia oxidation activity measured via SOUR. The inhibitory effect of cyanide may be attributed to the affinity of cyanide to bind ferric heme proteins, which disrupt protein structure and function. The correspondence between the relative expression of functional genes and SOUR shown in this study demonstrates the efficacy of RNA based function-specific assays for better understanding of the effect of toxic compounds on nitrification activity in wastewater. Nitrification is the first step of nitrogen removal is wastewater, and it is susceptible to inhibition by many industrial chemical. We looked at

  14. Angiogenesis is inhibitory for mammalian digit regeneration.

    Science.gov (United States)

    Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D; Leininger, Eric; Han, Manjong; Muneoka, Ken

    2014-06-01

    The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti-angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551-559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium-derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration.

  15. Structural studies on leukaemia inhibitory factor

    Energy Technology Data Exchange (ETDEWEB)

    Norton, R.S.; Maurer, T.; Smith, D.K. [Biomolecular Research Institute, Parville (Australia); Nicola, N.A. [Institute of Medical Research, Melbourne (Australia)

    1994-12-01

    Leukaemia Inhibitory Factor (LIF) is a pleiotropic cytokine that acts on a wide range of target cells, including mega-karyocytes, osteoblasts, hepatocytes, adipocytes, neurons, embryonic stem cells, and primordial germ cells. Many of its activities are shared with other cytokines, particularly interleukin-6, oncostatin-M, ciliary neurotrophic factor, and granulocyte colony-stimulating factor (G-CSF). Although secreted in vivo as a glycoprotein, nonglycosylated recombinant protein expressed in E. coli is fully active and has been used in our nuclear magnetic resonance (NMR) studies of the three-dimensional structure and structure-function relationships of LIF. With 180 amino acids and a molecular mass of about 20 kDa, OF is too large for direct structure determination by two-dimensional and three-dimensional {sup 1}HNMR. It is necessary to label the protein with the stable isotopes {sup 15}N and {sup 13}C and employ heteronuclear three-dimensional NMR in order to resolve and interpret the spectral information required for three-dimensional structure determination. This work has been undertaken with both human LIF and a mouse-human chimaera that binds to the human LIF receptor with the same affinity as the human protein and yet expresses in E. coli at much higher levels. Sequence-specific resonance assignments and secondary structure elements for these proteins will be presented and progress towards determination of their three-dimensional structures described.

  16. Angiogenesis is inhibitory for mammalian digit regeneration

    Science.gov (United States)

    Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D.; Leininger, Eric; Han, Manjong

    2014-01-01

    Abstract The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti‐angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551–559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium‐derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration. PMID:27499862

  17. Hippocampal CA1 Ripples as Inhibitory Transients.

    Directory of Open Access Journals (Sweden)

    Paola Malerba

    2016-04-01

    Full Text Available Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  18. Hippocampal CA1 Ripples as Inhibitory Transients.

    Science.gov (United States)

    Malerba, Paola; Krishnan, Giri P; Fellous, Jean-Marc; Bazhenov, Maxim

    2016-04-01

    Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  19. Monoamine oxidase inhibitory activities of heterocyclic chalcones.

    Science.gov (United States)

    Minders, Corné; Petzer, Jacobus P; Petzer, Anél; Lourens, Anna C U

    2015-11-15

    Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1-ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6-methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders.

  20. Tyrosinase inhibitory flavonoid from Juniperus communis fruits.

    Science.gov (United States)

    Jegal, Jonghwan; Park, Sang-A; Chung, KiWung; Chung, Hae Young; Lee, Jaewon; Jeong, Eun Ju; Kim, Ki Hyun; Yang, Min Hye

    2016-12-01

    The fruits of Juniperus communis have been traditionally used in the treatment of skin diseases. In our preliminary experiment, the MeOH extract of J. communis effectively suppressed mushroom tyrosinase activity. Three monoflavonoids and five biflavonoids were isolated from J. communis by bioassay-guided isolation and their inhibitory effect against tyrosinase was evaluated. According to the results of all isolates, hypolaetin 7-O-β-xylopyranoside isolated from J. communis exhibited most potent effect of decreasing mushroom tyrosinase activity with an IC50 value of 45.15 μM. Further study provided direct experimental evidence for hypolaetin 7-O-β-D-xylopyranoside-attenuated tyrosinase activity in α-MSH-stimulated B16F10 murine melanoma cell. Hypolaetin 7-O-β-D-xylopyranoside from the EtOAc fraction of J. communis was also effective at suppressing α-MSH-induced melanin synthesis. This is the first report of the enzyme tyrosinase inhibition by J. communis and its constituent. Therapeutic attempts with J. communis and its active component, hypolaetin 7-O-β-D-xylopyranoside, might be useful in treating melanin pigmentary disorders.

  1. Dual Enrollment for High School Students

    Science.gov (United States)

    Edwards, Linsey; Hughes, Katherine

    2011-01-01

    Dual enrollment programs allow high school students to enroll in college courses and potentially earn college credit. The term concurrent enrollment is sometimes used interchangeably with dual enrollment, and sometimes to refer to a particular model of dual enrollment. In some programs, students earn high school and college credit simultaneously;…

  2. Dual Enrollment in Spanish: One Working Model

    Science.gov (United States)

    Bloom, Melanie; Chambers, Laura

    2009-01-01

    Dual enrollment is now a nation-wide phenomenon as all 50 states currently offer some form of dual-enrollment program to secondary-school students (Karp, Bailey, Hughes, and Fermin 2005). However, dual enrollment itself is often difficult to define as programs vary from school to school (Jordan, Cavalluzzo, and Corallo 2006). Therefore, language…

  3. Sparsity and spectral properties of dual frames

    DEFF Research Database (Denmark)

    Krahmer, Felix; Kutyniok, Gitta; Lemvig, Jakob

    2013-01-01

    We study sparsity and spectral properties of dual frames of a given finite frame. We show that any finite frame has a dual with no more than $n^2$ non-vanishing entries, where $n$ denotes the ambient dimension, and that for most frames no sparser dual is possible. Moreover, we derive an expressio...

  4. Dual Enrollment in Spanish: One Working Model

    Science.gov (United States)

    Bloom, Melanie; Chambers, Laura

    2009-01-01

    Dual enrollment is now a nation-wide phenomenon as all 50 states currently offer some form of dual-enrollment program to secondary-school students (Karp, Bailey, Hughes, and Fermin 2005). However, dual enrollment itself is often difficult to define as programs vary from school to school (Jordan, Cavalluzzo, and Corallo 2006). Therefore, language…

  5. Pairs of dual periodic frames

    DEFF Research Database (Denmark)

    Christensen, Ole; Goh, Say Song

    2012-01-01

    is needed. The purpose of the present paper is to provide constructions of dual pairs of frames in the setting of the Hilbert space of periodic functions L2(0,2π). The frames constructed are given explicitly as trigonometric polynomials, which allows for an efficient calculation of the coefficients...

  6. Design of dual pressure regulator

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Soo; Kim, Kang Dae; Kim, Myoung Sub [Korea Institute of Machinery and Materials, Daejeon (Korea, Republic of)

    2008-07-01

    In this paper, we designed sandwich type pressure regulator for air pressure control system. As a result of research, we obtained several important conclusions. First, we decided theory of poppet valve and relief valve which are used in sandwich type pressure regulator, and then designed prototype of pressure regulator. Second, we organized circuit diagram of dual pressure regulator of air pressure control system.

  7. Dual Processing and Diagnostic Errors

    Science.gov (United States)

    Norman, Geoff

    2009-01-01

    In this paper, I review evidence from two theories in psychology relevant to diagnosis and diagnostic errors. "Dual Process" theories of thinking, frequently mentioned with respect to diagnostic error, propose that categorization decisions can be made with either a fast, unconscious, contextual process called System 1 or a slow, analytical,…

  8. Physical Health and Dual Diagnosis

    OpenAIRE

    Robson, Debbie; Keen, Sarah; Mauro, Pia

    2008-01-01

    The physical health of people with mental illness may be neglected for a variety of reasons. This paper looks at the common physical health problems experienced by people with a dual diagnosis of substance misuse and serious mental illness, and suggests ways of assessing and managing them.

  9. Dual Roles of IL-27 in Cancer Biology and Immunotherapy

    Science.gov (United States)

    Fabbi, Marina; Carbotti, Grazia

    2017-01-01

    IL-27 is a pleiotropic two-chain cytokine, composed of EBI3 and IL-27p28 subunits, which is structurally related to both IL-12 and IL-6 cytokine families. IL-27 acts through a heterodimer receptor consisting of IL-27Rα (WSX1) and gp130 chains, which mediate signaling predominantly through STAT1 and STAT3. IL-27 was initially reported as an immune-enhancing cytokine that supports CD4+ T cell proliferation, T helper (Th)1 cell differentiation, and IFN-γ production, acting in concert with IL-12. However, subsequent studies demonstrated that IL-27 displays complex immune-regulatory functions, which may result in either proinflammatory or anti-inflammatory effects in relationship to the biological context and experimental models considered. Several pieces of evidence, obtained in preclinical tumor models, indicated that IL-27 has a potent antitumor activity, related not only to the induction of tumor-specific Th1 and cytotoxic T lymphocyte (CTL) responses but also to direct inhibitory effects on tumor cell proliferation, survival, invasiveness, and angiogenic potential. Nonetheless, given its immune-regulatory functions, the effects of IL-27 on cancer may be dual and protumor effects may also occur. Here, we will summarize IL-27 biological activities and its functional overlaps with the IFNs and discuss its dual role in tumors in the light of potential applications to cancer immunotherapy. PMID:28255204

  10. Assessment of Dual Life Stage Antiplasmodial Activity of British Seaweeds

    Directory of Open Access Journals (Sweden)

    Deniz Tasdemir

    2013-10-01

    Full Text Available Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS and liver stage (LS Plasmodium parasites. The majority (14 of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC50s around 3 μg/mL. The extracts generally had high selectivity indices (>10. Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7 cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC50 values 14.9 to 28.8 μg/mL. The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds.

  11. Privacy and dual loyalties in occupational health practice.

    Science.gov (United States)

    Heikkinen, Anne M; Wickström, Gustav J; Leino-Kilpi, Helena; Katajisto, Jouko

    2007-09-01

    This survey set out to explore occupational health professionals' courses of action with respect to privacy in a situation of dual loyalty between employees and employers. A postal questionnaire was sent to randomly selected potential respondents. The overall response rate was 64%: 140 nurses and 94 physicians returned the questionnaire. Eight imaginary cases involving an ethical dilemma of privacy were presented to the respondents. Six different courses of action were constructed within the set alternatives proposed. The study indicated that privacy as an absolute value is not in the interest of either employees or employers. It also showed that, where dual loyalty is concerned, the most valid course of action in dealing with sensitive subjects such as drug and work community problems, sexual harassment and sick leave is to rely on tripartite co-operation. If they maintain their professional independence and impartiality, health professionals are well placed to succeed in this challenging task; if not, there are bound to be severe violations of privacy.

  12. Impulsive action and motivation

    NARCIS (Netherlands)

    Frijda, N.H.

    2010-01-01

    This paper explores the way in which emotions are causal determinants of action. It argues that emotional events, as appraised by the individual, elicit changes in motive states (called states of action readiness), which in turn may (or may not) cause action. Actions can be elicited automatically,

  13. Action Research: Rethinking Lewin.

    Science.gov (United States)

    Dickens, Linda; Watkins, Karen

    1999-01-01

    Explores both historical and contemporary definitions of action research. Describes the process and goals of action research in the tradition of Lewin. Presents a case study of an action-research project involving two teams in a high-technology corporation that depicts the process in action. (Author/CCM)

  14. Hedonic value of intentional action provides reinforcement for voluntary generation but not voluntary inhibition of action.

    Science.gov (United States)

    Parkinson, Jim; Haggard, Patrick

    2013-12-01

    Intentional inhibition refers to stopping oneself from performing an action at the last moment, a vital component of self-control. It has been suggested that intentional inhibition is associated with negative hedonic value, perhaps due to the frustration of cancelling an intended action. Here we investigate hedonic implications of the free choice to act or inhibit. Participants gave aesthetic ratings of arbitrary visual stimuli that immediately followed voluntary decisions to act or to inhibit action. We found that participants for whom decisions to act produced a strong positive hedonic value for the immediately following visual stimulus made more choices to act than those with weaker hedonic value for action. This finding is consistent with reinforcement learning of action decisions. However, participants who experienced inhibition as generating more positive hedonic value did not choose to inhibit more than other participants. Thus, voluntary inhibition of action did not act as reinforcement for future inhibitory behaviour. Our finding that inhibition of action lacks motivational capacity may explain why self-control is both difficult and limited.

