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Sample records for action including inhibition

  1. Action spectra for photosynthetic inhibition

    NASA Technical Reports Server (NTRS)

    Caldwell, M. M.; Flint, S.; Camp, L. B.

    1981-01-01

    The ultraviolet action spectrum for photosynthesis inhibition was determined to fall between that of the general DNA action spectrum and the generalized plant action spectrum. The characteristics of this action spectrum suggest that a combination of pronounced increase in effectiveness with decreasing wavelength, substantial specificity for the UV-B waveband, and very diminished response in the UV-A waveband result in large radiation amplification factors when the action spectra are used as weighting functions. Attempted determination of dose/response relationships for leaf disc inhibition provided inconclusive data from which to deconvolute an action spectrum.

  2. In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs.

    PubMed

    Cassese, Angela; Esposito, Iolanda; Fiory, Francesca; Barbagallo, Alessia P M; Paturzo, Flora; Mirra, Paola; Ulianich, Luca; Giacco, Ferdinando; Iadicicco, Claudia; Lombardi, Angela; Oriente, Francesco; Van Obberghen, Emmanuel; Beguinot, Francesco; Formisano, Pietro; Miele, Claudia

    2008-12-26

    Chronic hyperglycemia promotes insulin resistance at least in part by increasing the formation of advanced glycation end products (AGEs). We have previously shown that in L6 myotubes human glycated albumin (HGA) induces insulin resistance by activating protein kinase Calpha (PKCalpha). Here we show that HGA-induced PKCalpha activation is mediated by Src. Coprecipitation experiments showed that Src interacts with both the receptor for AGE (RAGE) and PKCalpha in HGA-treated L6 cells. A direct interaction of PKCalpha with Src and insulin receptor substrate-1 (IRS-1) has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKCalpha co-precipitation. AGEs were able to induce insulin resistance also in vivo, as insulin tolerance tests revealed a significant impairment of insulin sensitivity in C57/BL6 mice fed a high AGEs diet (HAD). In tibialis muscle of HAD-fed mice, insulin-induced glucose uptake and protein kinase B phosphorylation were reduced. This was paralleled by a 2.5-fold increase in PKCalpha activity. Similarly to in vitro observations, Src phosphorylation was increased in tibialis muscle of HAD-fed mice, and co-precipitation experiments showed that Src interacts with both RAGE and PKCalpha. These results indicate that AGEs impairment of insulin action in the muscle might be mediated by the formation of a multimolecular complex including RAGE/IRS-1/Src and PKCalpha.

  3. 40 CFR 1502.14 - Alternatives including the proposed action.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 34 2012-07-01 2012-07-01 false Alternatives including the proposed action. 1502.14 Section 1502.14 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY ENVIRONMENTAL IMPACT STATEMENT § 1502.14 Alternatives including the proposed action. This section is the heart of...

  4. 40 CFR 1502.14 - Alternatives including the proposed action.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Alternatives including the proposed action. 1502.14 Section 1502.14 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY ENVIRONMENTAL IMPACT STATEMENT § 1502.14 Alternatives including the proposed action. This section is the heart of...

  5. 40 CFR 1502.14 - Alternatives including the proposed action.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 33 2011-07-01 2011-07-01 false Alternatives including the proposed action. 1502.14 Section 1502.14 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY ENVIRONMENTAL IMPACT STATEMENT § 1502.14 Alternatives including the proposed action. This section is the heart of...

  6. 40 CFR 1502.14 - Alternatives including the proposed action.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Alternatives including the proposed action. 1502.14 Section 1502.14 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY ENVIRONMENTAL IMPACT STATEMENT § 1502.14 Alternatives including the proposed action. This section is the heart of...

  7. 40 CFR 1502.14 - Alternatives including the proposed action.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... impacts of the proposal and the alternatives in comparative form, thus sharply defining the issues and... alternatives which were eliminated from detailed study, briefly discuss the reasons for their having been... action so that reviewers may evaluate their comparative merits. (c) Include reasonable alternatives...

  8. Mechanisms of Hop Inhibition Include the Transmembrane Redox Reaction▿

    PubMed Central

    Behr, Jürgen; Vogel, Rudi F.

    2010-01-01

    In this work, a novel mechanistic model of hop inhibition beyond the proton ionophore action toward (beer spoiling) bacteria was developed. Investigations were performed with model systems using cyclic voltammetry for the determination of redox processes/conditions in connection with growth challenges with hop-sensitive and -resistant Lactobacillus brevis strains in the presence of oxidants. Cyclic voltammetry identified a transmembrane redox reaction of hop compounds at low pH (common in beer) and in the presence of manganese (present in millimolar levels in lactic acid bacteria). The antibacterial action of hop compounds could be extended from the described proton ionophore activity, lowering the intracellular pH, to pronounced redox reactivity, causing cellular oxidative damage. Accordingly, a correlation between the resistance of L. brevis strains to a sole oxidant to their resistance to hop could not be expected and was not detected. However, in connection with our recent study concerning hop ionophore properties and the resistance of hop-sensitive and -tolerant L. brevis strains toward proton ionophores (J. Behr and R. F. Vogel, J. Agric. Food Chem. 57:6074-6081, 2009), we suggest that both ionophore and oxidant resistance are required for survival under hop stress conditions and confirmed this correlation according to the novel mechanistic model. In consequence, the expression of several published hop resistance mechanisms involved in manganese binding/transport and intracellular redox balance, as well as that of proteins involved in oxidative stress under “highly reducing” conditions (cf. anaerobic cultivation and “antioxidative” hop compounds in the growth medium), is now comprehensible. Accordingly, hop resistance as a multifactorial dynamic property at least implies distinct resistance levels against two different mechanisms of hop inhibition, namely, proton ionophore-induced and oxidative stress-induced mechanisms. Beyond this specific model of

  9. Auditory startle reflex inhibited by preceding self-action.

    PubMed

    Kawachi, Yousuke; Matsue, Yoshihiko; Shibata, Michiaki; Imaizumi, Osamu; Gyoba, Jiro

    2014-01-01

    A startle reflex to a startle pulse is inhibited when preceded by a prestimulus. We introduced a key-press action (self-action) or an 85 dB noise burst as a prestimulus, followed by a 115 dB noise burst as a startle pulse. We manipulated temporal offsets between the prestimulus and the startle pulse from 30-1,500 ms to examine whether self-action modulates the startle reflex and the temporal properties of the modulatory effect. We assessed eyeblink reflexes by electromyography. Both prestimuli decreased reflexes compared to pulse-alone trials. Moreover, the temporal windows of inhibition were different between the types of prestimuli. A faster maximal inhibition and narrower temporal window in self-action trials suggest that preceding self-action inhibits the startle reflex and allows prediction of the coming pulse in different ways from auditory prestimuli.

  10. Hedonic value of intentional action provides reinforcement for voluntary generation but not voluntary inhibition of action.

    PubMed

    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.

  11. Henri Laborit and the inhibition of action.

    PubMed

    Kunz, Edward

    2014-03-01

    Henri Laborit was one of the founders of modern neuropsychopharmacology, having discovered, or participated in, the discovery of chlorpromazine, gamma-OH, clomethiazole, and minaprine. He also put forward a theory regarding the necessity of counteracting the negative consequences of defense mechanisms during anesthesia or behavioral inhibition. The scope of his work covers neurophysiology, pharmacology, psychiatry, and psychosomatics. His independence of spirit meant that most of his research was not done within university settings.