  15. Physicochemical basis for the inhibitory effects of organic and inorganic salts on the growth of Pectobacterium carotovorum subsp. carotovorum and Pectobacterium atrosepticum.

    Science.gov (United States)

    Yaganza, Elian-Simplice; Tweddell, Russell J; Arul, Joseph

    2009-03-01

    Twenty-one salts were tested for their effects on the growth of Pectobacterium carotovorum subsp. carotovorum and Pectobacterium atrosepticum. In liquid medium, 11 salts (0.2 M) exhibited strong inhibition of bacterial growth. The inhibitory action of salts relates to the water-ionizing capacity and the lipophilicity of their constituent ions.

  16. Physicochemical Basis for the Inhibitory Effects of Organic and Inorganic Salts on the Growth of Pectobacterium carotovorum subsp. carotovorum and Pectobacterium atrosepticum▿

    OpenAIRE

    Yaganza, Elian-Simplice; Tweddell, Russell J.; Arul, Joseph

    2008-01-01

    Twenty-one salts were tested for their effects on the growth of Pectobacterium carotovorum subsp. carotovorum and Pectobacterium atrosepticum. In liquid medium, 11 salts (0.2 M) exhibited strong inhibition of bacterial growth. The inhibitory action of salts relates to the water-ionizing capacity and the lipophilicity of their constituent ions.

  17. ADHD的抑制缺陷和厌恶延迟——来自双通道模型的解释%The Inhibition Deficit and Delay Aversion of Attention Deficit Hyperactivity Disorder:the Explanation from the Dual Pathway Model

    Institute of Scientific and Technical Information of China (English)

    何梅; 张微; 宋红艳

    2012-01-01

    Historically,there have been difficulties in precisely specifying the symptom structure of ADHD because of the heterogeneity and the close associations with other problems of childhood.A number of important theories have been proposed to explain the psychological mechanisms of ADHD.The behavioral inhibition theory regards disinhibition as the core deficit of ADHD,but Sonuga-Barke's delay aversion theory deems that delayed aversion contributes to the nature of ADHD.Delayed aversion cannot explain all the symptoms of ADHD,so Sonuga-Barke modified his theory and proposed the dual pathway model of ADHD.According the dual pathway theory, psychological accounts have characterized attention-deficit/hyperactivity disorder(ADHD) as either a neuro-cognitive disorder of regulation or a motivational style.Poor inhibitory control is thought to underpin ADHD children's dysregulation while delay aversion is a dominant characteristic of their motivational style.Delayed aversion and poor inhibitory control are independent co-existing characteristics of ADHD.Sonuga-Barkes dual pathway model of ADHD recognizes two quite distinct subtypes of the disorder.The DTAP pathway emphasizes the defective inhibitory control of ADHD.ADHD is the result of the dysregulation of action and thought resulting from poor inhibitory control.And the inhibitory control is associated with the meso-cortical branch of the dopamine system projecting in the cortical control centers.The MSP pathway emphasizes that the abnormality of the reward circuit causes the stronger delayed aversion.ADHD is a motivational style characterized by an altered delay of reward gradient linked to the meso-limbic dopamine branch associated with the reward circuits.The two pathways are further distinguished at the levels of symptoms,cognitive and motivation profiles and genetic and non-genetic origins.This article introduces the empirical researches,diagnosis and intervention and the limitation related to the dual pathway theory.%

  18. A comparison about the inhibitory effect of curcunmin and Avastin on the rat corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Yi Wu

    2013-06-01

    Full Text Available AIM: To compare the inhibitory effect of curcunmin and Avastin on the rat corneal neovascularization(CNV, and approach the mechanism of the curcunmin's inhibition. METHODS: CNV was established in thirty SD rats by alkaline burning. Rats were divided equally to group A and group B at random. In group A, right eyes were experimental group A1, treated by 40μmol/L curcunmin solution, and left eyes were control group A2, treated by 0.09% sodium chloride. In group B, right eyes were experimental group group B1, treated by 5g/L avastin, and left eyes were control group B2, treated by 0.09% sodium chloride. Cornea and aqueous humor were collected by time spot. The capillary vessels were study, and the expressions of VEGF were detected by Enzyme-Linked immunosorbnent Assay(ELISA. RESULTS: No toxic effects of the drugs were found. The capillary vessels in experimental group were less than those of control group(P<0.01. No statistical different of the capillary vessels between two drugs were found. The expressions of VEGF in experimental group were less than those in control group(P<0.01. The expressions of VEGF in B1 group were less than in group A1. CONCLUSION: The inhibitory effect to CNV of curcunmin and avastin have no statistical different in the experiment, but curcunmin has the less inhibitory effect to the expressions of VEGF than avastin. Curcunmin may have other mechanism in the inhibitory action on CNV.

  19. Multiplicative gain modulation arising from inhibitory synaptic plasticity in the cerebellar nuclei

    Directory of Open Access Journals (Sweden)

    Dimitris Bampasakis

    2014-03-01

    Full Text Available Neurons use the rate of action potentials to encode sensory variables. This makes the output rate as a function of input, also known as input-output (I–O relationship, a core computational function in neuronal processing. The introduction, or increase, of a modulatory input, can transform this function in multiple ways: additive transformations result in a shift, and multiplicative transformations in a change of slope of the I–O relationship. This slope change is known as gain modulation, and it can implement important forms of neural computation such as coordinate transformations. Gain modulation can be found in a wide range of brain systems, including the cerebellum, where it can be enabled by synaptic plasticity at both excitatory and inhibitory synapses. We use a realistic, conductance based, multi-compartmental model of a cerebellar nucleus (CN neuron, to investigate the determinants of gain modulation mediated by synaptic plasticity. In particular, we are interested in the effect of short term depression (STD at the inhibitory synapse from Purkinje cells (PCs to CN neurons. Considering the inhibitory PC input as the driving input, we compare the I–O relationship of the CN neuron in the presence and absence of STD for 20 Hz of excitatory synaptic input from mossy fibers (MFs, and find that STD introduces a gain change, changing the slope of the I–O function. We then proceed to compare the transformation performed by the increase of the modulatory input from 20 to 50 Hz, in the presence and absence of STD. We find that the presence of STD in the inhibitory synapse introduces a multiplicative component in the transformation performed by the excitatory input, an effect that persists for different levels of STD, and various combinations of regularity and synchronicity in the input.

  20. The effect of attention to distractor on inhibitory processes in selective attention

    Institute of Scientific and Technical Information of China (English)

    GENG Haiyan; SONG Qianlan; LI Yunfeng; ZHU Ying

    2005-01-01

    Selective attention has been viewed as a dualprocess mechanism, that is, exciting targets and inhibiting distractors. Most early studies concentrated mainly on the target-excitation, whereas recent investigations began to pay more attention to the inhibitory selective attention mechanism. A measure named negative priming (NP) was extensively employed to probe into the inhibitory processes. The Houghton and Tipper Model put forward a notion: the inhibition that feeds back to the distractor is reactive. That means, the level of inhibition is determined by the activation state of the distractor. Distractors that are more salient and intrude into the control of action receive greater inhibitory feedbacks than less salient distractors. Because increasing attention to an object would enhance the early processing of this object, we thus hypothesized that augmenting the level of attention to a distractor might lead to a higher level of inhibition, revealed as a corresponding augmentation in the magnitude of NP effect. To test this assumption, an object- based identification task was then applied, and participants were asked to make the animate/inanimate categorization. Attention level was manipulated by varying the relative spatial locations of target and distractor (overlapped or separated). A reliable greater NP effect was found in the overlapped than separated condition, indicating that distractors under the high-level attention condition (overlapped) got greater initial excitation, and then evoked greater subsequent inhibitory feedbacks, therefore resulting in a larger NP effect. These results provide direct evidence for the reactive inhibition suggested by the Houghton and Tipper model. Meanwhile a coincident greater positive priming (PP) effect was obtained under the overlapped than separated condition, which could be attributed to the higher level of target activation in the overlapped condition. The covariation of NP and PP effects further confirmed that the way of

  1. Inseparability of Go and Stop in Inhibitory Control: Go Stimulus Discriminability Affects Stopping Behavior

    Directory of Open Access Journals (Sweden)

    Ning eMa

    2016-03-01

    Full Text Available Inhibitory control, the ability to stop or modify preplanned actions under changing task conditions, is an important component of cognitive functions. Two lines of models of inhibitory control have previously been proposed for human response in the classical stop-signal task, in which subjects must inhibit a default go response upon presentation of an infrequent stop signal: (1 the race model, which posits two independent go and stop processes that race to determine the behavioral outcome, go or stop; and (2 an optimal decision-making model, which posits that observers decides whether and when to go based on continually (Bayesian updated information about both the go and stop stimuli. In this work, we probe the relationship between go and stop processing by explicitly manipulating the discrimination difficulty of the go stimulus. While the race model assumes the go and stop processes are independent, and therefore go stimulus discriminability should not affect the stop stimulus processing, we simulate the optimal model to show that it predicts harder go discrimination results in a longer go reaction time (RT, a lower stop error rate, as well as a faster stop-signal RT. We then present novel behavioral data that validate these model predictions. The results thus favor a fundamentally inseparable account of go and stop processing, in a manner consistent with the optimal model, and contradicting the independence assumption of the race model. More broadly, our findings contribute to the growing evidence that the computations underlying inhibitory control are systematically modulated by cognitive influences in a Bayes-optimal manner, thus opening new avenues for interpreting neural responses underlying inhibitory control.

  2. Inseparability of Go and Stop in Inhibitory Control: Go Stimulus Discriminability Affects Stopping Behavior.

    Science.gov (United States)

    Ma, Ning; Yu, Angela J

    2016-01-01

    Inhibitory control, the ability to stop or modify preplanned actions under changing task conditions, is an important component of cognitive functions. Two lines of models of inhibitory control have previously been proposed for human response in the classical stop-signal task, in which subjects must inhibit a default go response upon presentation of an infrequent stop signal: (1) the race model, which posits two independent go and stop processes that race to determine the behavioral outcome, go or stop; and (2) an optimal decision-making model, which posits that observers decides whether and when to go based on continually (Bayesian) updated information about both the go and stop stimuli. In this work, we probe the relationship between go and stop processing by explicitly manipulating the discrimination difficulty of the go stimulus. While the race model assumes the go and stop processes are independent, and therefore go stimulus discriminability should not affect the stop stimulus processing, we simulate the optimal model to show that it predicts harder go discrimination should result in longer go reaction time (RT), lower stop error rate, as well as faster stop-signal RT. We then present novel behavioral data that validate these model predictions. The results thus favor a fundamentally inseparable account of go and stop processing, in a manner consistent with the optimal model, and contradicting the independence assumption of the race model. More broadly, our findings contribute to the growing evidence that the computations underlying inhibitory control are systematically modulated by cognitive influences in a Bayes-optimal manner, thus opening new avenues for interpreting neural responses underlying inhibitory control.

  3. Hybrid Action Systems

    DEFF Research Database (Denmark)

    Rönnkö, M.; Ravn, Anders Peter; Sere, K.

    2003-01-01

    In this paper we investigate the use of action systems with differential actions in the specifcation of hybrid systems. As the main contribution we generalize the definition of a differential action, allowing the use of arbitrary relations over model variables and their time-derivatives in modell......In this paper we investigate the use of action systems with differential actions in the specifcation of hybrid systems. As the main contribution we generalize the definition of a differential action, allowing the use of arbitrary relations over model variables and their time...... parallel composition. Moreover, as the strength of the action system formalism is the support for stepwise development by refinement, we investigate refinement involving a differential action. We show that, due to the predicate transformer semantics, standard action refinement techniques apply also...... to the differential action, thus, allowing stepwise development of hybrid systems Udgivelsesdato: JAN 1...

  4. Zinc enhances the inhibitory effects of strychnine-sensitive glycine receptors in mouse hippocampal neurons.

    Science.gov (United States)

    Zhang, Hai Xia; Thio, Liu Lin

    2007-12-01

    Although extracellular Zn(2+) is an endogenous biphasic modulator of strychnine-sensitive glycine receptors (GlyRs), the physiological significance of this modulation remains poorly understood. Zn(2+) modulation of GlyR may be especially important in the hippocampus where presynaptic Zn(2+) is abundant. Using cultured embryonic mouse hippocampal neurons, we examined whether 1 microM Zn(2+), a potentiating concentration, enhances the inhibitory effects of GlyRs activated by sustained glycine applications. Sustained 20 microM glycine (EC(25)) applications alone did not decrease the number of action potentials evoked by depolarizing steps, but they did in 1 microM Zn(2+). At least part of this effect resulted from Zn(2+) enhancing the GlyR-induced decrease in input resistance. Sustained 20 microM glycine applications alone did not alter neuronal bursting, a form of hyperexcitability induced by omitting extracellular Mg(2+). However, sustained 20 microM glycine applications depressed neuronal bursting in 1 microM Zn(2+). Zn(2+) did not enhance the inhibitory effects of sustained 60 microM glycine (EC(70)) applications in these paradigms. These results suggest that tonic GlyR activation could decrease neuronal excitability. To test this possibility, we examined the effect of the GlyR antagonist strychnine and the Zn(2+) chelator tricine on action potential firing by CA1 pyramidal neurons in mouse hippocampal slices. Co-applying strychnine and tricine slightly but significantly increased the number of action potentials fired during a depolarizing current step and decreased the rheobase for action potential firing. Thus Zn(2+) may modulate neuronal excitability normally and in pathological conditions such as seizures by potentiating GlyRs tonically activated by low agonist concentrations.

  5. Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions with Efavirenz Involving Simultaneous Inducing and Inhibitory Effects on Cytochromes.

    Science.gov (United States)

    Marzolini, Catia; Rajoli, Rajith; Battegay, Manuel; Elzi, Luigia; Back, David; Siccardi, Marco

    2017-04-01

    Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug-concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data. The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism. PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.

  6. Hybrid Action Systems

    DEFF Research Database (Denmark)

    Ronkko, Mauno; Ravn, Anders P.

    1997-01-01

    a differential action, which allows differential equations as primitive actions. The extension allows us to model hybrid systems with both continuous and discrete behaviour. The main result of this paper is an extension of such a hybrid action system with parallel composition. The extension does not change...... the original meaning of the parallel composition, and therefore also the ordinary action systems can be composed in parallel with the hybrid action systems....

  7. Inhibitory neuron and hippocampal circuit dysfunction in an aged mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Anupam Hazra

    Full Text Available In Alzheimer's disease (AD, a decline in explicit memory is one of the earliest signs of disease and is associated with hippocampal dysfunction. Amyloid protein exerts a disruptive impact on neuronal function, but the specific effects on hippocampal network activity are not well known. In this study, fast voltage-sensitive dye imaging and extracellular and whole-cell electrophysiology were used on entorhinal cortical-hippocampal slice preparations to characterize hippocampal network activity in 12-16 month old female APPswe/PSEN1DeltaE9 (APdE9 mice mice. Aged APdE9 mice exhibited profound disruptions in dentate gyrus circuit activation. High frequency stimulation of the perforant pathway in the dentate gyrus (DG area of APdE9 mouse tissue evoked abnormally large field potential responses corresponding to the wider neural activation maps. Whole-cell patch clamp recordings of the identified inhibitory interneurons in the molecular layer of DG revealed that they fail to reliably fire action potentials. Taken together, abnormal DG excitability and an inhibitory neuron failure to generate action potentials are suggested to be important contributors to the underlying cellular mechanisms of early-stage Alzheimer's disease pathophysiology.

  8. Tuned Inhibitory Responses in Binocular Natural Images

    Directory of Open Access Journals (Sweden)

    R Goutcher

    2013-10-01

    Full Text Available Binocular neurons in primary visual cortex are typically categorised as either Near, Far, Tuned Excitatory (TE or Tuned Inhibitory (TI cells (Poggio & Fischer, 1977, J. Neurophysiol., 40, 1392-1405. Both TI and TE responses may be approximated through differing arrangements of the binocular energy model (Ohzawa, De Angelis & Freeman, 1990, Science, 249, 1037-1041, with TE neurons responding to instances of binocular correlation, and TI neurons responding to a lack of correlation. Differences in the inter-ocular phase or position of receptive fields allow model TE cells to be used for the measurement of binocular disparity. Previous research (Hibbard, 2008, Vision Research, 48, 1427-1439 has examined the responses of these disparity tuned TE neurons to binocular natural images. However, the responses of TI neurons to such images are not clear. We examined these TI responses for a set of binocular natural images, and compared them to responses for random-dot stereograms (RDSs. TI neuron responses were modelled by placing left and right eye receptive fields in anti-phase arrangement. In addition, TI responses were normalised by monocular energy. This provides a response with a range of ±1, with a value of +1 indicating that two image regions are anti-correlated. TI responses were generally negative for both RDSs and natural images. For binocular natural images, positive TI responses were found for a small proportion of units. Typically, positive TI responses were found when monocular energy was low, occurred across all orientation channels, and increased in prevalence at lower spatial frequencies. Positive responses were clustered around object edges, suggesting a functional role for TI neurons in the detection of depth boundaries.

  9. Holographic Model of Dual Superconductor for Quark Confinement

    CERN Document Server

    Huang, Tsung-Sheng

    2016-01-01

    We show that a hairy black hole solution can provide a holographically dual description of quark confinement. There exists a one-parameter sensible metric which receives the backreaction of matter contents in the holographic action, where the scalar and gauge field are responsible for the condensation of chromomagnetic monopoles. This model features a preconfining phase triggered by second-order monopole condensation and a first-order confinement/deconfinement phase transition. To confirm the confinement, the quark-antiquark potential is calculated by probing a QCD string in both phases. At last, contribution from Kaluza-Klein monopoles in the confining phase is discussed.

  10. Design of dual DC motor control system based on DSP

    Science.gov (United States)

    Shi, Peicheng; Wang, Suo; Xu, Zengwei; Xiao, Ping

    2017-08-01

    Multi-motor control systems are widely used in actual production and life, such as lifting stages, robots, printing systems. This paper through serial communication between PC and DSP, dual DC motor control system consisting of PC as the host computer, DSP as the lower computer with synchronous PWM speed regulation, commutation and selection functions is designed. It sends digital control instructions with host computer serial debugger to lower computer, to instruct the motor to complete corresponding actions. The hardware and software design of the control system are given, and feasibility and validity of the control system are verified by experiments. The expected design goal is achieved.

  11. Simultaneous Control of Phenanthrene and Drought by Dual Exposure System

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Holmstrup, Martin; Damgaard, Christian;

    2014-01-01

    and independent control of chemical and drought exposure in bioassays with terrestrial organisms: Passive dosing from silicone controlled the chemical activity of phenanthrene (chemical stress), while saline solutions controlled the water activity (drought stress) in the closed exposure system. The dual exposure...... system was then applied in a full factorial experiment with seven exposure levels (72), which aimed at determining the combined effects of phenanthrene and drought on the survival of the terrestrial springtail Folsomia candida after 7 d exposure. Fitting an "independent action" model to the complete data...... set revealed statistically significant synergy between phenanthrene and drought (p

  12. Inhibitory effects of antimicrobial agents against Fusarium species.

    Science.gov (United States)

    Kawakami, Hideaki; Inuzuka, Hiroko; Hori, Nobuhide; Takahashi, Nobumichi; Ishida, Kyoko; Mochizuki, Kiyofumi; Ohkusu, Kiyofumi; Muraosa, Yasunori; Watanabe, Akira; Kamei, Katsuhiko

    2015-08-01

    We investigated the inhibitory effects of antibacterial, biocidal, and antifungal agents against Fusarium spp. Seven Fusarium spp: four F. falciforme (Fusarium solani species complex), one Fusarium spp, one Fusarium spp. (Fusarium incarnatum-equiseti species complex), and one F. napiforme (Gibberella fujikuroi species complex), isolated from eyes with fungal keratitis were used in this study. Their susceptibility to antibacterial agents: flomoxef, imipenem, gatifloxacin, levofloxacin, moxifloxacin, gentamicin, tobramycin, and Tobracin® (contained 3,000 μg/ml of tobramycin and 25 μg/ml of benzalkonium chloride (BAK), a biocidal agent: BAK, and antifungal agents: amphotericin B, pimaricin (natamycin), fluconazole, itraconazole, miconazole, voriconazole, and micafungin, was determined by broth microdilution tests. The half-maximal inhibitory concentration (IC50), 100% inhibitory concentration (IC100), and minimum inhibitory concentration (MIC) against the Fusarium isolates were determined. BAK had the highest activity against the Fusarium spp. except for the antifungal agents. Three fluoroquinolones and two aminoglycosides had inhibitory effects against the Fusarium spp. at relatively high concentrations. Tobracin® had a higher inhibitory effect against Fusarium spp. than tobramycin alone. Amphotericin B had the highest inhibitory effect against the Fusarium spp, although it had different degrees of activity against each isolate. Our findings showed that fluoroquinolones, aminoglycosides, and BAK had some degree of inhibitory effect against the seven Fusarium isolates, although these agents had considerably lower effect than amphotericin B. However, the inhibitory effects of amphotericin B against the Fusarium spp. varied for the different isolates. Further studies for more effective medications against Fusarium, such as different combinations of antibacterial, biocidal, and antifungal agents are needed. © The Author 2015. Published by Oxford University Press on

  13. DAPs: Deep Action Proposals for Action Understanding

    KAUST Repository

    Escorcia, Victor

    2016-09-17

    Object proposals have contributed significantly to recent advances in object understanding in images. Inspired by the success of this approach, we introduce Deep Action Proposals (DAPs), an effective and efficient algorithm for generating temporal action proposals from long videos. We show how to take advantage of the vast capacity of deep learning models and memory cells to retrieve from untrimmed videos temporal segments, which are likely to contain actions. A comprehensive evaluation indicates that our approach outperforms previous work on a large scale action benchmark, runs at 134 FPS making it practical for large-scale scenarios, and exhibits an appealing ability to generalize, i.e. to retrieve good quality temporal proposals of actions unseen in training.

  14. Dual leadership in a hospital practice

    DEFF Research Database (Denmark)

    Thude, Bettina Ravnborg; Thomsen, Svend Erik; Stenager, Egon

    2017-01-01

    in the hospital context and develops a categorizing tool for being able to distinguish dual leadership teams from each other. It is important to reveal if there are any indicators that can be used for optimising dual leadership teams in the health-care sector and in other organisations......., this study aims to analyse three different dual leadership pairs at a Danish hospital. Furthermore, this study develops a tool to characterize dual leadership teams from each other. Design/methodology/approach This is a qualitative study using semi-structured interviews. Six leaders were interviewed...... that power balance, personal relations and decision processes are important factors for creating efficient dual leaderships. The study develops a categorizing tool to use for further research or for organizations, to describe and analyse dual leaderships. Originality/value The study describes dual leadership...

  15. Construction of action for heterotic string field theory including the Ramond sector

    Science.gov (United States)

    Goto, Keiyu; Kunitomo, Hiroshi

    2016-12-01

    Extending the formulation for open superstring field theory given in arXiv:1508.00366, we attempt to construct a complete action for heterotic string field theory. The action is non-polynomial in the Ramond string field Ψ, and we construct it order by order in Ψ. Using a dual formulation in which the role of η and Q is exchanged, the action is explicitly obtained at the quadratic and quartic order in Ψ with the gauge transformations.

  16. Construction of action for heterotic string field theory including the Ramond sector

    CERN Document Server

    Goto, Keiyu

    2016-01-01

    Extending the formulation for open superstring field theory given in arXiv:1508.00366, we attempt to construct a complete action for heterotic string field theory. The action is non-polynomial in the Ramond string field Psi, and we construct it order by order in Psi. Using a dual formulation in which the role of eta and Q is exchanged, the action is explicitly obtained at the quadratic and quartic order in Psi with the gauge transformations.

  17. Dual Mode Slotted Monopole Antenna

    Science.gov (United States)

    2017-01-05

    of 15 DUAL MODE SLOTTED MONOPOLE ANTENNA STATEMENT OF GOVERNMENT INTEREST [0001] The invention described herein may be manufactured and used by...REFERENCE TO OTHER PATENT APPLICATIONS [0002] None. BACKGROUND OF THE INVENTION (1) Field of the Invention [0003] The present invention is directed...such as this that is capable of radiating at a different frequency below this cutoff. The present invention provides a means by which the overall

  18. Dual geometries and spacetime singularities

    CERN Document Server

    Quirós, I

    2000-01-01

    The concept of geometrical duality is disscused in the context of Brans-Dicke theory and extended to general relativity. It is shown, in some generic cases, that spacetime singularities that arise in usual Riemannian general relativity, may be avoided in its dual representation: Weyl-like general relativity, thus providing a singularity-free picture of the World that is physicaly equivalent to the canonical general relativistic one.

  19. Dual arm master controller concept

    Energy Technology Data Exchange (ETDEWEB)

    Kuban, D.P.; Perkins, G.S.

    1984-01-01

    The Advanced Servomanipulator (ASM) slave was designed with an anthropomorphic stance, gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape-driven manipulators. Studies were performed which addressed the human factors design and performance trade-offs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented. 6 references, 3 figures.