  12. Henri Laborit and the inhibition of action

    PubMed Central

    Kunz, Edward

    2014-01-01

    Henri Laborit was one of the founders of modern neuropsychopharmacology, having discovered, or participated in, the discovery of chlorpromazine, gamma-OH, clomethiazole, and minaprine. He also put forward a theory regarding the necessity of counteracting the negative consequences of defense mechanisms during anesthesia or behavioral inhibition. The scope of his work covers neurophysiology, pharmacology, psychiatry, and psychosomatics. His independence of spirit meant that most of his research was not done within university settings. PMID:24733976

  13. Acute inhibition of corticosteroidogenesis by inhibitors of calmodulin action.

    PubMed

    Carsia, R V; Moyle, W R; Wolff, D J; Malamed, S

    1982-11-01

    To identify the possible role of calmodulin in ACTH function, we tested the ability of chlorpromazine (CP) and other calmodulin antagonists to inhibit steroidogenesis of isolated adrenocortical cells of the rat. CP reversibly inhibited maximal ACTH-induced corticosterone (B) production. The presence of the drug did not alter the ED50 of ACTH stimulation (3.2 X 10(3) pg/ml), suggesting that it inhibited ACTH-induced steroidogenesis in a noncompetitive manner. The CP concentration required for half-maximal inhibition was 8.2 microM, a value close to the dissociation constant of the CP-calmodulin complex (5.3 microM). Concentrations greater than 40 microM resulted in complete inhibition. Similar concentrations of CP inhibited ACTH-induced cAMP accumulation in a dose-dependent manner, indicating an effect of the drug on early events in ACTH action. In addition, CP also apparently acted at a site distal to the point of cAMP formation, as shown by the finding that it inhibited cAMP-induced B production. CP inhibition of ACTH-induced B production was independent of the Ca2+ concentration, suggesting that the drug did not compete with Ca2+ directly. Concentrations of CP greater than 20 microM inhibited protein synthesis as measured by leucine incorporation into cellular proteins. Thus, although the inhibitory effect of high concentrations of CP on steroidogenesis might be explained by an effect on protein synthesis, the inhibition seen at 10 microM appeared to be independent of protein synthesis. Other antagonists of calmodulin action inhibited maximal ACTH-induced B production with the following relative potencies: trifluoperazine greater than CP greater than haloperidol greater than chlordiazepoxide. This order is similar to that reported for inhibition of calmodulin-activated phosphodiesterase and for binding to calmodulin. These findings suggest that calmodulin may modulate the effect of ACTH on steroidogenesis at multiple sites.

  14. Luteolin inhibits lipopolysaccharide actions on human gingival fibroblasts.

    PubMed

    Gutiérrez-Venegas, Gloria; Kawasaki-Cárdenas, Perla; Arroyo-Cruz, Santa Rita; Maldonado-Frías, Silvia

    2006-07-10

    Periodontal disease comprises a group of infections that lead to inflammation of the gingiva, periodontal tissue destruction, and in severe cases is accompanied by alveolar bone loss with tooth exfoliation. Actinobacillus actinomycetemcomitans is a Gram-negative microorganism, which possesses and produces lipopolysaccharide (LPS) molecules that play a key role in disease development. Human gingival fibroblasts are the major constituents of gingival connective tissue and may interact directly with bacteria and bacterial products including LPS. Flavonoids possess antioxidant and anti-inflammatory properties that reduce inflammatory molecule expression in macrophages and monocytes. In this study, we evaluated the ability of diverse flavonoids to regulate nitric oxide production of LPS-stimulated human gingival fibroblasts, and studied the effect of luteolin on diminish phosphorylation in mitogen-activated protein kinase (MAPK) family members as well as in protein kinase B (Akt), nuclear factor kappa B (NF-kappaB) activation, inducible nitric oxide synthase (NOS) expression, and nitric oxide (NO) synthesis. We also found that pretreatment with three flavonoids, including quercetin, genistein, and luteolin, blocked nitric oxide synthesis in a dose-dependent fashion. Luteolin exerted the strongest blocking action on expression of this inflammatory mediator. Luteolin pretreatment attenuated LPS-induced extracellular signal-regulated kinase, p38, and Akt phosphorylation. LPS treatment of human gingival fibroblasts resulted in NF-kappaB translocation. Cell pretreatment with luteolin abolished LPS effects on NF-kappaB translocation. In addition, luteolin treatment blocked LPS-induced cellular proliferation inhibition without affecting genetic material integrity. We concluded that luteolin interferes with LPS signaling pathways, reducing activation of several mitogen-activated protein kinase family members, and inhibits inflammatory mediator expression.

  15. Dissecting PUGNAc-mediated inhibition of the pro-survival action of insulin.

    PubMed

    Teo, Chin Fen; El-Karim, Enas Gad; Wells, Lance

    2016-11-01

    Previous studies utilizing PUGNAc, the most widely used β-N-acetylglucosaminidase (OGA) inhibitor to increase global O-N-acetylglucosamine (GlcNAc) levels, have reported a variety of effects including insulin resistance as a direct result of elevated O-GlcNAc levels. The notion of OGA inhibition causing insulin resistance was not replicated in studies in which elevated global O-GlcNAc levels were achieved using two other OGA inhibitors. Related to insulin action, work by others has suggested that O-GlcNAc elevation may inhibit the anti-apoptotic action of insulin. Thus, we examined the pro-survival action of insulin upon serum deprivation in the presence of PUGNAc as well as two selective OGA inhibitors (GlcNAcstatin-g and Thiamet-G), and a selective lysosomal hexosaminidase inhibitor (INJ2). We established that PUGNAc inhibits the pro-survival action of insulin but this effect is not recapitulated by the selective OGA inhibitors suggesting that elevation in O-GlcNAc levels alone is not responsible for PUGNAc's effect on the anti-apoptotic action of insulin. Further, we demonstrate that a selective hexosaminidase A/B (HexA/B) inhibitor does not impact insulin action suggesting that PUGNAc's effect is not due to inhibition of lysosomal hexosaminidase. Finally, we tested a combination of selective OGA and lysosomal hexosaminidase inhibitors but were not able to recapitulate the inhibition of insulin action generated by PUGNAc alone. These results strongly suggest that the defect in insulin action upon PUGNAc treatment does not derive from its inhibition of OGA or HexA/B, and that there is an unknown target of PUGNAc that is the likely culprit in inhibiting the protective effect of insulin from apoptosis.

  16. Berberine inhibits PTP1B activity and mimics insulin action.

    PubMed

    Chen, Chunhua; Zhang, Yuebo; Huang, Cheng

    2010-07-02

    Type 2 diabetes patients show defects in insulin signal transduction that include lack of insulin receptor, decrease in insulin stimulated receptor tyrosine kinase activity and receptor-mediated phosphorylation of insulin receptor substrates (IRSs). A small molecule that could target insulin signaling would be of significant advantage in the treatment of diabetes. Berberine (BBR) has recently been shown to lower blood glucose levels and to improve insulin resistance in db/db mice partly through the activation of AMP-activated protein kinase (AMPK) signaling and induction of phosphorylation of insulin receptor (IR). However, the underlying mechanism remains largely unknown. Here we report that BBR mimics insulin action by increasing glucose uptake ability by 3T3-L1 adipocytes and L6 myocytes in an insulin-independent manner, inhibiting phosphatase activity of protein tyrosine phosphatase 1B (PTP1B), and increasing phosphorylation of IR, IRS1 and Akt in 3T3-L1 adipocytes. In diabetic mice, BBR lowers hyperglycemia and improves impaired glucose tolerance, but does not increase insulin release and synthesis. The results suggest that BBR represents a different class of anti-hyperglycemic agents.

  17. Motor Inhibition during Overt and Covert Actions: An Electrical Neuroimaging Study.

    PubMed

    Angelini, Monica; Calbi, Marta; Ferrari, Annachiara; Sbriscia-Fioretti, Beatrice; Franca, Michele; Gallese, Vittorio; Umiltà, Maria Alessandra

    2015-01-01

    Given ample evidence for shared cortical structures involved in encoding actions, whether or not subsequently executed, a still unsolved problem is the identification of neural mechanisms of motor inhibition, preventing "covert actions" as motor imagery from being performed, in spite of the activation of the motor system. The principal aims of the present study were the evaluation of: 1) the presence in covert actions as motor imagery of putative motor inhibitory mechanisms; 2) their underlying cerebral sources; 3) their differences or similarities with respect to cerebral networks underpinning the inhibition of overt actions during a Go/NoGo task. For these purposes, we performed a high density EEG study evaluating the cerebral microstates and their related sources elicited during two types of Go/NoGo tasks, requiring the execution or withholding of an overt or a covert imagined action, respectively. Our results show for the first time the engagement during motor imagery of key nodes of a putative inhibitory network (including pre-supplementary motor area and right inferior frontal gyrus) partially overlapping with those activated for the inhibition of an overt action during the overt NoGo condition. At the same time, different patterns of temporal recruitment in these shared neural inhibitory substrates are shown, in accord with the intended overt or covert modality of action performance. The evidence that apparently divergent mechanisms such as controlled inhibition of overt actions and contingent automatic inhibition of covert actions do indeed share partially overlapping neural substrates, further challenges the rigid dichotomy between conscious, explicit, flexible and unconscious, implicit, inflexible forms of motor behavioral control.