  20. Orbifold E-functions of dual invertible polynomials

    Science.gov (United States)

    Ebeling, Wolfgang; Gusein-Zade, Sabir M.; Takahashi, Atsushi

    2016-08-01

    An invertible polynomial is a weighted homogeneous polynomial with the number of monomials coinciding with the number of variables and such that the weights of the variables and the quasi-degree are well defined. In the framework of the search for mirror symmetric orbifold Landau-Ginzburg models, P. Berglund and M. Henningson considered a pair (f , G) consisting of an invertible polynomial f and an abelian group G of its symmetries together with a dual pair (f ˜ , G ˜) . We consider the so-called orbifold E-function of such a pair (f , G) which is a generating function for the exponents of the monodromy action on an orbifold version of the mixed Hodge structure on the Milnor fibre of f. We prove that the orbifold E-functions of Berglund-Henningson dual pairs coincide up to a sign depending on the number of variables and a simple change of variables. The proof is based on a relation between monomials (say, elements of a monomial basis of the Milnor algebra of an invertible polynomial) and elements of the whole symmetry group of the dual polynomial.

  1. Dual Superconductivity in Abelian Higgs Model of QCD

    Science.gov (United States)

    Rajput, B. S.

    2017-04-01

    The study of generalized field associated with Abelian dyons has been undertaken and it has been demonstrated that topologically, a non-Abelian gauge theory is equivalent to a set of Abelian gauge theories supplemented by dyons which undergo condensation leading to confinement and consequently to superconducting model of QCD vacuum, where the Higgs field plays the role of a regulator only. Constructing the effective action for dyonic field in Abelian projection of QCD, it has been demonstrated that any charge (electrical or magnetic) of dyon screens its own direct potential to which it minimally couples and anti-screens the dual potential leading to dual superconductivity in accordance with generalized Meissner effect. In this Abelian projection of QCD an Abelian Higgs model (AHM) has been successfully constructed and it has been shown to incorporate dual superconductivity and confinement as the consequence of dyonic condensation. It has been demonstrated that in AHM t' Hooft loop creates the string (AHM-string) around which the monopole current under London limit leads to vanishing coherence length in the chromo-magnetic superconductor. It has also been shown that in London limit the squared density of monopole current around AHM-string has a maximum at the distance of the order of penetration length.

  2. Dual systems of speech category learning across the lifespan

    Science.gov (United States)

    Maddox, W. Todd; Chandrasekaran, Bharath; Smayda, Kirsten; Yi, Han-Gyol

    2013-01-01

    Although categorization is fundamental to speech processing, little is known about the learning systems that mediate auditory categorization and even less is known about changes across the lifespan. Vision research supports dual-learning systems that are grounded in neuroscience and are partially-dissociable. The reflective, rule-based system is prefrontally mediated and uses working memory and executive attention to develop and test rules for classifying in an explicit fashion. The reflexive, information-integration system is striatally mediated and operates by implicitly associating perception with actions that lead to reinforcement. We examine the extent to which dual-learning systems mediate auditory and speech learning in younger and older adults. We examined auditory category learning when a rule-based strategy (Experiment 1) or information-integration strategy (Experiment 2) was optimal, and found an age-related rule-based deficit, but intact information-integration learning. Experiment 3 examined natural auditory category learning, and found an age-related performance deficit. Computational modeling suggested that this was due to older adults’ persistent reliance on sub-optimal, uni-dimensional strategies when two-dimensional strategies were optimal. Working memory capacity was also found to be associated with improved rule-based and natural auditory category learning, but not information-integration category learning. These results suggest that dual-learning systems are operative in speech category learning across the lifespan, and that performance deficits, when present are due to deficiencies in frontally-mediated, rule-based processes. PMID:24364408

  3. Dual field combination for unmanned video surveillance

    Science.gov (United States)

    Sarrabezolles, Louise; Manzanera, Antoine; Hueber, Nicolas; Perrot, Maxime; Raymond, Pierre

    2017-05-01

    Unmanned systems used for threat detection and identification are still not efficient enough for monitoring autonomously the battlefield. The limitation on size and energy makes those systems unable to use most state- of-the-art computer vision algorithms for recognition. The bio-inspired approach based on the humans peripheral and foveal visions has been reported as a way to combine recognition performance and computational efficiency. As a low resolution camera observes a large zone and detects significant changes, a second camera focuses on each event and provides a high resolution image of it. While such biomimetic existing approaches usually separate the two vision modes according to their functionality (e.g. detection, recognition) and to their basic primitives (i.e. features, algorithms), our approach uses common structures and features for both peripheral and foveal cameras, thereby decreasing the computational load with respect to the previous approaches. The proposed approach is demonstrated using simulated data. The outcome proves particularly attractive for real time embedded systems, as the primitives (features and classifier) have already proven good performances in low power embedded systems. This first result reveals the high potential of dual views fusion technique in the context of long duration unmanned video surveillance systems. It also encourages us to go further into miming the mechanisms of the human eye. In particular, it is expected that adding a retro-action of the fovea towards the peripheral vision will further enhance the quality and efficiency of the detection process.

  4. Action Video Gaming and Cognitive Control: Playing First Person Shooter Games Is Associated with Improved Action Cascading but Not Inhibition.

    Science.gov (United States)

    Steenbergen, Laura; Sellaro, Roberta; Stock, Ann-Kathrin; Beste, Christian; Colzato, Lorenza S

    2015-01-01

    There is a constantly growing interest in developing efficient methods to enhance cognitive functioning and/or to ameliorate cognitive deficits. One particular line of research focuses on the possibly cognitive enhancing effects that action video game (AVG) playing may have on game players. Interestingly, AVGs, especially first person shooter games, require gamers to develop different action control strategies to rapidly react to fast moving visual and auditory stimuli, and to flexibly adapt their behaviour to the ever-changing context. This study investigated whether and to what extent experience with such videogames is associated with enhanced performance on cognitive control tasks that require similar abilities. Experienced action videogame-players (AVGPs) and individuals with little to no videogame experience (NVGPs) performed a stop-change paradigm that provides a relatively well-established diagnostic measure of action cascading and response inhibition. Replicating previous findings, AVGPs showed higher efficiency in response execution, but not improved response inhibition (i.e. inhibitory control), as compared to NVGPs. More importantly, compared to NVGPs, AVGPs showed enhanced action cascading processes when an interruption (stop) and a change towards an alternative response were required simultaneously, as well as when such a change had to occur after the completion of the stop process. Our findings suggest that playing AVGs is associated with enhanced action cascading and multi-component behaviour without affecting inhibitory control.

  5. Action Video Gaming and Cognitive Control: Playing First Person Shooter Games Is Associated with Improved Action Cascading but Not Inhibition.

    Directory of Open Access Journals (Sweden)

    Laura Steenbergen

    Full Text Available There is a constantly growing interest in developing efficient methods to enhance cognitive functioning and/or to ameliorate cognitive deficits. One particular line of research focuses on the possibly cognitive enhancing effects that action video game (AVG playing may have on game players. Interestingly, AVGs, especially first person shooter games, require gamers to develop different action control strategies to rapidly react to fast moving visual and auditory stimuli, and to flexibly adapt their behaviour to the ever-changing context. This study investigated whether and to what extent experience with such videogames is associated with enhanced performance on cognitive control tasks that require similar abilities. Experienced action videogame-players (AVGPs and individuals with little to no videogame experience (NVGPs performed a stop-change paradigm that provides a relatively well-established diagnostic measure of action cascading and response inhibition. Replicating previous findings, AVGPs showed higher efficiency in response execution, but not improved response inhibition (i.e. inhibitory control, as compared to NVGPs. More importantly, compared to NVGPs, AVGPs showed enhanced action cascading processes when an interruption (stop and a change towards an alternative response were required simultaneously, as well as when such a change had to occur after the completion of the stop process. Our findings suggest that playing AVGs is associated with enhanced action cascading and multi-component behaviour without affecting inhibitory control.

  6. Prolonged modification of action potential shape by synaptic inputs in molluscan neurones.

    Science.gov (United States)

    Winlow, W

    1985-01-01

    1. Somatic action potentials of Lymnaea neurons are modified by excitatory or inhibitory synaptic inputs and have been studied using phase-plane techniques and an action potential duration monitor. 2. Excitatory synaptic inputs increase the rate of neuronal discharge, cause action potential broadening, a decrease in the maximum rate of depolarization (Vd) and a decrease in the maximum rate of repolarization (Vr). 3. Inhibitory synaptic inputs decrease the discharge rate and cause narrowing of action potentials, an increase in Vd and an increase in Vr. 4. The effects reported above outlast the original synaptic inputs by many seconds and, if the somatic action potentials are similar to those in the axon terminals, they may have far-reaching effects on transmitter release.

  7. Dual targeting of peroxisomal proteins

    Directory of Open Access Journals (Sweden)

    Julia eAst

    2013-10-01

    Full Text Available Cellular compartmentalization into organelles serves to separate biological processes within the environment of a single cell. While some metabolic reactions are specific to a single organelle, others occur in more than one cellular compartment. Specific targeting of proteins to compartments inside of eukaryotic cells is mediated by defined sequence motifs. To achieve multiple targeting to different compartments cells use a variety of strategies. Here, we focus on mechanisms leading to dual targeting of peroxisomal proteins. In many instances, isoforms of peroxisomal proteins with distinct intracellular localization are encoded by separate genes. But also single genes can give rise to differentially localized proteins. Different isoforms can be generated by use of alternative transcriptional start sites, by differential splicing or ribosomal read-through of stop codons. In all these cases different peptide variants are produced, of which only one carries a peroxisomal targeting signal. Alternatively, peroxisomal proteins contain additional signals that compete for intracellular targeting. Dual localization of proteins residing in both the cytoplasm and in peroxisomes may also result from use of inefficient targeting signals. The recent observation that some bona fide cytoplasmic enzymes were also found in peroxisomes indicates that dual targeting of proteins to both the cytoplasm and the peroxisome might be more widespread. Although current knowledge of proteins exhibiting only partial peroxisomal targeting is far from being complete, we speculate that the metabolic capacity of peroxisomes might be larger than previously assumed.

  8. Macrophage migration inhibitory factor and autism spectrum disorders

    NARCIS (Netherlands)

    Grigorenko, Elena L.; Han, Summer S.; Yrigollen, Carolyn M.; Leng, Lin; Mizue, Yuka; Anderson, George M.; Mulder, Erik J.; de Bildt, Annelies; Minderaa, Ruud B.; Volkmar, Fred R.; Chang, Joseph T.; Bucala, Richard

    2008-01-01

    OBJECTIVE. Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage

  9. Xanthine oxidase inhibitory activity of Hungarian wild-growing mushrooms.

    Science.gov (United States)

    Ványolós, Attila; Orbán-Gyapai, Orsolya; Hohmann, Judit

    2014-08-01

    Mushrooms represent a remarkable and yet largely unexplored source of new, biologically active natural products. In this work, we report on the xanthine oxidase (XO) inhibitory activity of 47 wild-growing mushrooms native to Hungary. Aqueous and organic (n-hexane, chloroform, and 50% methanol) extracts of selected mushrooms from different families were screened for their XO inhibitory activities. Among the 188 extracts investigated, the chloroform and 50% methanol fractions proved to be the most effective. Some species exhibited high inhibitory activity, e.g., Hypholoma fasciculare (IC50  =67.76 ± 11.05 µg/mL), Suillus grevillei (IC50  =13.28 ± 1.58 µg/mL), and Tricholoma populinum (IC50  =85.08 ± 15.02 µg/mL); others demonstrated moderate or weak activity. Additional studies are warranted to characterize the compounds responsible for the XO inhibitory activity of mushroom extracts.

  10. Anisotropic loop quantum cosmology with self-dual variables

    CERN Document Server

    Wilson-Ewing, Edward

    2015-01-01

    A loop quantization of the diagonal class A Bianchi models starting from the complex-valued self-dual connection variables is presented in this paper. The basic operators in the quantum theory correspond to areas and generalized holonomies of the Ashtekar connection and the reality conditions are implemented via the choice of the inner product on the kinematical Hilbert space. The action of the Hamiltonian constraint operator is given explicitly for the case when the matter content is a massless scalar field (in which case the scalar field can be used as a relational clock), and it is shown that the big-bang and big-crunch singularities are resolved in the sense that singular and non-singular states decouple under the action of the Hamiltonian constraint operator.