  18. Motor Inhibition during Overt and Covert Actions: An Electrical Neuroimaging Study

    PubMed Central

    Angelini, Monica; Calbi, Marta; Ferrari, Annachiara; Sbriscia-Fioretti, Beatrice; Franca, Michele; Gallese, Vittorio; Umiltà, Maria Alessandra

    2015-01-01

    Given ample evidence for shared cortical structures involved in encoding actions, whether or not subsequently executed, a still unsolved problem is the identification of neural mechanisms of motor inhibition, preventing “covert actions” as motor imagery from being performed, in spite of the activation of the motor system. The principal aims of the present study were the evaluation of: 1) the presence in covert actions as motor imagery of putative motor inhibitory mechanisms; 2) their underlying cerebral sources; 3) their differences or similarities with respect to cerebral networks underpinning the inhibition of overt actions during a Go/NoGo task. For these purposes, we performed a high density EEG study evaluating the cerebral microstates and their related sources elicited during two types of Go/NoGo tasks, requiring the execution or withholding of an overt or a covert imagined action, respectively. Our results show for the first time the engagement during motor imagery of key nodes of a putative inhibitory network (including pre-supplementary motor area and right inferior frontal gyrus) partially overlapping with those activated for the inhibition of an overt action during the overt NoGo condition. At the same time, different patterns of temporal recruitment in these shared neural inhibitory substrates are shown, in accord with the intended overt or covert modality of action performance. The evidence that apparently divergent mechanisms such as controlled inhibition of overt actions and contingent automatic inhibition of covert actions do indeed share partially overlapping neural substrates, further challenges the rigid dichotomy between conscious, explicit, flexible and unconscious, implicit, inflexible forms of motor behavioral control. PMID:26000451

  19. Aloe emodin inhibits the cytotoxic action of tumor necrosis factor.

    PubMed

    Harhaji, Ljubica; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela; Popadic, Dusan; Isakovic, Aleksandra; Todorovic-Markovic, Biljana; Trajkovic, Vladimir

    2007-07-30

    We demonstrate the capacity of an herbal anthraquinone aloe emodin to reduce the cytotoxicity of the proinflammatory cytokine tumor necrosis factor (TNF) towards L929 mouse fibrosarcoma and U251 human glioma cell lines. Aloe emodin inhibited both TNF-induced cell necrosis and apoptosis, but it did not reduce cell death induced by UV radiation or hydrogen peroxide. Aloe emodin inhibited both basal and TNF-triggered activation of extracellular signal-regulated kinase (ERK), and a selective blockade of ERK activation mimicked the cytoprotective action of the drug. On the other hand, aloe emodin did not affect TNF-induced activation of p38 mitogen-activated protein kinase or generation of reactive oxygen species. The combination of aloe emodin and TNF caused an intracellular appearance of acidified autophagic vesicles, and the inhibition of autophagy with bafilomycin or 3-methyladenine efficiently blocked the cytoprotective action of aloe emodin. These data indicate that aloe emodin could prevent TNF-triggered cell death through mechanisms involving induction of autophagy and blockade of ERK activation.

  20. NMDAR inhibition-independent antidepressant actions of ketamine metabolites

    PubMed Central

    Zanos, Panos; Moaddel, Ruin; Morris, Patrick J.; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I.; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J.; Singh, Nagendra S.; Dossou, Katina S.S.; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L.; Wainer, Irving W.; Albuquerque, Edson X.; Thompson, Scott M.; Thomas, Craig J.; Zarate, Carlos A.; Gould, Todd D.

    2016-01-01

    Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants. PMID:27144355

  1. 36 CFR 72.17 - Preliminary Action Program-commitments to be included.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... support services necessary for the development and completion of the Recovery Action Program...-commitments to be included. 72.17 Section 72.17 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR URBAN PARK AND RECREATION RECOVERY ACT OF 1978 Local Recovery Action Programs §...

  2. 36 CFR 72.17 - Preliminary Action Program-commitments to be included.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... support services necessary for the development and completion of the Recovery Action Program...-commitments to be included. 72.17 Section 72.17 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR URBAN PARK AND RECREATION RECOVERY ACT OF 1978 Local Recovery Action Programs §...

  3. 36 CFR 72.17 - Preliminary Action Program-commitments to be included.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... support services necessary for the development and completion of the Recovery Action Program...-commitments to be included. 72.17 Section 72.17 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR URBAN PARK AND RECREATION RECOVERY ACT OF 1978 Local Recovery Action Programs §...

  4. 36 CFR 72.17 - Preliminary Action Program-commitments to be included.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... support services necessary for the development and completion of the Recovery Action Program...-commitments to be included. 72.17 Section 72.17 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR URBAN PARK AND RECREATION RECOVERY ACT OF 1978 Local Recovery Action Programs §...

  5. 36 CFR 72.17 - Preliminary Action Program-commitments to be included.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... support services necessary for the development and completion of the Recovery Action Program...-commitments to be included. 72.17 Section 72.17 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR URBAN PARK AND RECREATION RECOVERY ACT OF 1978 Local Recovery Action Programs §...

  6. NMDAR inhibition-independent antidepressant actions of ketamine metabolites.

    PubMed

    Zanos, Panos; Moaddel, Ruin; Morris, Patrick J; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J; Singh, Nagendra S; Dossou, Katina S S; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L; Wainer, Irving W; Albuquerque, Edson X; Thompson, Scott M; Thomas, Craig J; Zarate, Carlos A; Gould, Todd D

    2016-05-26

    Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.

  7. Momentum relation and classical limit in the future-not-included complex action theory

    NASA Astrophysics Data System (ADS)

    Nagao, Keiichi; Nielsen, Holger Bech

    2013-07-01

    Studying the time development of the expectation value in the future-not-included complex action theory, we point out that the momentum relation (the relation analogous to p=frac {partial L}{partial dot {q}}), which was derived via the Feynman path integral and was shown to be correct in the future-included theory in our previous papers, is not valid in the future-not-included theory. We provide the correct momentum relation in the future-not-included theory, and argue that the future-not-included classical theory is described by a certain real action. In addition, we provide another way to understand the time development of the future-not-included theory by utilizing the future-included theory. Furthermore, properly applying the method used in our previous paper to the future-not-included theory by introducing a formal Lagrangian, we derive the correct momentum relation in the future-not-included theory.

  8. Mode of action of triflumezopyrim: A novel mesoionic insecticide which inhibits the nicotinic acetylcholine receptor.

    PubMed

    Cordova, Daniel; Benner, Eric A; Schroeder, Mark E; Holyoke, Caleb W; Zhang, Wenming; Pahutski, Thomas F; Leighty, Robert M; Vincent, Daniel R; Hamm, Jason C

    2016-07-01

    Triflumezopyrim, a newly commercialized molecule from DuPont Crop Protection, belongs to the novel class of mesoionic insecticides. This study characterizes the biochemical and physiological action of this novel insecticide. Using membranes from the aphid, Myzus persicae, triflumezopyrim was found to displace (3)H-imidacloprid with a Ki value of 43 nM with competitive binding results indicating that triflumezopyrim binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR). In voltage clamp studies using dissociated Periplaneta americana neurons, triflumezopyrim inhibits nAChR currents with an IC50 of 0.6 nM. Activation of nAChR currents was minimal and required concentrations ≥100 μM. Xenopus oocytes expressing chimeric nAChRs (Drosophila α2/chick β2) showed similar inhibitory effects from triflumezopyrim. In P. americana neurons, co-application experiments with acetylcholine reveal the inhibitory action of triflumezopyrim to be rapid and prolonged in nature. Such physiological action is distinct from other insecticides in IRAC Group 4 in which the toxicological mode of action is attributed to nAChR agonism. Mesoionic insecticides act via inhibition of the orthosteric binding site of the nAChR despite previous beliefs that such action would translate to poor insect control. Triflumezopyrim is the first commercialized insecticide from this class and provides outstanding control of hoppers, including the brown planthopper, Nilaparvata lugens, which is already displaying strong resistance to neonicotinoids such as imidacloprid.

  9. Mode of Action of the Natural Insecticide, Decaleside Involves Sodium Pump Inhibition

    PubMed Central

    Rajashekar, Yallappa; Shivanandappa, Thimmappa

    2017-01-01

    Decalesides are a new class of natural insecticides which are toxic to insects by contact via the tarsal gustatory chemosensilla. The symptoms of their toxicity to insects and the rapid knockdown effect suggest neurotoxic action, but the precise mode of action and the molecular targets for decaleside action are not known. We have presented experimental evidence for the involvement of sodium pump inhibition in the insecticidal action of decaleside in the cockroach and housefly. The knockdown effect of decaleside is concomitant with the in vivo inhibition of Na+, K+ -ATPase in the head and thorax. The lack of insecticidal action by experimental ablation of tarsi or blocking the tarsal sites with paraffin correlated with lack of inhibition of Na+- K+ ATPase in vivo. Maltotriose, a trisaccharide, partially rescued the toxic action of decaleside as well as inhibition of the enzyme, suggesting the possible involvement of gustatory sugar receptors. In vitro studies with crude insect enzyme preparation and purified porcine Na+, K+ -ATPase showed that decaleside competitively inhibited the enzyme involving the ATP binding site. Our study shows that the insecticidal action of decaleside via the tarsal gustatory sites is causally linked to the inhibition of sodium pump which represents a unique mode of action. The precise target(s) for decaleside in the tarsal chemosensilla and the pathway linked to inhibition of sodium pump and the insecticidal action remain to be understood. PMID:28125742

  10. Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors. A review.