  11. Anisotropic loop quantum cosmology with self-dual variables

    Science.gov (United States)

    Wilson-Ewing, Edward

    2016-04-01

    A loop quantization of the diagonal class A Bianchi models starting from the complex-valued self-dual connection variables is presented in this paper. The basic operators in the quantum theory correspond to areas and generalized holonomies of the Ashtekar connection, and the reality conditions are implemented via the choice of the inner product on the kinematical Hilbert space. The action of the Hamiltonian constraint operator is given explicitly for the case when the matter content is a massless scalar field (in which case the scalar field can be used as a relational clock), and it is shown that the big bang and big crunch singularities are resolved in the sense that singular and nonsingular states decouple under the action of the Hamiltonian constraint operator.

  12. Recovery Action Mapping Tool

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Recovery Action Mapping Tool is a web map that allows users to visually interact with and query actions that were developed to recover species listed under the...

  13. Various Actions for Pregeometry

    Science.gov (United States)

    Terazawa, H.

    1991-08-01

    Various actions for pregeometry are presented and compared. The ``space-field identity'' which equates the n-beins to the derivatives of fundamental scalars is derived from a simple action but seems to be too restrictive to be practical.

  14. Action Rules Mining

    CERN Document Server

    Dardzinska, Agnieszka

    2013-01-01

    We are surrounded by data, numerical, categorical and otherwise, which must to be analyzed and processed to convert it into information that instructs, answers or aids understanding and decision making. Data analysts in many disciplines such as business, education or medicine, are frequently asked to analyze new data sets which are often composed of numerous tables possessing different properties. They try to find completely new correlations between attributes and show new possibilities for users.   Action rules mining discusses some of data mining and knowledge discovery principles and then describe representative concepts, methods and algorithms connected with action. The author introduces the formal definition of action rule, notion of a simple association action rule and a representative action rule, the cost of association action rule, and gives a strategy how to construct simple association action rules of a lowest cost. A new approach for generating action rules from datasets with numerical attributes...

  15. Optimization of inhibitory decision rules relative to length and coverage

    KAUST Repository

    Alsolami, Fawaz

    2012-01-01

    The paper is devoted to the study of algorithms for optimization of inhibitory rules relative to the length and coverage. In contrast with usual rules that have on the right-hand side a relation "attribute ≠ value", inhibitory rules have a relation "attribute = value" on the right-hand side. The considered algorithms are based on extensions of dynamic programming. © 2012 Springer-Verlag.

  16. A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients.

    Science.gov (United States)

    Sun, Yishan; Paşca, Sergiu P; Portmann, Thomas; Goold, Carleton; Worringer, Kathleen A; Guan, Wendy; Chan, Karen C; Gai, Hui; Vogt, Daniel; Chen, Ying-Jiun J; Mao, Rong; Chan, Karrie; Rubenstein, John Lr; Madison, Daniel V; Hallmayer, Joachim; Froehlich-Santino, Wendy M; Bernstein, Jonathan A; Dolmetsch, Ricardo E

    2016-07-26

    Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons.

  17. Inhibitory Activity of Yokukansankachimpihange against Nerve Growth Factor-Induced Neurite Growth in Cultured Rat Dorsal Root Ganglion Neurons

    Directory of Open Access Journals (Sweden)

    Chiaki Murayama

    2015-08-01

    Full Text Available Chronic pruritus is a major and distressing symptom of many cutaneous diseases, however, the treatment remains a challenge in the clinic. The traditional Chinese-Japanese medicine (Kampo medicine is a conservative and increasingly popular approach to treat chronic pruritus for both patients and medical providers. Yokukansankachimpihange (YKH, a Kampo formula has been demonstrated to be effective in the treatment of itching of atopic dermatitis in Japan although its pharmacological mechanism is unknown clearly. In an attempt to clarify its pharmacological actions, in this study, we focused on the inhibitory activity of YKH against neurite growth induced with nerve growth factor (NGF in cultured rat dorsal root ganglion (DRG neurons because epidermal hyperinnervation is deeply related to itch sensitization. YKH showed approximately 200-fold inhibitory activity against NGF-induced neurite growth than that of neurotropin (positive control, a drug used clinically for treatment of chronic pruritus. Moreover, it also found that Uncaria hook, Bupleurum root and their chemical constituents rhynchophylline, hirsutine, and saikosaponin a, d showed inhibitory activities against NGF-induced neurite growth, suggesting they should mainly contribute to the inhibitory activity of YKH. Further study on the effects of YKH against epidermal nerve density in “itch-scratch” animal models is under investigation.

  18. Long-term effects of brain-derived neurotrophic factor on the frequency of inhibitory synaptic events in the rat superficial dorsal horn.

    Science.gov (United States)

    Lu, V B; Colmers, W F; Smith, P A

    2009-07-21

    Chronic constriction injury (CCI) of rat sciatic nerve produces a specific pattern of electrophysiological changes in the superficial dorsal horn that lead to central sensitization that is associated with neuropathic pain. These changes can be recapitulated in spinal cord organotypic cultures by long term (5-6 days) exposure to brain-derived neurotrophic factor (BDNF) (200 ng/ml). Certain lines of evidence suggest that both CCI and BDNF increase excitatory synaptic drive to putative excitatory neurons while reducing that to putative inhibitory interneurons. Because BDNF slows the rate of discharge of synaptically-driven action potentials in inhibitory neurons, it should also decrease the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) throughout the superficial dorsal horn. To test this possibility, we characterized superficial dorsal horn neurons in organotypic cultures according to five electrophysiological phenotypes that included tonic, delay and irregular firing neurons. Five to 6 days of treatment with 200 ng/ml BDNF decreased sIPSC frequency in tonic and irregular neurons as might be expected if BDNF selectively decreases excitatory synaptic drive to inhibitory interneurons. The frequency of sIPSCs in delay neurons was however increased. Further analysis of the action of BDNF on tetrodotoxin-resistant miniature inhibitory postsynaptic currents (mIPSC) showed that the frequency was increased in delay neurons, unchanged in tonic neurons and decreased in irregular neurons. BDNF may thus reduce action potential frequency in those inhibitory interneurons that project to tonic and irregular neurons but not in those that project to delay neurons.

  19. On Action Theory Change

    OpenAIRE

    Varzinczak, Ivan José

    2014-01-01

    As historically acknowledged in the Reasoning about Actions and Change community, intuitiveness of a logical domain description cannot be fully automated. Moreover, like any other logical theory, action theories may also evolve, and thus knowledge engineers need revision methods to help in accommodating new incoming information about the behavior of actions in an adequate manner. The present work is about changing action domain descriptions in multimodal logic. Its contribution is threefold: ...

  20. Action Theory Evolution

    OpenAIRE

    Varzinczak, Ivan

    2008-01-01

    Like any other logical theory, domain descriptions in reasoning about actions may evolve, and thus need revision methods to adequately accommodate new information about the behavior of actions. The present work is about changing action domain descriptions in propositional dynamic logic. Its contribution is threefold: first we revisit the semantics of action theory contraction that has been done in previous work, giving more robust operators that express minimal change based on a notion of dis...

  1. Identifying HIV-1 dual infections

    Directory of Open Access Journals (Sweden)

    Cornelissen Marion

    2007-09-01

    Full Text Available Abstract Transmission of human immunodeficiency virus (HIV is no exception to the phenomenon that a second, productive infection with another strain of the same virus is feasible. Experiments with RNA viruses have suggested that both coinfections (simultaneous infection with two strains of a virus and superinfections (second infection after a specific immune response to the first infecting strain has developed can result in increased fitness of the viral population. Concerns about dual infections with HIV are increasing. First, the frequent detection of superinfections seems to indicate that it will be difficult to develop a prophylactic vaccine. Second, HIV-1 superinfections have been associated with accelerated disease progression, although this is not true for all persons. In fact, superinfections have even been detected in persons controlling their HIV infections without antiretroviral therapy. Third, dual infections can give rise to recombinant viruses, which are increasingly found in the HIV-1 epidemic. Recombinants could have increased fitness over the parental strains, as in vitro models suggest, and could exhibit increased pathogenicity. Multiple drug resistant (MDR strains could recombine to produce a pan-resistant, transmittable virus. We will describe in this review what is presently known about super- and re-infection among ambient viral infections, as well as the first cases of HIV-1 superinfection, including HIV-1 triple infections. The clinical implications, the impact of the immune system, and the effect of anti-retroviral therapy will be covered, as will as the timing of HIV superinfection. The methods used to detect HIV-1 dual infections will be discussed in detail. To increase the likelihood of detecting a dual HIV-1 infection, pre-selection of patients can be done by serotyping, heteroduplex mobility assays (HMA, counting the degenerate base codes in the HIV-1 genotyping sequence, or surveying unexpected increases in the

  2. Triality and Dual Equivalence Between Dirac Field and Topologically Massive Gauge Field

    Institute of Scientific and Technical Information of China (English)

    LIU Yu-Fen

    2006-01-01

    It is proved that there exists a vector representation of Dirac's spinor field andin one sense it is equivalent to biquaternion (i.e. complexified quaternion) representation. This can be considered as a generalization of Cartan's idea of triality to Dirac's spinors. In the vector representation the first-order Dirac Lagrangian is dual-equivalent to the two-order Lagrangian of topologically massive gauge field. The potential field which corresponds to the Dirac field is obtained by using master (or parent) action approach. The novel gauge field is self-dual and contains both anti-symmetric Lee and symmetric Jordan structure.

  3. Duality equivalence between nonlinear self-dual and topologically massive models

    CERN Document Server

    Ilha, A; Ilha, Anderson; Wotzasek, Clovis

    2001-01-01

    In this report we study the dual equivalence between the generalized self-dual (SD) and topologically massive (TM) models. To this end we linearize the model using an auxiliary field and apply a gauge embedding procedure to construct a gauge equivalent model. We clearly show that, under the above conditions, a nonlinear SD model always has a duality equivalent TM action.The general result obtained is then particularized for a number of examples, including the Born-Infeld-Chern-Simons (BICS) model recently discussed in the literature.

  4. Combined action of carbenicillin and gentamicin on Pseudomonas aeruginosa in vitro.

    Science.gov (United States)

    Sonne, M; Jawetz, E

    1969-06-01

    The minimal inhibitory and minimal bactericidal concentrations of carbenicillin and gentamicin were determined for 10 strains of Pseudomonas aeruginosa isolated from the urinary tract. Combinations of the two drugs were tested for possible enhanced activity. Such enhancement was demonstrated in the inhibitory activity of combinations for eight strains. Striking bactericidal activity against five strains was achieved by the combination, whereas neither drug alone in low dosage was capable of bactericidal action. The possible mode of action and the possible merit of pursuing these preliminary findings are discussed.

  5. Action and Interactiv research

    DEFF Research Database (Denmark)

    Nielsen, Kurt Aagaard; Svensson, Lennart

    The text is written as a first version of editors introduction to a book about action research/interactive research in Nordic countries. You can read abouttrends and contradictions in the history of action research.The authors question the trends and demands a more explicit critical approach...... to actual action research/interactive research....

  6. Action Research for Democracy

    DEFF Research Database (Denmark)

    , to innovation policies combining Action Research with gender science. In the second part of the book epistemological and ontological dimensions of Action Research are discussed addressing questions of validity criteria related to Action Research, the transformation of knowledge institutions and the specific...

  7. Conservation Action Handbook.

    Science.gov (United States)

    National Rifle Association, Washington, DC.

    Conservation problems are identified, with some suggestions for action. General areas covered are: Wildlife Conservation, Soil Conservation, Clean Water, Air Pollution Action, and Outdoor Recreation Action. Appendices list private organizations or agencies concerned with natural resource use and/or management, congressional committees considering…

  8. Putting Action in Perspective

    Science.gov (United States)

    Lozano, Sandra C.; Hard, Bridgette Martin; Tversky, Barbara

    2007-01-01

    Embodied approaches to cognition propose that our own actions influence our understanding of the world. Do other people's actions also have this influence? The present studies show that perceiving another person's actions changes the way people think about objects in a scene. In Study 1, participants viewed a photograph and answered a question…

  9. Enkephalins modulate inhibitory neuromuscular transmission in circular muscle of human colon via delta-opioid receptors.