    PubMed

    Ricketts, Marie-Louise; Moore, David D; Banz, William J; Mezei, Orsolya; Shay, Neil F

    2005-06-01

    Consumption of soy has been demonstrated to reduce circulating cholesterol levels, most notably reducing low-density lipoprotein (LDL) cholesterol levels in hypercholesterolemic individuals. The component or components that might be responsible for this effect is still a matter of debate or controversy among many researchers. Candidate agents include an activity of soy protein itself, bioactive peptides produced during the digestive process, or the soy isoflavones. Although soy intake may provide other health benefits including preventative or remediative effects on cancer, osteoporosis and symptoms of menopause, this review will focus on isoflavones as agents affecting lipid metabolism. Isoflavones were first discovered as a bioactive agent disrupting estrogen action in female sheep, thereby earning the often-used term 'phytoestrogens'. Subsequent work confirmed the ability of isoflavones to bind to estrogen receptors. Along with the cholesterol-lowering effect of soy intake, research that is more recent has pointed to a beneficial antidiabetic effect of soy intake, perhaps mediated by soy isoflavones. The two common categories of antidiabetic drugs acting on nuclear receptors known as peroxisome proliferator activated receptors (PPARs) are the fibrates and glitazones. We and others have recently asked the research question 'do the soy isoflavones have activities as either "phytofibrates" or "phytoglitazones"?' Such an activity should be able to be confirmed both in vivo and in vitro. In both the in vivo and in vitro cases, this action has indeed been confirmed. Further work suggests a possible action of isoflavones similar to the nonestrogenic ligands that bind the estrogen-related receptors (ERRs). Recently, these receptors have been demonstrated to contribute to lipolytic processes. Finally, evaluation of receptor activation studies suggests that thyroid receptor activation may provide additional clues explaining the metabolic action of isoflavones. The recent

  11. Corrective Action Decision Document for Corrective Action Unit 204: Storage Bunkers, Nevada Test Site, Nevada: Revision 0, Including Errata Sheet

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office

    2004-04-01

    This Corrective Action Decision Document identifies the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office's corrective action alternative recommendation for each of the corrective action sites (CASs) within Corrective Action Unit (CAU) 204: Storage Bunkers, Nevada Test Site (NTS), Nevada, under the Federal Facility Agreement and Consent Order. An evaluation of analytical data from the corrective action investigation, review of current and future operations at each CAS, and a detailed comparative analysis of potential corrective action alternatives were used to determine the appropriate corrective action for each CAS. There are six CASs in CAU 204, which are all located between Areas 1, 2, 3, and 5 on the NTS. The No Further Action alternative was recommended for CASs 01-34-01, 02-34-01, 03-34-01, and 05-99-02; and a Closure in Place with Administrative Controls recommendation was the preferred corrective action for CASs 05-18-02 and 05-33-01. These alternatives were judged to meet all requirements for the technical components evaluated as well as applicable state and federal regulations for closure of the sites and will eliminate potential future exposure pathways to the contaminated media at CAU 204.

  12. Inhibition Potentiates the Synchronizing Action of Electrical Synapses

    PubMed Central

    Pfeuty, Benjamin; Golomb, David; Mato, Germán; Hansel, David

    2007-01-01

    In vivo and in vitro experimental studies have found that blocking electrical interactions connecting GABAergic interneurons reduces oscillatory activity in the γ range in cortex. However, recent theoretical works have shown that the ability of electrical synapses to promote or impede synchrony, when alone, depends on their location on the dendritic tree of the neurons, the intrinsic properties of the neurons and the connectivity of the network. The goal of the present paper is to show that this versatility in the synchronizing ability of electrical synapses is greatly reduced when the neurons also interact via inhibition. To this end, we study a model network comprising two-compartment conductance-based neurons interacting with both types of synapses. We investigate the effect of electrical synapses on the dynamical state of the network as a function of the strength of the inhibition. We find that for weak inhibition, electrical synapses reinforce inhibition-generated synchrony only if they promote synchrony when they are alone. In contrast, when inhibition is sufficiently strong, electrical synapses improve synchrony even if when acting alone they would stabilize asynchronous firing. We clarify the mechanism underlying this cooperative interplay between electrical and inhibitory synapses. We show that it is relevant in two physiologically observed regimes: spike-to-spike synchrony, where neurons fire at almost every cycle of the population oscillations, and stochastic synchrony, where neurons fire irregularly and at a rate which is substantially lower than the frequency of the global population rhythm. PMID:18946530

  13. Do displacement activities help preschool children to inhibit a forbidden action?

    PubMed

    Pecora, Giulia; Addessi, Elsa; Schino, Gabriele; Bellagamba, Francesca

    2014-10-01

    Displacement activities are commonly recognized as behavioral patterns, mostly including self-directed actions (e.g., scratching, self-touching), that often occur in situations involving conflicting motivational tendencies. In ethology, several researchers have suggested that displacement activities could facilitate individuals in dealing with the stress experienced in a frustrating context. In child developmental research, some authors have assessed whether distraction strategies could help children to inhibit a dominant response during delay of gratification tasks. However, little is known about the displacement activities that young children may produce in such situations. This study was aimed at investigating whether displacement activities had an effect on preschool children's ability to postpone an immediate gratification (i.e., interacting with an attractive toy, a musical box), thereby functioning as regulators of their emotional state. To this end, we administered 143 2- to 4-year-olds with a delay maintenance task and related their performance with displacement activities they produced during the task and with actions with an external object. Children's latency to touch the musical box was positively related to their rate of displacement activities. However, the rate of displacement activities increased progressively as long as the children were able to inhibit the interaction with the musical box. In addition, the rate of displacement activities during the first 1 min of test did not predict the ability of children to inhibit the interaction with the box. These results suggest that displacement activities represented a functionless by-product of motivational conflict rather than a strategy that children used to inhibit their response to an attractive stimulus.

  14. Tamoxifen inhibition of prolactin action in the mouse mammary gland.

    PubMed

    Biswas, R; Vonderhaar, B K

    1991-01-01

    Binding of lactogenic hormones to particulate and solubilized microsomal membranes isolated from mammary glands of lactating mice is inhibited by direct addition of 10(-10) M or greater concentrations of triphenylethylene antiestrogens [i.e. tamoxifen (TAM), 4-hydroxy-tamoxifen, and Nafoxidine] to the binding assays. Estradiol and other antiestrogens such as BPEA (-2-(4-tert-butyl-phenoxy) ethyl diethylamine hydrochloride, LY117018, and LY 156758 do not have this effect. The triphenylethylene antiestrogens bind to the membrane-associated antiestrogen binding sites (AEBS). Effectiveness of binding to the AEBS parallels the effectiveness of inhibition of the lactogen binding. The effect is selective in that binding of epidermal growth factor and insulin to these same membranes is unaffected by the antiestrogens. Binding of PRL to membranes prepared from the livers of the lactating mice is also unaffected. Both the PRL receptor and AEBS are primarily localized to the microsomal membrane fraction of cells. Maximal inhibition of PRL binding by TAM is observed in the light microsomes that contain plasma membranes. In addition to inhibition of PRL binding, TAM also prevents the PRL-induced accumulation of caseins by cultured mouse mammary explants. Thus it appears that the triphenylethylene antiestrogens, acting through the AEBS, act as antilactogens in the normal mammary gland.

  15. Is social inhibition of return due to action co-representation?

    PubMed

    Atkinson, Mark A; Simpson, Andrew; Skarratt, Paul A; Cole, Geoff G

    2014-07-01

    When two individuals alternate reaching responses to visual targets presented on a shared workspace, one individual is slower to respond to targets occupying the same position as their partner's previous response. This phenomenon is thought to be due to processes that inhibit the initiation of a movement to a location recently acted upon. However, two distinct forms of the inhibition account have been posited, one based on inhibition of an action, the other based on inhibition of an action and location. Furthermore, an additional recent explanation suggests the phenomenon is due to mechanisms that give rise to action congruency effects. Thus the three different theories differ in the degree to which action co-representation plays a role in the effect. The aim of the present work was to examine these competing accounts. Three experiments demonstrated that when identical actions are made, the effect is modulated by the configuration of the visual stimuli acted upon and the perceptual demands of the task. In addition, when the co-actors perform different actions to the same target, the effect is still observed. These findings support the hypothesis that this particular joint action phenomenon is generated via social cues that induce location-based inhibition of return rather than being due to shared motor co-representations.