    Science.gov (United States)

    Hoyle, C H; Kamm, M A; Burnstock, G; Lennard-Jones, J E

    1990-01-01

    1. A sucrose-gap technique was used to investigate the neuromodulatory actions of enkephalins on non-adrenergic, non-cholinergic inhibitory junction potentials (IJPs) in the circular muscle of the human large intestine. 2. The native enkephalins, [Leu5]enkephalin (LENK) and [Met5]enkephalin (MENK) caused a concentration-dependent reduction in amplitude of IJPs without a significant effect on the smooth muscle membrane. 3. The actions of LENK and MENK were mimicked by the delta-selective opioid receptor agonists [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2, D-Leu5]enkephalin (DADLE). 4. The actions of LENK, MENK and DPDPE were antagonized to similar extents by the delta-selective opioid receptor antagonist ICI 174,864. 5. The mu-selective opioid receptor agonist [D-Ala2, Me Phe, Gly-ol5]enkephalin was approximately 100-fold less potent than any of the native or synthetic enkephalins at reducing the amplitude of the IJP. Dynorphin A and beta-endorphin both had very weak activity. 6. Responses to all of the agonists were inhibited by naloxone. The degree of antagonism of DPDPE or DADLE by naloxone (1 microM) was the same as that of LENK or MENK. 7. Neither MENK nor LENK affected hyperpolarization of the smooth muscle membrane induced by ATP or 5-hydroxytryptamine. Vasoactive intestinal polypeptide (1 pM-1 microM) did not produce any observable responses and this lack of reactivity was not affected by the enkephalins. 8. It is concluded that in the circular muscle of the human colon, LENK and MENK can act on prejunctional delta-opioid receptors to produce inhibition of non-adrenergic, non-cholinergic inhibitory neuromuscular transmission. Possible physiological significance of this prejunctional receptor is discussed. PMID:1966052

  10. Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells.

    Science.gov (United States)

    Einbond, Linda Saxe; Wen-Cai, Ye; He, Kan; Wu, Hsan-au; Cruz, Erica; Roller, Marc; Kronenberg, Fredi

    2008-06-01

    The purpose of this report is to explore the growth inhibitory effect of extracts and compounds from black cohosh and related Cimicifuga species on human breast cancer cells and to determine the nature of the active components. Black cohosh fractions enriched for triterpene glycosides and purified components from black cohosh and related Asian species were tested for growth inhibition of the ER(-) Her2 overexpressing human breast cancer cell line MDA-MB-453. Growth inhibitory activity was assayed using the Coulter Counter, MTT and colony formation assays. Results suggested that the growth inhibitory activity of black cohosh extracts appears to be related to their triterpene glycoside composition. The most potent Cimicifuga component tested was 25-acetyl-7,8-didehydrocimigenol 3-O-beta-d-xylopyranoside, which has an acetyl group at position C-25. It had an IC(50) of 3.2microg/ml (5microM) compared to 7.2microg/ml (12.1microM) for the parent compound 7,8-didehydrocimigenol 3-O-beta-d-xylopyranoside. Thus, the acetyl group at position C-25 enhances growth inhibitory activity. The purified triterpene glycoside actein (beta-d-xylopyranoside), with an IC(50) equal to 5.7microg/ml (8.4microM), exhibited activity comparable to cimigenol 3-O-beta-d-xyloside. MCF7 (ER(+)Her2 low) cells transfected for Her2 are more sensitive than the parental MCF7 cells to the growth inhibitory effects of actein from black cohosh, indicating that Her2 plays a role in the action of actein. The effect of actein on Her2 overexpressing MDA-MB-453 and MCF7 (ER(+)Her2 low) human breast cancer cells was examined by fluorescent microscopy. Treatment with actein altered the distribution of actin filaments and induced apoptosis in these cells. These findings, coupled with our previous evidence that treatment with the triterpene glycoside actein induced a stress response and apoptosis in human breast cancer cells, suggest that compounds from Cimicifuga species may be useful in the prevention and

  11. Action mechanism of betahistine in the vestibular end organs.

    Science.gov (United States)

    Chávez, H; Vega, R; Valli, P; Mira, E; Benvenuti, C; Guth, P S; Soto, E

    2001-06-01

    Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the betahistine action mechanism at the vestibular end organs. Experiments were carried out in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM, n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with antagonists of nitric oxide sintethizing enzyme, cholinergic drugs, and excitatory amino acids were studied. Betahistine 1 mM (n = 5) was coadministered with NG-nitro-L-arginine 3 microM. The action of betahistine remained as in control experiments. Betahistine 1 mM reduced the excitatory action of carbachol (200 microM, n = 5) in a 30 +/- 3.4%. Cholinergic antagonists atropine (10 microM, n = 3) and d-tubocurarine (10 microM, n = 3) did not modify betahistine actions. Betahistine 1 mM also reduced kainic acid (10 microM, n = 4) excitatory action in 45.5 +/- 9.8%. These results corroborate that betahistine has a peripheral inhibitory action in the spike discharge of the afferent neurons in the vestibule. This action seems to involve neither NO production nor modifications in the release of acetylcholine from the efferent fibers. The inhibitory action of betahistine seems to be due to a postsynaptic binding site on the afferent neurons.

  12. Differential presynaptic actions of pyrethroid insecticides on glutamatergic and GABAergic neurons in the hippocampus.

    Science.gov (United States)

    Hossain, Muhammad Mubarak; Suzuki, Tadahiko; Unno, Toshihiro; Komori, Seiichi; Kobayashi, Haruo

    2008-01-14

    This study was designed to investigate the effects of several pyrethroids on the extracellular level of glutamate and gamma-aminobutyric acid (GABA) in the hippocampus of rats measured using microdialysis following systemic (i.p.) administration. Pyrethroids, allethrin (type I), cyhalothrin (type II) and deltamethrin (type II), were found to have differential effects on glutamatergic and GABAergic neurons in the hippocampus. Allethrin had an interesting dual effect, increasing glutamate release with low doses (10 and 20mg/kg) to about 175-150% and decreasing glutamate release with high dose (60 mg/kg) to about 50% of baseline. Cyhalothrin (10, 20 and 60 mg/kg) inhibited the release of glutamate dose-dependently to about 60-30% of baseline. The extracellular level of GABA was decreased to about 50% of baseline by 10 and 20mg/kg allethrin. The high dose of allethrin (60 mg/kg) and all doses of cyhalothrin (10, 20 and 60 mg/kg) increased the extracellular level of GABA while decreasing the level of glutamate. Deltamethrin dose-dependently increased extracellular glutamate levels to about 190-275% of baseline while decreasing the level of GABA. Local infusion of TTX (1 microM), a Na(+) channel blocker, completely prevented the effect of allethrin (10, 20 and 60 mg/kg), cyhalothrin (20 and 60 mg/kg) and deltamethrin (20mg/kg) on glutamate and GABA release, but only partially blocked the effects of 60 mg/kg deltamethrin. The effect of deltamethrin (60 mg/kg) on glutamate release was completely prevented by local infusion of nimodipine (10 microM), an L-type Ca(2+) channel blocker. Collectively, results from this study suggest that the excitatory glutamatergic neurons in the hippocampus are modulated by inhibitory GABA-releasing interneurons and that other mechanisms, beside sodium channels, may be involved with the neurotoxic action of pyrethroids.

  13. Aberrant expression of leukemia inhibitory factor receptor (LIFR) and leukemia inhibitory factor (LIF) is associated with tubal pregnancy occurrence

    OpenAIRE

    Li, Yong; Sun, Lizhou; ZHAO, Denmei; Ouyang, Jun; Xiang, Mei

    2015-01-01

    Tubal pregnancy is a major cause of maternal death in the first trimester and exploration of its underlying molecular mechanism is of great importance. This study aimed to explore the association of tubal pregnancy with leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (LIFR) expression in oviduct tissues. Materials and methods: Immunohistochemistry was performed to probe the differential expression of LIF and LIFR in oviduct tissues among a control group (including NP...

  14. Understanding affirmative action.

    Science.gov (United States)

    Crosby, Faye J; Iyer, Aarti; Sincharoen, Sirinda

    2006-01-01

    Affirmative action is a controversial and often poorly understood policy. It is also a policy that has been widely studied by social scientists. In this review, we outline how affirmative action operates in employment and education settings and consider the major points of controversy. In addition, we detail the contributions of psychologists and other social scientists in helping to demonstrate why affirmative action is needed; how it can have unintended negative consequences; and how affirmative action programs can be most successful. We also review how psychologists have examined variations in people's attitudes toward affirmative action, in part as a means for testing different theories of social behavior.

  15. Differential Equations as Actions

    DEFF Research Database (Denmark)

    Ronkko, Mauno; Ravn, Anders P.

    1997-01-01

    We extend a conventional action system with a primitive action consisting of a differential equation and an evolution invariant. The semantics is given by a predicate transformer. The weakest liberal precondition is chosen, because it is not always desirable that steps corresponding to differential...... actions shall terminate. It is shown that the proposed differential action has a semantics which corresponds to a discrete approximation when the discrete step size goes to zero. The extension gives action systems the power to model real-time clocks and continuous evolutions within hybrid systems....

  16. The GABA excitatory/inhibitory developmental sequence: a personal journey.

    Science.gov (United States)

    Ben-Ari, Y

    2014-10-24

    The developing brain is talkative but its language is not that of the adult. Most if not all voltage and transmitter-gated ionic currents follow a developmental sequence and network-driven patterns differ in immature and adult brains. This is best illustrated in studies engaged almost three decades ago in which we observed elevated intracellular chloride (Cl(-))i levels and excitatory GABA early during development and a perinatal excitatory/inhibitory shift. This sequence is observed in a wide range of brain structures and animal species suggesting that it has been conserved throughout evolution. It is mediated primarily by a developmentally regulated expression of the NKCC1 and KCC2 chloride importer and exporter respectively. The GABAergic depolarization acts in synergy with N-methyl-d-aspartate (NMDA) receptor-mediated and voltage-gated calcium currents to enhance intracellular calcium exerting trophic effects on neuritic growth, migration and synapse formation. These sequences can be deviated in utero by genetic or environmental insults leading to a persistence of immature features in the adult brain. This "neuroarcheology" concept paves the way to novel therapeutic perspectives based on the use of drugs that block immature but not adult currents. This is illustrated notably with the return to immature high levels of chloride and excitatory actions of GABA observed in many pathological conditions. This is due to the fact that in the immature brain a down regulation of KCC2 and an up regulation of NKCC1 are seen. Here, I present a personal history of how an unexpected observation led to novel concepts in developmental neurobiology and putative treatments of autism and other developmental disorders. Being a personal account, this review is neither exhaustive nor provides an update of this topic with all the studies that have contributed to this evolution. We all rely on previous inventors to allow science to advance. Here, I present a personal summary of this

  17. Dual Headquarters Involvement in Subsidiary Innovation

    DEFF Research Database (Denmark)

    Dellestrand, Henrik; Kappen, Philip; Nell, Phillip Christopher

    2014-01-01

    innovation importance, i.e., an innovation that is important for the division and the corporate level, drives dual headquarters involvement in innovation development. Contrary to expectations, no significant effect of dual embeddedness on dual headquarters involvement is found. The network size......The strategy and international business literature has identified the overall potential for headquarters to add value by allocating resources to subsidiary activities, but little is known about the extent to which multiple headquarters simultaneously involves itself in subsidiary operations...

  18. Conformal Higher Spin Theory and Twistor Space Actions

    CERN Document Server

    Haehnel, Philipp

    2016-01-01

    We consider the twistor description of conformal higher spin theories and give twistor space actions for the self-dual sector of theories with spin greater than two that produce the correct flat space-time spectrum. We identify a ghost-free subsector, analogous to the embedding of Einstein gravity with cosmological constant in Weyl gravity, which generates the unique spin-s three-point anti-MHV amplitude consistent with Poincare invariance and helicity constraints. By including interactions between the infinite tower of higher-spin fields we give a geometric interpretation to the twistor equations of motion as the integrability condition for a holomorphic structure on an infinite jet bundle. Finally, we introduce anti-self-dual interaction terms to define a twistor action for the full conformal higher spin theory.

  19. J-kink domain walls and the DBI action

    CERN Document Server

    Eto, Minoru

    2015-01-01

    We study $J$-kink domain walls in $D=4$ massive $\\mathbb{C}P^1$ sigma model. The domain walls are not static but stationary, since they rotate in an internal $S^1$ space with a frequency $\\omega$ and a momentum ${\\bf k}$ along the domain wall. They are characterized by a conserved current $J_\\mu = (Q,{\\bf J})$, and are classified into magnetic ($J^2 0$) types. Under a natural assumption that a low energy effective action of the domain wall is dual to the $D=4$ DBI action for a membrane, we are lead to a coincidence between the $J$-kink domain wall and the membrane with constant magnetic field $B$ and electric field ${\\bf E}$. We also find that $(Q, {\\bf J}, \\omega, {\\bf k})$ is dual to $(B, {\\bf E}, H, {\\bf D})$ with $H$ and ${\\bf D}$ being a magnetizing field and a displacement field, respectively.