  16. Action Video Gaming and Cognitive Control: Playing First Person Shooter Games Is Associated with Improved Action Cascading but Not Inhibition.

    PubMed

    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.

  17. Action Video Gaming and Cognitive Control: Playing First Person Shooter Games Is Associated with Improved Action Cascading but Not Inhibition

    PubMed Central

    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. PMID:26655929

  18. Prostaglandin E₂ inhibits human lung fibroblast chemotaxis through disparate actions on different E-prostanoid receptors.

    PubMed

    Li, Ying-Ji; Wang, Xing-Qi; Sato, Tadashi; Kanaji, Nobuhiro; Nakanishi, Masanori; Kim, Miok; Michalski, Joel; Nelson, Amy J; Sun, Jian-Hong; Farid, Maha; Basma, Hesham; Patil, Amol; Toews, Myron L; Liu, Xiangde; Rennard, Stephen I

    2011-01-01

    The migration of fibroblasts is believed to play a key role in both normal wound repair and abnormal tissue remodeling. Prostaglandin E (PGE)(2), a mediator that can inhibit many fibroblast functions including chemotaxis, was reported to be mediated by the E-prostanoid (EP) receptor EP2. PGE(2), however, can act on four receptors. This study was designed to determine if EP receptors, in addition to EP2, can modulate fibroblast chemotaxis. Using human fetal lung fibroblasts, the expression of all four EP receptors was demonstrated by Western blotting. EP2-selective and EP4-selective agonists inhibited both chemotaxis toward fibronectin in the blindwell assay and migration in a wound-closure assay. In contrast, EP1-selective and EP3-selective agonists stimulated cell migration in both assay systems. These results were confirmed using EP-selective antagonists. The role of both EP2 and EP4 receptors in mediating the PGE(2) inhibition of chemotaxis was also confirmed by small interfering RNA suppression. Furthermore, the role of EP receptors was confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE(2) can act on multiple EP receptors in human lung fibroblasts, to exert disparate effects. Alterations in EP receptor expression may have the potential to alter PGE(2) action. Targeting specific EP receptors may offer therapeutic opportunities in conditions characterized by abnormal tissue repair and remodeling.

  19. Nootropic nefiracetam inhibits proconvulsant action of peripheral-type benzodiazepines in epileptic mutant EL mice.

    PubMed

    Nakamoto, Yurie; Shiotani, Tadashi; Watabe, Shigeo; Nabeshima, Toshitaka; Yoshii, Mitsunobu

    2004-10-01

    Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5-4864, a specific agonist for peripheral-type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5-4864 (i.p.) in comparison with nonepileptic DDY mice. Nefiracetam administered orally to EL mice inhibited spontaneous seizures. In DDY mice, convulsions induced by Ro 5-4864 were prevented by nefiracetam when administered by i.v. injection. Aniracetam (i.v.) was partially effective, but piracetam and oxiracetam were ineffective as anticonvulsants. Binding assay for brain tissues revealed a higher density of mitochondrial PBR in EL mice compared with DDY mice. Binding of the PBR ligands Ro 5-4864 to either EL or DDY mouse brain was inhibited by micromolar concentrations of these nootropic agents in the sequence of nefiracetam > aniracetam > oxiracetam, piracetam. This rank order is identical to potency as anticonvulsants. These data suggest that nefiracetam may prevent toxic effects of PBR agonists through interacting with PBR.

  20. All optical experimental design for neuron excitation, inhibition, and action potential detection

    NASA Astrophysics Data System (ADS)

    Walsh, Alex J.; Tolstykh, Gleb; Martens, Stacey; Sedelnikova, Anna; Ibey, Bennett L.; Beier, Hope T.

    2016-03-01

    Recently, infrared light has been shown to both stimulate and inhibit excitatory cells. However, studies of infrared light for excitatory cell inhibition have been constrained by the use of invasive and cumbersome electrodes for cell excitation and action potential recording. Here, we present an all optical experimental design for neuronal excitation, inhibition, and action potential detection. Primary rat neurons were transfected with plasmids containing the light sensitive ion channel CheRiff. CheRiff has a peak excitation around 450 nm, allowing excitation of transfected neurons with pulsed blue light. Additionally, primary neurons were transfected with QuasAr2, a fast and sensitive fluorescent voltage indicator. QuasAr2 is excited with yellow or red light and therefore does not spectrally overlap CheRiff, enabling imaging and action potential activation, simultaneously. Using an optic fiber, neurons were exposed to blue light sequentially to generate controlled action potentials. A second optic fiber delivered a single pulse of 1869nm light to the neuron causing inhibition of the evoked action potentials (by the blue light). When used in concert, these optical techniques enable electrode free neuron excitation, inhibition, and action potential recording, allowing research into neuronal behaviors with high spatial fidelity.

  1. Solar urticaria. Determinations of action and inhibition spectra.

    PubMed

    Hasei, K; Ichihashi, M

    1982-05-01

    A 42-year-old woman acquired solar urticaria approximately ten minutes after exposure to sunlight. Urticaria developed from visible light emitted from a projector lamp after a similar time lag. Monochromatic rays between 400 and 500 nm induced immediate urticaria by irradiation, with four times the minimal urticarial dose. Urticaria that was induced by monochromatic rays of the projector lamp was completely inhibited by immediate reirradiation of test sites with light waves longer that 530 nm. Radiant heat exposure from an electric hair dryer at 50 degrees C had no suppressive effects on the development of urticarial lesions.

  2. 76 FR 13665 - Cambridge Tool & Die, Including On-Site Leased Workers From Action Total Staffing, Cambridge, OH...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-14

    ... certification to include workers leased from Action Total Staffing working on-site at the Cambridge, Ohio... Employment and Training Administration Cambridge Tool & Die, Including On-Site Leased Workers From Action Total Staffing, Cambridge, OH; Amended Certification Regarding Eligibility To Apply for...

  3. A global call for action to include gender in research impact assessment.

    PubMed

    Ovseiko, Pavel V; Greenhalgh, Trisha; Adam, Paula; Grant, Jonathan; Hinrichs-Krapels, Saba; Graham, Kathryn E; Valentine, Pamela A; Sued, Omar; Boukhris, Omar F; Al Olaqi, Nada M; Al Rahbi, Idrees S; Dowd, Anne-Maree; Bice, Sara; Heiden, Tamika L; Fischer, Michael D; Dopson, Sue; Norton, Robyn; Pollitt, Alexandra; Wooding, Steven; Balling, Gert V; Jakobsen, Ulla; Kuhlmann, Ellen; Klinge, Ineke; Pololi, Linda H; Jagsi, Reshma; Smith, Helen Lawton; Etzkowitz, Henry; Nielsen, Mathias W; Carrion, Carme; Solans-Domènech, Maite; Vizcaino, Esther; Naing, Lin; Cheok, Quentin H N; Eckelmann, Baerbel; Simuyemba, Moses C; Msiska, Temwa; Declich, Giovanna; Edmunds, Laurel D; Kiparoglou, Vasiliki; Buchan, Alison M J; Williamson, Catherine; Lord, Graham M; Channon, Keith M; Surender, Rebecca; Buchan, Alastair M

    2016-07-19

    Global investment in biomedical research has grown significantly over the last decades, reaching approximately a quarter of a trillion US dollars in 2010. However, not all of this investment is distributed evenly by gender. It follows, arguably, that scarce research resources may not be optimally invested (by either not supporting the best science or by failing to investigate topics that benefit women and men equitably). Women across the world tend to be significantly underrepresented in research both as researchers and research participants, receive less research funding, and appear less frequently than men as authors on research publications. There is also some evidence that women are relatively disadvantaged as the beneficiaries of research, in terms of its health, societal and economic impacts. Historical gender biases may have created a path dependency that means that the research system and the impacts of research are biased towards male researchers and male beneficiaries, making it inherently difficult (though not impossible) to eliminate gender bias. In this commentary, we - a group of scholars and practitioners from Africa, America, Asia and Europe - argue that gender-sensitive research impact assessment could become a force for good in moving science policy and practice towards gender equity. Research impact assessment is the multidisciplinary field of scientific inquiry that examines the research process to maximise scientific, societal and economic returns on investment in research. It encompasses many theoretical and methodological approaches that can be used to investigate gender bias and recommend actions for change to maximise research impact. We offer a set of recommendations to research funders, research institutions and research evaluators who conduct impact assessment on how to include and strengthen analysis of gender equity in research impact assessment and issue a global call for action.

  4. Theory including future not excluded: Formulation of complex action theory II

    NASA Astrophysics Data System (ADS)

    Nagao, Keiichi; Nielsen, Holger Bech

    2013-02-01

    We study a complex action theory (CAT) whose path runs over not only past but also future. We show that, if we regard a matrix element defined in terms of the future state at time TB and the past state at time TA as an expectation value in the CAT, then we are allowed to have the Heisenberg equation, Ehrenfest's theorem, and the conserved probability current density. In addition, we show that the expectation value at the present time t of a future-included theory for large TB - t and large t - TA corresponds to that of a future-not-included theory with a proper inner product for large t - TA. Hence, the CAT with future explicitly present in the formalism and influencing in principle the past is not excluded phenomenologically, because the effects are argued to be very small in the present era. Furthermore, we explicitly derive the Hamiltonian for the future state via a path integral, and confirm that it is given by the Hermitian conjugate of the Hamiltonian for the past state.

  5. Construction of action for heterotic string field theory including the Ramond sector

    NASA Astrophysics Data System (ADS)

    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.

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

    SciTech Connect

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

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

  7. 24 CFR 248.233 - Approval of a plan of action that includes incentives.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HOUSING ACT AND OTHER AUTHORITIES PREPAYMENT OF LOW INCOME HOUSING MORTGAGES Prepayment and Plans of Action Under the Emergency Low Income Preservation Act of 1987 § 248.233 Approval of a plan of action...— (1) The housing will be retained as housing affordable for very low income families,...

  8. Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.

    PubMed

    Lundin, Anna; Dijkman, Ronald; Bergström, Tomas; Kann, Nina; Adamiak, Beata; Hannoun, Charles; Kindler, Eveline; Jónsdóttir, Hulda R; Muth, Doreen; Kint, Joeri; Forlenza, Maria; Müller, Marcel A; Drosten, Christian; Thiel, Volker; Trybala, Edward

    2014-05-01

    Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

  9. Mechanism of Action and Inhibition of dehydrosqualene Synthase

    SciTech Connect

    F Lin; C Liu; Y Liu; Y Zhang; K Wang; W Jeng; T Ko; R Cao; A Wang; E Oldfield

    2011-12-31

    'Head-to-head' terpene synthases catalyze the first committed steps in sterol and carotenoid biosynthesis: the condensation of two isoprenoid diphosphates to form cyclopropylcarbinyl diphosphates, followed by ring opening. Here, we report the structures of Staphylococcus aureus dehydrosqualene synthase (CrtM) complexed with its reaction intermediate, presqualene diphosphate (PSPP), the dehydrosqualene (DHS) product, as well as a series of inhibitors. The results indicate that, on initial diphosphate loss, the primary carbocation so formed bends down into the interior of the protein to react with C2,3 double bond in the prenyl acceptor to form PSPP, with the lower two-thirds of both PSPP chains occupying essentially the same positions as found in the two farnesyl chains in the substrates. The second-half reaction is then initiated by the PSPP diphosphate returning back to the Mg{sup 2+} cluster for ionization, with the resultant DHS so formed being trapped in a surface pocket. This mechanism is supported by the observation that cationic inhibitors (of interest as antiinfectives) bind with their positive charge located in the same region as the cyclopropyl carbinyl group; that S-thiolo-diphosphates only inhibit when in the allylic site; activity results on 11 mutants show that both DXXXD conserved domains are essential for PSPP ionization; and the observation that head-to-tail isoprenoid synthases as well as terpene cyclases have ionization and alkene-donor sites which spatially overlap those found in CrtM.

  10. 30 CFR 250.526 - What must I include in my notification of corrective action?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and... action: (a) Lessee or Operator name; (b) Area name and OCS block number; (c) Well name and API...

  11. 30 CFR 250.527 - What must I include in my notification of corrective action?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and... action: (a) Lessee or Operator name; (b) Area name and OCS block number; (c) Well name and API...

  12. 30 CFR 250.527 - What must I include in my notification of corrective action?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and... action: (a) Lessee or Operator name; (b) Area name and OCS block number; (c) Well name and API...

  13. Corrective Action Investigation Plan for Corrective Action Unit 204: Storage Bunkers, Nevada Test Site, Nevada (December 2002, Revision No.: 0), Including Record of Technical Change No. 1

    SciTech Connect

    NNSA /NSO

    2002-12-12

    The Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 204 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 204 is located on the Nevada Test Site approximately 65 miles northwest of Las Vegas, Nevada. This CAU is comprised of six Corrective Action Sites (CASs) which include: 01-34-01, Underground Instrument House Bunker; 02-34-01, Instrument Bunker; 03-34-01, Underground Bunker; 05-18-02, Chemical Explosives Storage; 05-33-01, Kay Blockhouse; 05-99-02, Explosive Storage Bunker. Based on site history, process knowledge, and previous field efforts, contaminants of potential concern for Corrective Action Unit 204 collectively include radionuclides, beryllium, high explosives, lead, polychlorinated biphenyls, total petroleum hydrocarbons, silver, warfarin, and zinc phosphide. The primary question for the investigation is: ''Are existing data sufficient to evaluate appropriate corrective actions?'' To address this question, resolution of two decision statements is required. Decision I is to ''Define the nature of contamination'' by identifying any contamination above preliminary action levels (PALs); Decision II is to ''Determine the extent of contamination identified above PALs. If PALs are not exceeded, the investigation is completed. If PALs are exceeded, then Decision II must be resolved. In addition, data will be obtained to support waste management decisions. Field activities will include radiological land area surveys, geophysical surveys to identify any subsurface metallic and nonmetallic debris, field screening for applicable contaminants of potential concern, collection and analysis of surface and subsurface soil samples from biased locations, and step-out sampling to define the extent of

  14. 24 CFR 968.315 - Comprehensive Plan (including five-year action plan).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...-year action plan). (a) Submission. As soon as possible after modernization funds first become available... components of the comprehensive plan. The meeting shall be open to all residents and duly elected resident... addition, the PHA shall identify the funds or other resources in the consolidated plan that are to be...

  15. Aqueous leaf extract of Jatropha gossypiifolia L. (Euphorbiaceae) inhibits enzymatic and biological actions of Bothrops jararaca snake venom.

    PubMed

    Félix-Silva, Juliana; Souza, Thiago; Menezes, Yamara A S; Cabral, Bárbara; Câmara, Rafael B G; Silva-Junior, Arnóbio A; Rocha, Hugo A O; Rebecchi, Ivanise M M; Zucolotto, Silvana M; Fernandes-Pedrosa, Matheus F

    2014-01-01

    Snakebites are a serious public health problem due their high morbi-mortality. The main available specific treatment is the antivenom serum therapy, which has some disadvantages, such as poor neutralization of local effects, risk of immunological reactions, high cost and difficult access in some regions. In this context, the search for alternative therapies is relevant. Therefore, the aim of this study was to evaluate the antiophidic properties of Jatropha gossypiifolia, a medicinal plant used in folk medicine to treat snakebites. The aqueous leaf extract of the plant was prepared by decoction and phytochemical analysis revealed the presence of sugars, alkaloids, flavonoids, tannins, terpenes and/or steroids and proteins. The extract was able to inhibit enzymatic and biologic activities induced by Bothrops jararaca snake venom in vitro and in vivo. The blood incoagulability was efficiently inhibited by the extract by oral route. The hemorrhagic and edematogenic local effects were also inhibited, the former by up to 56% and the latter by 100%, in animals treated with extract by oral and intraperitoneal routes, respectively. The inhibition of myotoxic action of B. jararaca reached almost 100%. According to enzymatic tests performed, it is possible to suggest that the antiophidic activity may be due an inhibitory action upon snake venom metalloproteinases (SVMPs) and/or serine proteinases (SVSPs), including fibrinogenolytic enzymes, clotting factors activators and thrombin like enzymes (SVTLEs), as well upon catalytically inactive phospholipases A2 (Lys49 PLA2). Anti-inflammatory activity, at least partially, could also be related to the inhibition of local effects. Additionally, protein precipitating and antioxidant activities may also be important features contributing to the activity presented. In conclusion, the results demonstrate the potential antiophidic activity of J. gossypiifolia extract, including its significant action upon local effects, suggesting that

  16. Aqueous Leaf Extract of Jatropha gossypiifolia L. (Euphorbiaceae) Inhibits Enzymatic and Biological Actions of Bothrops jararaca Snake Venom

    PubMed Central

    Félix-Silva, Juliana; Souza, Thiago; Menezes, Yamara A. S.; Cabral, Bárbara; Câmara, Rafael B. G.; Silva-Junior, Arnóbio A.; Rocha, Hugo A. O.; Rebecchi, Ivanise M. M.; Zucolotto, Silvana M.; Fernandes-Pedrosa, Matheus F.