  20. Action Theory Evolution

    CERN Document Server

    Varzinczak, Ivan

    2008-01-01

    Like any other logical theory, domain descriptions in reasoning about actions may evolve, and thus need revision methods to adequately accommodate new information about the behavior of actions. The present work is about changing action domain descriptions in propositional dynamic logic. Its contribution is threefold: first we revisit the semantics of action theory contraction that has been done in previous work, giving more robust operators that express minimal change based on a notion of distance between Kripke-models. Second we give algorithms for syntactical action theory contraction and establish their correctness w.r.t. our semantics. Finally we state postulates for action theory contraction and assess the behavior of our operators w.r.t. them. Moreover, we also address the revision counterpart of action theory change, showing that it benefits from our semantics for contraction.

  1. Running at Double Pace: Women in Dual-Profession Marriages.

    Science.gov (United States)

    Arfken, Deborah Elwell

    Although the problems facing dual-profession couples are almost universally acknowledged, studies on dual-profession couples have only recently emerged from those on dual-worker or dual-career families. To explore the perceptions that women in dual-profession marriages have of their roles, conflicts, and coping strategies, focus group interviews…

  2. Decorrelation of Neural-Network Activity by Inhibitory Feedback

    Science.gov (United States)

    Einevoll, Gaute T.; Diesmann, Markus

    2012-01-01

    Correlations in spike-train ensembles can seriously impair the encoding of information by their spatio-temporal structure. An inevitable source of correlation in finite neural networks is common presynaptic input to pairs of neurons. Recent studies demonstrate that spike correlations in recurrent neural networks are considerably smaller than expected based on the amount of shared presynaptic input. Here, we explain this observation by means of a linear network model and simulations of networks of leaky integrate-and-fire neurons. We show that inhibitory feedback efficiently suppresses pairwise correlations and, hence, population-rate fluctuations, thereby assigning inhibitory neurons the new role of active decorrelation. We quantify this decorrelation by comparing the responses of the intact recurrent network (feedback system) and systems where the statistics of the feedback channel is perturbed (feedforward system). Manipulations of the feedback statistics can lead to a significant increase in the power and coherence of the population response. In particular, neglecting correlations within the ensemble of feedback channels or between the external stimulus and the feedback amplifies population-rate fluctuations by orders of magnitude. The fluctuation suppression in homogeneous inhibitory networks is explained by a negative feedback loop in the one-dimensional dynamics of the compound activity. Similarly, a change of coordinates exposes an effective negative feedback loop in the compound dynamics of stable excitatory-inhibitory networks. The suppression of input correlations in finite networks is explained by the population averaged correlations in the linear network model: In purely inhibitory networks, shared-input correlations are canceled by negative spike-train correlations. In excitatory-inhibitory networks, spike-train correlations are typically positive. Here, the suppression of input correlations is not a result of the mere existence of correlations between

  3. Inhibitory nature of tiagabine-augmented GABAA receptor-mediated depolarizing responses in hippocampal pyramidal cells.

    Science.gov (United States)

    Jackson, M F; Esplin, B; Capek, R

    1999-03-01

    Tiagabine is a potent GABA uptake inhibitor with demonstrated anticonvulsant activity. GABA uptake inhibitors are believed to produce their anticonvulsant effects by prolonging the postsynaptic actions of GABA, released during episodes of neuronal hyperexcitability. However, tiagabine has recently been reported to facilitate the depolarizing actions of GABA in the CNS of adult rats following the stimulation of inhibitory pathways at a frequency (100 Hz) intended to mimic interneuronal activation during epileptiform activity. In the present study, we performed extracellular and whole cell recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the functional consequences of tiagabine-augmented GABA-mediated depolarizing responses. Orthodromic population spikes (PSs), elicited from the stratum radiatum, were inhibited following the activation of recurrent inhibitory pathways by antidromic conditioning stimulation of the alveus, which consisted of either a single stimulus or a train of stimuli delivered at high-frequency (100 Hz, 200 ms). The inhibition of orthodromic PSs produced by high-frequency conditioning stimulation (HFS), which was always of much greater strength and duration than that produced by a single conditioning stimulus, was greatly enhanced following the bath application of tiagabine (2-100 microM). Thus, in the presence of tiagabine (20 microM), orthodromic PSs, evoked 200 and 800 ms following HFS, were inhibited to 7.8 +/- 2.6% (mean +/- SE) and 34.4 +/- 18.5% of their unconditioned amplitudes compared with only 35.4 +/- 12.7% and 98.8 +/- 12.4% in control. Whole cell recordings revealed that the bath application of tiagabine (20 microM) either caused the appearance or greatly enhanced the amplitude of GABA-mediated depolarizing responses (DR). Excitatory postsynaptic potentials (EPSPs) evoked from stratum radiatum at time points that coincided with the DR were inhibited to below the threshold for action-potential firing

  4. Dual Language Learning / Duale Spracherlernung. Learning German through English

    Directory of Open Access Journals (Sweden)

    Fee-Alexandra Haase

    2014-07-01

    Full Text Available In this article we examine the impact of English in the learning process of the German language exemplified with the example of the second language acquisition process of the German language in the programs of German in the Department of Foreign Languages of the University of Nizwa in Oman. This study focuses on the distinct features of students in Oman learning German as a second language in an institution of higher education in Oman. The contrastive rhetoric of a German – Oman Arabic language contact situation is challenging and a unique field of research, which allows us to study the process of foreign language learning (L2 and the implementation of the culture of the native language L1 (Arabic. The reflection of the L1 culture, the Arab Oman culture, in the language learning process of the L2 language (German will be described, analyzed and discussed aiming the improvement of the L2 learning process. This article investigates into the process of learning German in an Arabic country of native speakers of Arabic from the perspective of the cultural differences of both cultures in terms of their linguistic prepositions.Received: 17/09/2013 / Accepted: 23/11/2013How to reference this articleHaase, F-A. (2014. Dual Language Learning / Duale Spracherlernung. Learning German through English. Foro de Educación, 12(17, pp. 197-216. doi: http://dx.doi.org/10.14516/fde.2014.012.017.010

  5. Dual-fuel, dual-mode rocket engine

    Science.gov (United States)

    Martin, James A. (Inventor)

    1989-01-01

    The invention relates to a dual fuel, dual mode rocket engine designed to improve the performance of earth-to-orbit vehicles. For any vehicle that operates from the earth's surface to earth orbit, it is advantageous to use two different fuels during its ascent. A high density impulse fuel, such as kerosene, is most efficient during the first half of the trajectory. A high specific impulse fuel, such as hydrogen, is most efficient during the second half of the trajectory. The invention allows both fuels to be used with a single rocket engine. It does so by adding a minimum number of state-of-the-art components to baseline single made rocket engines, and is therefore relatively easy to develop for near term applications. The novelty of this invention resides in the mixing of fuels before exhaust nozzle cooling. This allows all of the engine fuel to cool the exhaust nozzle, and allows the ratio of fuels used throughout the flight depend solely on performance requirements, not cooling requirements.

  6. EVALUATION OF ALPHA-AMYLASE AND ALPHA-GLUCOSIDASE INHIBITORY PROPERTIES OF SELECTED SEAWEEDS FROM GULF OF MANNAR

    Directory of Open Access Journals (Sweden)

    Palanisamy SenthilKumar

    2012-08-01

    Full Text Available Aqueous extracts of four seaweeds collected from Gulf of Mannar coastal waters were tested for α-amylase and α-glucosidase inhibition properties. The aqueous extracts of seaweeds in the order of Gracilaria edulis, Sargassum polycystum, Ulva lactuca and Gracilaria corticata showed significant inhibitory activity against α-amylase and α-glucosidase enzymes. G. edulis was found to be a potent inhibitor of α-glucosidase with an IC50 value of 46μg/mL. The aqueous extract of S. polycystum at a concentration of 10-100 µg/ml showed maximum α-amylase inhibitory activity with an IC50 value of 60μg/mL. This study warrants further investigation on the antidiabetic activity and identifies the hyperglycemic principle to elucidate their mode of action.

  7. The effects of safety behaviors during exposure therapy for anxiety: Critical analysis from an inhibitory learning perspective.

    Science.gov (United States)

    Blakey, Shannon M; Abramowitz, Jonathan S

    2016-11-01

    In the context of clinical anxiety, safety behaviors are actions performed to prevent, escape, or minimize feared catastrophes and/or associated distress. Research consistently implicates safety behaviors in the development and maintenance of anxiety disorders; accordingly, safety behaviors are traditionally eliminated during exposure treatments for pathological anxiety. The notion that safety behaviors are ubiquitously deleterious in the context of exposure has recently been challenged, yet findings regarding safety behaviors' effects on exposure outcomes are limited, mixed, and controversial. Furthermore, developments in explanatory models for exposure's effectiveness (e.g., inhibitory learning theory) highlight other possible consequences of safety behaviors performed during exposure. Unfortunately, these theoretical advances are neglected in experimental research. The present review critically examines the literature addressing the role of safety behaviors in exposure therapy from an inhibitory learning perspective. Limitations, future directions, and clinical recommendations are also discussed.

  8. The Dual Language Program Planner: A Guide for Designing and Implementing Dual Language Programs.

    Science.gov (United States)

    Howard, Elizabeth R.; Olague, Natalie; Rogers, David

    This guide offers a framework to facilitate the planning process for dual language programs, assuming at least a basic working knowledge of the central characteristics and essential features of dual language models. It provides an overview of the various models that serve linguistically diverse student populations, defining the term dual language…

  9. Dual arm master controller development

    Energy Technology Data Exchange (ETDEWEB)

    Kuban, D.P.; Perkins, G.S.

    1985-01-01

    The advanced servomanipulator (ASM) slave was designed with an anthropomorphic stance, gear/torque tube power drives, and modular construction. These features resulted in increased inertia, friction, and backlash relative to tape-driven manipulators. Studies were performed which addressed the human factors design and performance trade-offs associated with the corresponding master controller best suited for the ASM. The results of these studies, as well as the conceptual design of the dual arm master controller, are presented. This work was performed as part of the Consolidated Fuel Reprocessing Program at the Oak Ridge National Laboratory. 5 refs., 7 figs., 1 tab.

  10. [Pharmacological action of bromazepam suppository].

    Science.gov (United States)

    Kasama, T; Fujii, Y; Aida, Y; Mayuzumi, K; Mayuzumi, Y; Goto, M; Gomita, Y; Moriyama, M; Ichimaru, Y

    1983-02-01

    Differences between the pharmacological effects of bromazepam given by oral and rectal administration were investigated in mice and rats. 1) Bromazepam dose-dependently prolonged the sleeping time induced by thiopental-Na, ethanol and ether by both administration routes. 2) The analgesic action of bromazepam was recognized by the hot-plate method and the algolytic test. In the hot-plate test, analgesic actions of morphine and pentazocine were potentiated by bromazepam in a dose of 0.5 mg/kg by both routes. 3) The muscle relaxant effect of bromazepam administered rectally was more potent than that administered orally in the inclined screen test and the rotarod test. This effect of bromazepam by rectal administration was approximately 2 times as potent as that by oral administration. 4) Bromazepam inhibited the convulsion induced by maximum electric shock, pentylenetetrazol and picrotoxin. In pentylenetetrazol-induced convulsion, the inhibitory effect of bromazepam administered rectally was 2 times as potent as that administered orally. In the other convulsion test, no significant differences between oral and rectal administration could be recognized. 5) Hyperemotionality and muricide (mouse-killing behaviour) of rats with bilateral olfactory bulb ablations (OB rat) were reduced by oral and rectal administrations of bromazepam in a dose-dependent manner. The effects by rectal administration were more potent than that by oral administration. Bromazepam was approximately 20 times as potent as diazepam administered by the same route. Fighting behaviour in mice subjected to footshock was suppressed by rectal administration of bromazepam, and this effect was as same as that by oral administration. 6) The rate of lever pressing response in the lateral hypothalamic self-stimulation test in the Skinner box was markedly increased by rectal administration of 0.2 mg/kg bromazepam. 7) Methamphetamine-induced hyperactivity of mice was significantly suppressed only by bromazepam

  11. Inhibitory effect of kaolin minerals compound against hepatitis C virus in Huh-7 cell lines.

    Science.gov (United States)

    Ali, Liaqat; Idrees, Muhammad; Ali, Muhammad; Hussain, Abrar; Ur Rehman, Irshad; Ali, Amjad; Iqbal, Syed Abbas; Kamel, Eyad Hassan

    2014-04-17

    Hepatitis C virus (HCV) is estimated to infect 200 million individuals in the globe, including approximately 10 million in Pakistan causing both acute and chronic hepatitis. The standard treatment against HCV is pegylated interferon therapy in combination with a nucleoside analogue ribavirin. In addition, several herbal extracts and phytochemicals derivatives are used traditionally in the treatment of liver diseases as well as HCV infection. The present study determines the inhibitory effect of kaolin minerals compound against hepatitis C virus in Huh-7 cell lines. Huh-7 cell lines were used for the in vitro HCV replication by using HCV positive sera from different patients with known HCV genotypes and viral titer/load. Total RNA was extracted from these infected cells and was quantified by real-time polymerase chain reaction (Real-time PCR). The viral titer was compared with the control samples to determine the anti-HCV activity of kaolin derived compounds. Kaolin is a group of clay minerals, with the chemical composition Al2 Si2O5 (OH)4. The results showed promising effectiveness of local kaolin derived anti-HCV compounds by causing 28% to 77% decrease in the HCV titer, when applied to infected Huh-7 cell lines. This study provides the basis for future work on these compounds especially to determine the specific pathway and mechanism for inhibitory action in the replicon systems of viral hepatitis. Kaolin mineral derivatives show promising inhibitory effects against HCV genotypes 3a and 1a infection, which suggests its possible use as complementary and alternative medicine for HCV viral infection.