    2014-01-01

    Snakebites are a serious public health problem due their high morbi-mortality. The main available specific treatment is the antivenom serum therapy, which has some disadvantages, such as poor neutralization of local effects, risk of immunological reactions, high cost and difficult access in some regions. In this context, the search for alternative therapies is relevant. Therefore, the aim of this study was to evaluate the antiophidic properties of Jatropha gossypiifolia, a medicinal plant used in folk medicine to treat snakebites. The aqueous leaf extract of the plant was prepared by decoction and phytochemical analysis revealed the presence of sugars, alkaloids, flavonoids, tannins, terpenes and/or steroids and proteins. The extract was able to inhibit enzymatic and biologic activities induced by Bothrops jararaca snake venom in vitro and in vivo. The blood incoagulability was efficiently inhibited by the extract by oral route. The hemorrhagic and edematogenic local effects were also inhibited, the former by up to 56% and the latter by 100%, in animals treated with extract by oral and intraperitoneal routes, respectively. The inhibition of myotoxic action of B. jararaca reached almost 100%. According to enzymatic tests performed, it is possible to suggest that the antiophidic activity may be due an inhibitory action upon snake venom metalloproteinases (SVMPs) and/or serine proteinases (SVSPs), including fibrinogenolytic enzymes, clotting factors activators and thrombin like enzymes (SVTLEs), as well upon catalytically inactive phospholipases A2 (Lys49 PLA2). Anti-inflammatory activity, at least partially, could also be related to the inhibition of local effects. Additionally, protein precipitating and antioxidant activities may also be important features contributing to the activity presented. In conclusion, the results demonstrate the potential antiophidic activity of J. gossypiifolia extract, including its significant action upon local effects, suggesting that

  17. Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain

    PubMed Central

    Hirasawa, Michiru; Schwab, Yannick; Natah, Sirajedin; Hillard, Cecilia J; Mackie, Ken; Sharkey, Keith A; Pittman, Quentin J

    2004-01-01

    Oxytocin is released from supraoptic magnocellular neurones and is thought to act at presynaptic receptors to inhibit transmitter release. We now show that this effect is mediated by endocannabinoids, but that oxytocin nonetheless plays an important role in endocannabinoid signalling. WIN55,212-2, a cannabinoid receptor agonist, mimicked the action of oxytocin and occluded oxytocin-induced presynaptic inhibition. The cannabinoid action is at the presynaptic terminal as shown by alteration in paired pulse ratio, a reduction in miniature EPSC frequency and immunohistochemical localization of CB1 receptors on presynaptic terminals. AM251, a CB1 receptor antagonist, blocked both the WIN55,212-2 and the oxytocin-induced presynaptic inhibition of EPSCs. Depolarization of postsynaptic magnocellular neurones (which contain fatty acid amide hydrolase, a cannabinoid catabolic enzyme) caused a transient inhibition of EPSCs that could be blocked by both the AM251 and Manning compound, an oxytocin/vasopressin receptor antagonist. This indicates that somatodendritic peptide release and action on previously identified autoreceptors facilitates the release of endocannabinoids that act as mediators of presynaptic inhibition. PMID:15254151

  18. Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain.

    PubMed

    Hirasawa, Michiru; Schwab, Yannick; Natah, Sirajedin; Hillard, Cecilia J; Mackie, Ken; Sharkey, Keith A; Pittman, Quentin J

    2004-09-01

    Oxytocin is released from supraoptic magnocellular neurones and is thought to act at presynaptic receptors to inhibit transmitter release. We now show that this effect is mediated by endocannabinoids, but that oxytocin nonetheless plays an important role in endocannabinoid signalling. WIN55,212-2, a cannabinoid receptor agonist, mimicked the action of oxytocin and occluded oxytocin-induced presynaptic inhibition. The cannabinoid action is at the presynaptic terminal as shown by alteration in paired pulse ratio, a reduction in miniature EPSC frequency and immunohistochemical localization of CB1 receptors on presynaptic terminals. AM251, a CB1 receptor antagonist, blocked both the WIN55,212-2 and the oxytocin-induced presynaptic inhibition of EPSCs. Depolarization of postsynaptic magnocellular neurones (which contain fatty acid amide hydrolase, a cannabinoid catabolic enzyme) caused a transient inhibition of EPSCs that could be blocked by both the AM251 and Manning compound, an oxytocin/vasopressin receptor antagonist. This indicates that somatodendritic peptide release and action on previously identified autoreceptors facilitates the release of endocannabinoids that act as mediators of presynaptic inhibition.

  19. Minocycline inhibits D-amphetamine-elicited action potential bursts in a central snail neuron.

    PubMed

    Chen, Y-H; Lin, P-L; Wong, R-W; Wu, Y-T; Hsu, H-Y; Tsai, M-C; Lin, M-J; Hsu, Y-C; Lin, C-H

    2012-10-25

    Minocycline is a second-generation tetracycline that has been reported to have powerful neuroprotective properties. In our previous studies, we found that d-amphetamine (AMPH) elicited action potential bursts in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. This study sought to determine the effects of minocycline on the AMPH-elicited action potential pattern changes in the central snail neuron, using the two-electrode voltage clamping method. Extracellular application of AMPH at 300 μM elicited action potential bursts in the RP4 neuron. Minocycline dose-dependently (300-900 μM) inhibited the action potential bursts elicited by AMPH. The inhibitory effects of minocycline on AMPH-elicited action potential bursts were restored by forskolin (50 μM), an adenylate cyclase activator, and by dibutyryl cAMP (N(6),2'-O-Dibutyryladenosine 3',5'-cyclic monophosphate; 1mM), a membrane-permeable cAMP analog. Co-administration of forskolin (50 μM) plus tetraethylammonium chloride (TEA; 5mM) or co-administration of TEA (5mM) plus dibutyryl cAMP (1mM) also elicited action potential bursts, which were prevented and inhibited by minocycline. In addition, minocycline prevented and inhibited forskolin (100 μM)-elicited action potential bursts. Notably, TEA (50mM)-elicited action potential bursts in the RP4 neuron were not affected by minocycline. Minocycline did not affect steady-state outward currents of the RP4 neuron. However, minocycline did decrease the AMPH-elicited steady-state current changes. Similarly, minocycline decreased the effects of forskolin-elicited steady-state current changes. Pretreatment with H89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride; 10 μM), a protein kinase A inhibitor, inhibited AMPH-elicited action potential bursts and decreased AMPH-elicited steady-state current changes. These results suggest that the cAMP-protein kinase A signaling pathway and the steady-state current are involved in

  20. Hypouricaemic action of mangiferin results from metabolite norathyriol via inhibiting xanthine oxidase activity.

    PubMed

    Niu, Yanfen; Liu, Jia; Liu, Hai-Yang; Gao, Li-Hui; Feng, Guo-Hua; Liu, Xu; Li, Ling

    2016-09-01

    Context Mangiferin has been reported to possess a potential hypouricaemic effect. However, the pharmacokinetic studies in rats showed that its oral bioavailability was only 1.2%, suggesting that mangiferin metabolites might exert the action. Objective The hypouricaemic effect and the xanthine oxidase inhibition of mangiferin and norathyriol, a mangiferin metabolite, were investigated. Inhibition of norathyriol analogues (compounds 3-9) toward xanthine oxidase was also evaluated. Materials and methods For a dose-dependent study, mangiferin (1.5-6.0 mg/kg) and norathyriol (0.92-3.7 mg/kg) were administered intragastrically to mice twice daily for five times. For a time-course study, mice received mangiferin and norathyriol both at a single dose of 7.1 μmol/kg. In vitro, inhibition of test compounds (2.4-2.4 mM) against xanthine oxidase activity was evaluated by the spectrophotometrical method. The inhibition type was identified from Lineweaver-Burk plots. Results Norathyriol (0.92, 1.85 and 3.7 mg/kg) dose dependently decreased the serum urate levels by 27.0, 33.6 and 37.4%, respectively. The action was more potent than that of mangiferin at the low dose, but was equivalent at the higher doses. Additionally, the hypouricaemic action of them exhibited a time dependence. In vitro, norathyriol markedly inhibited the xanthine oxidase activities, with the IC50 value of 44.6 μM, but mangiferin did not. The kinetic studies showed that norathyriol was an uncompetitive inhibitor by Lineweaver-Burk plots. The structure-activity relationships exhibited that three hydroxyl groups in norathyriol at the C-1, C-3 and C-6 positions were essential for maintaining xanthine oxidase inhibition. Discussion and conclusion Norathyriol was responsible for the hypouricaemic effect of mangiferin via inhibiting xanthine oxidase activity.