  12. Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs.

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    Pothmann, Leonie; Müller, Christina; Averkin, Robert G; Bellistri, Elisa; Miklitz, Carolin; Uebachs, Mischa; Remy, Stefan; Menendez de la Prida, Liset; Beck, Heinz

    2014-07-16

    The mechanisms of action of many CNS drugs have been studied extensively on the level of their target proteins, but the effects of these compounds on the level of complex CNS networks that are composed of different types of excitatory and inhibitory neurons are not well understood. Many currently used anticonvulsant drugs are known to exert potent use-dependent blocking effects on voltage-gated Na(+) channels, which are thought to underlie the inhibition of pathological high-frequency firing. However, some GABAergic inhibitory neurons are capable of firing at very high rates, suggesting that these anticonvulsants should cause impaired GABAergic inhibition. We have, therefore, studied the effects of anticonvulsant drugs acting via use-dependent block of voltage-gated Na(+) channels on GABAergic inhibitory micronetworks in the rodent hippocampus. We find that firing of pyramidal neurons is reliably inhibited in a use-dependent manner by the prototypical Na(+) channel blocker carbamazepine. In contrast, a combination of intrinsic and synaptic properties renders synaptically driven firing of interneurons essentially insensitive to this anticonvulsant. In addition, a combination of voltage imaging and electrophysiological experiments reveal that GABAergic feedforward and feedback inhibition is unaffected by carbamazepine and additional commonly used Na(+) channel-acting anticonvulsants, both in control and epileptic animals. Moreover, inhibition in control and epileptic rats recruited by in vivo activity patterns was similarly unaffected. These results suggest that sparing of inhibition is an important principle underlying the powerful reduction of CNS excitability exerted by anticonvulsant drugs. Copyright © 2014 the authors 0270-6474/14/349720-16$15.00/0.

  13. Identification of an Inhibitory Alcohol Binding Site in GABAA ρ1 Receptors.

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    Borghese, Cecilia M; Ruiz, Carlos I; Lee, Ui S; Cullins, Madeline A; Bertaccini, Edward J; Trudell, James R; Harris, R Adron

    2016-01-20

    Alcohols inhibit γ-aminobutyric acid type A ρ1 receptor function. After introducing mutations in several positions of the second transmembrane helix in ρ1, we studied the effects of ethanol and hexanol on GABA responses using two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes. The 6' mutations produced the following effects on ethanol and hexanol responses: small increase or no change (T6'M), increased inhibition (T6'V), and small potentiation (T6'Y and T6'F). The 5' mutations produced mainly increases in hexanol inhibition. Other mutations produced small (3' and 9') or no changes (2' and L277 in the first transmembrane domain) in alcohol effects. These results suggest an inhibitory alcohol binding site near the 6' position. Homology models of ρ1 receptors based on the X-ray structure of GluCl showed that the 2', 5', 6', and 9' residues were easily accessible from the ion pore, with 5' and 6' residues from neighboring subunits facing each other; L3' and L277 also faced the neighboring subunit. We tested ethanol through octanol on single and double mutated ρ1 receptors [ρ1(I15'S), ρ1(T6'Y), and ρ1(T6'Y,I15'S)] to further characterize the inhibitory alcohol pocket in the wild-type ρ1 receptor. The pocket can only bind relatively short-chain alcohols and is eliminated by introducing Y in the 6' position. Replacing the bulky 15' residue with a smaller side chain introduced a potentiating binding site, more sensitive to long-chain than to short-chain alcohols. In conclusion, the net alcohol effect on the ρ1 receptor is determined by the sum of its actions on inhibitory and potentiating sites.

  14. Enzyme Inhibitory Properties, Antioxidant Activities, and Phytochemical Profile of Three Medicinal Plants from Turkey

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    Gokhan Zengin

    2015-01-01

    Full Text Available We aimed to investigate the inhibitory potential of three medicinal plants (Hedysarum varium, Onobrychis hypargyrea, and Vicia truncatula from Turkey against key enzymes involved in human pathologies, namely, diabetes (α-amylase and α-glucosidase, neurodegenerative disorders (tyrosinase, acetylcholinesterase, and butyrylcholinesterase, and hyperpigmentation (tyrosinase. The antioxidant potential, phenolic and flavonoid content of ethyl acetate, and methanolic and aqueous extracts were investigated using in vitro assays. The total antioxidant capacity (TAC, β-carotene/linoleic acid bleaching activity, 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH•, 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+, cupric ion reducing antioxidant capacity (CUPRAC, ferric reducing antioxidant power (FRAP, and metal chelating activity on ferrous ions were used to evaluate the antioxidant capabilities of the extracts. The half-maximal inhibitory concentrations (IC50 of the extracts on cholinesterase, tyrosinase, and α-amylase were significantly higher than the references, galantamine, kojic acid, and acarbose, respectively. The half-maximal effective concentrations (EC50 of the extracts on TAC, CUPRAC, and FRAP were significantly higher than trolox. The phenol and flavonoid contents of the plant extracts were in the range 20.90±0.190–83.25±0.914 mg gallic acid equivalent/g extract and 1.45±0.200–39.71±0.092 mg rutin equivalent/g extract, respectively. The plants were found to possess moderate antioxidant capacities and interesting inhibitory action against key enzymes.

  15. Activity-dependent transmission and integration control the timescales of auditory processing at an inhibitory synapse.

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    Ammer, Julian J; Siveke, Ida; Felmy, Felix

    2015-06-15

    To capture the context of sensory information, neural networks must process input signals across multiple timescales. In the auditory system, a prominent change in temporal processing takes place at an inhibitory GABAergic synapse in the dorsal nucleus of the lateral lemniscus (DNLL). At this synapse, inhibition outlasts the stimulus by tens of milliseconds, such that it suppresses responses to lagging sounds, and is therefore implicated in echo suppression. Here, we untangle the cellular basis of this inhibition. We demonstrate with in vivo whole-cell patch-clamp recordings in Mongolian gerbils that the duration of inhibition increases with sound intensity. Activity-dependent spillover and asynchronous release translate the high presynaptic firing rates found in vivo into a prolonged synaptic output in acute slice recordings. A key mechanism controlling the inhibitory time course is the passive integration of the hyperpolarizing inhibitory conductance. This prolongation depends on the synaptic conductance amplitude. Computational modeling shows that this prolongation is a general mechanism and relies on a non-linear effect caused by synaptic conductance saturation when approaching the GABA reversal potential. The resulting hyperpolarization generates an efficient activity-dependent suppression of action potentials without affecting the threshold or gain of the input-output function. Taken together, the GABAergic inhibition in the DNLL is adjusted to the physiologically relevant duration by passive integration of inhibition with activity-dependent synaptic kinetics. This change in processing timescale combined with the reciprocal connectivity between the DNLLs implements a mechanism to suppress the distracting localization cues of echoes and helps to localize the initial sound source reliably.

  16. Dual-wavelength distributed Bragg reflector semiconductor laser based on a composite resonant cavity

    Science.gov (United States)

    Chen, Cheng; Zhao, Ling-Juan; Qiu, Ji-Fang; Liu, Yang; Wang, Wei; Lou, Cai-Yun

    2012-09-01

    We report a monolithic integrated dual-wavelength laser diode based on a distributed Bragg reflector (DBR) composite resonant cavity. The device consists of three sections, a DBR grating section, a passive phase section, and an active gain section. The gain section facet is cleaved to work as a laser cavity mirror. The other laser mirror is the DBR grating, which also functions as a wavelength filter and can control the number of wavelengths involved in the laser action. The reflection bandwidth of the DBR grating is fabricated to have an appropriate value to make the device work at the dual-wavelength lasing state. We adopt the quantum well intermixing (QWI) technique to provide low-absorption loss grating and passive phase section in the fabrication process. By tuning the injection currents on the DBR and the gain sections, the device can generate 0.596 nm-spaced dual-wavelength lasing at room temperature.

  17. Vocational Dual Education System: comparison between the German model and the new Spanish vocational training

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    Laura Rego Agraso

    2015-06-01

    Full Text Available The German dual system of vocational training has been object of transfer in some countries all over the world, among them Spain. Indeed, in this article we try to clarify the key elements in the adapting process of this Dual System to our country, analyzing its chances of success. To do this, we contribute a descriptive study of the main elements of the German Dual System. Then, the focus will be in the changes in our country, from the LOMCE project to the legislation governing apprenticeship and training. As a kind of discussion, we pretend to clarify how cultural and organizational elements of the production system have a strongly influence in the chances of success on the Vocational Training reform policy initiatives. Finally, we completed a series of proposals for action that would contribute to the employment and an increase in the qualification among Spanish young people.

  18. Chronic exercise keeps working memory and inhibitory capacities fit

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    Concepción ePadilla

    2014-03-01

    Full Text Available Padilla et al. (2013 recently showed that chronic aerobic exercise in young adults is associated with better inhibitory control as measured by the strategic Stop Signal Task (SST. The aim of the current study was to explore whether better inhibitory abilities, associated with high levels of physical fitness, were also associated with higher working memory capacity (WMC in young healthy adults. Participants aged between 18 and 30 years and showing different levels of fitness confirmed by the Rockport 1-mile walking fitness test took part in this study. Active and passive participants were administered the SST to measure inhibitory control, and the Automatic Operation Span to measure verbal WMC. We first replicated Padilla et al.’s results showing that exercise specifically modulates strategic inhibitory processes. Our results also showed that active participants presented with better WMC than sedentary ones, showing a better capacity to manage simultaneously two verbal tasks and to inhibit interference. The results point to an association between chronic exercise, inhibitory abilities and WMC. The theoretical relationship between these variables will be discussed.

  19. Training-induced behavioral and brain plasticity in inhibitory control

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    Lucas eSpierer

    2013-08-01

    Full Text Available Deficits in inhibitory control, the ability to suppress ongoing or planned motor or cognitive processes, contribute to many psychiatric and neurological disorders. The rehabilitation of inhibition-related disorders may therefore benefit from neuroplasticity-based training protocols aiming at normalizing inhibitory control proficiency and the underlying brain networks. Current literature on training-induced behavioral and brain plasticity in inhibitory control suggests that improvements may follow either from the development of automatic forms of inhibition or from the strengthening of top-down, controlled inhibition. Automatic inhibition develops in conditions of consistent and repeated associations between inhibition-triggering stimuli and stopping goals. Once established, the stop signals directly elicit inhibition, thereby bypassing slow, top-down executive control and accelerating stopping processes. In contrast, training regimens involving varying stimulus-response associations or frequent inhibition failures prevent the development of automatic inhibition and thus strengthen top-down inhibitory processes rather than bottom-up ones. We discuss these findings in terms of developing optimal inhibitory control training regimens for rehabilitation purposes.

  20. Effects of Response Preparation on Developmental Improvements in Inhibitory Control

    Science.gov (United States)

    Ordaz, Sarah; Stephanie, Davis; Luna, Beatriz

    2010-01-01

    Studies in adults indicate that response preparation is crucial to inhibitory control, but it remains unclear whether preparation contributes to improvements in inhibitory control over the course of childhood and adolescence. In order to assess the role of response preparation in developmental improvements in inhibitory control, we parametrically manipulated the duration of the instruction period in an antisaccade (AS) task given to participants ages 8 to 31 years. Regressions showing a protracted development of AS performance were consistent with existing research, and two novel findings emerged. First, all participants showed improved performance with increased preparation time, indicating that response preparation is crucial to inhibitory control at all stages of development. Preparatory processes did not deteriorate at even the longest preparatory period, indicating that the youngest participants were able to sustain preparation at even the longest interval. Second, developmental trajectories did not differ for different preparatory period lengths, highlighting that the processes supporting response preparation continue to mature in tandem with improvements in AS performance. Our findings suggest that developmental improvements are not simply due to an inhibitory system that is faster to engage but may also reflect qualitative changes in the processes engaged during the preparatory period. PMID:20347061