  1. Optimisation of driver actions in RWD race car including tyre thermodynamics

    NASA Astrophysics Data System (ADS)

    Maniowski, Michal

    2016-04-01

    The paper presents an innovative method for a lap time minimisation by using genetic algorithms for a multi objective optimisation of a race driver-vehicle model. The decision variables consist of 16 parameters responsible for actions of a professional driver (e.g. time traces for brake, accelerator and steering wheel) on a race track part with RH corner. Purpose-built, high fidelity, multibody vehicle model (called 'miMa') is described by 30 generalised coordinates and 440 parameters, crucial in motorsport. Focus is put on modelling of the tyre tread thermodynamics and its influence on race vehicle dynamics. Numerical example considers a Rear Wheel Drive BMW E36 prepared for track day events. In order to improve the section lap time (by 5%) and corner exit velocity (by 4%) a few different driving strategies are found depending on thermal conditions of semi-slick tyres. The process of the race driver adaptation to initially cold or hot tyres is explained.

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

    PubMed

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

    Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC50 values of 1.2 and 1.5mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC50=0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  3. Apoptosis May Explain the Pharmacological Mode of Action and Adverse Effects of Isotretinoin, Including Teratogenicity.

    PubMed

    Melnik, Bodo C

    2017-02-08

    Isotretinoin (13-cis retinoic acid) is the most effective sebum-suppressive drug for the treatment of severe acne. Its effect depends on sebocyte apoptosis, which results from isotretinoin-induced expression of the apoptotic protein tumour necrosis factor-related apoptosis-inducing ligand, insulin-like growth factor-binding protein-3 and neutrophil gelatinase-associated lipocalin. This review proposes that the pharmacological mode of action of isotretinoin in the treatment of severe acne, acute promyelocytic leukaemia, and neuroblastoma results from apoptosis. Furthermore, apoptosis may be the underlying and unifying mechanism of the adverse effects of isotretinoin on neural crest cells (teratogenicity), hippocampal neurones (depression), epidermal keratinocytes and mucosa cells (mucocutaneous side-effects), hair follicle cells (telogen effluvium), intestinal epithelial cells (inflammatory bowel disease), skeletal muscle cells (myalgia and release of creatine kinase), and hepatocytes (release of transaminases and very low-density lipoproteins). Genetic variants of components of the apoptotic signalling cascade, such as RARA polymorphisms, might explain variations in the magnitude of isotretinoin-induced apoptotic signalling and apparently identify subgroups of patients who experience either stronger adverse effects with isotretinoin therapy or resistance to treatment.

  4. High concentrations of dexmedetomidine inhibit compound action potentials in frog sciatic nerves without α2 adrenoceptor activation

    PubMed Central

    Kosugi, Toshifumi; Mizuta, Kotaro; Fujita, Tsugumi; Nakashima, Mikio; Kumamoto, Eiichi

    2010-01-01

    BACKGROUND AND PURPOSE Dexmedetomidine, an α2-adrenoceptor agonist, exhibits anti-nociceptive actions at the spinal cord and enhances the effect of local anaesthetics in the peripheral nervous system. Although the latter action may be attributed in part to inhibition of nerve conduction produced by dexmedetomidine, this has not been fully examined yet. EXPERIMENTAL APPROACH We examined the effects of various adrenoceptor agonists including dexmedetomidine, and tetracaine, a local anaesthetic, on compound action potentials (CAPs) recorded from the frog sciatic nerve, using the air-gap method. KEY RESULTS Dexmedetomidine reversibly and concentration-dependently reduced the peak amplitude of CAPs (IC50 = 0.40 mmol·L−1). This action was not antagonized by two α2-adrenoceptor antagonists, yohimbine and atipamezole; the latter antagonist itself reduced CAP peak amplitude. Clonidine and oxymetazoline, two other α2-adrenoceptor agonists, also inhibited CAPs; the maximum effect of clonidine was only 20%, while oxymetazoline was less potent (IC50 = 1.5 mmol·L−1) than dexmedetomidine. On the other hand, (±)-adrenaline, (±)-noradrenaline, α1-adrenoceptor agonist (-)-phenylephrine and β-adrenoceptor agonist (-)-isoprenaline (each 1 mmol·L−1) had no effect on CAPs. Tetracaine reversibly reduced CAP peak amplitude (IC50 of 0.014 mmol·L−1). CONCLUSIONS AND IMPLICATIONS Dexmedetomidine reduced CAP peak amplitude without α2-adrenoceptor activation (at concentrations >1000-fold higher than those used as α2 adrenoceptor agonist), with a lower potency than tetracaine. CAPs were inhibited by other α2 adrenoceptor agonists, oxymetazoline and clonidine, and also an α2 adrenoceptor antagonist atipamezole. Thus, some drugs acting on α2 adrenoceptors are able to block nerve conduction. PMID:20649570

  5. Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine.

    PubMed

    Dobbs, Lauren K; Kaplan, Alanna R; Lemos, Julia C; Matsui, Aya; Rubinstein, Marcelo; Alvarez, Veronica A

    2016-06-01

    Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. VIDEO ABSTRACT.

  6. 24 CFR 968.315 - Comprehensive Plan (including five-year action plan).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... level at least equal to applicable HUD standards with respect to modernization standards, energy... estimated per unit unfunded hard cost is equal to or less than the per unit TDC for the smallest bedroom... equal to the modernization and energy conservation standards. This includes specifying the work to...

  7. Feed-forward inhibition of androgen receptor activity by glucocorticoid action in human adipocytes.

    PubMed

    Hartig, Sean M; He, Bin; Newberg, Justin Y; Ochsner, Scott A; Loose, David S; Lanz, Rainer B; McKenna, Neil J; Buehrer, Benjamin M; McGuire, Sean E; Marcelli, Marco; Mancini, Michael A

    2012-09-21

    We compared transcriptomes of terminally differentiated mouse 3T3-L1 and human adipocytes to identify cell-specific differences. Gene expression and high content analysis (HCA) data identified the androgen receptor (AR) as both expressed and functional, exclusively during early human adipocyte differentiation. The AR agonist dihydrotestosterone (DHT) inhibited human adipocyte maturation by downregulation of adipocyte marker genes, but not in 3T3-L1. It is interesting that AR induction corresponded with dexamethasone activation of the glucocorticoid receptor (GR); however, when exposed to the differentiation cocktail required for adipocyte maturation, AR adopted an antagonist conformation and was transcriptionally repressed. To further explore effectors within the cocktail, we applied an image-based support vector machine (SVM) classification scheme to show that adipocyte differentiation components inhibit AR action. The results demonstrate human adipocyte differentiation, via GR activation, upregulates AR but also inhibits AR transcriptional activity.

  8. Corrective Action Investigation Plan for Corrective Action Unit 410: Waste Disposal Trenches, Tonopah Test Range, Nevada, Revision 0 (includes ROTCs 1, 2, and 3)

    SciTech Connect

    NNSA /NV

    2002-07-16

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 410 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 410 is located on the Tonopah Test Range (TTR), which is included in the Nevada Test and Training Range (formerly the Nellis Air Force Range) approximately 140 miles northwest of Las Vegas, Nevada. This CAU is comprised of five Corrective Action Sites (CASs): TA-19-002-TAB2, Debris Mound; TA-21-003-TANL, Disposal Trench; TA-21-002-TAAL, Disposal Trench; 09-21-001-TA09, Disposal Trenches; 03-19-001, Waste Disposal Site. This CAU is being investigated because contaminants may be present in concentrations that could potentially pose a threat to human health and/or the environment, and waste may have been disposed of with out appropriate controls. Four out of five of these CASs are the result of weapons testing and disposal activities at the TTR, and they are grouped together for site closure based on the similarity of the sites (waste disposal sites and trenches). The fifth CAS, CAS 03-19-001, is a hydrocarbon spill related to activities in the area. This site is grouped with this CAU because of the location (TTR). Based on historical documentation and process know-ledge, vertical and lateral migration routes are possible for all CASs. Migration of contaminants may have occurred through transport by infiltration of precipitation through surface soil which serves as a driving force for downward migration of contaminants. Land-use scenarios limit future use of these CASs to industrial activities. The suspected contaminants of potential concern which have been identified are volatile organic compounds; semivolatile organic compounds; high explosives; radiological constituents including depleted uranium

  9. Selective Serotonin Reuptake Inhibitors (SSRIs) Inhibit Insulin Secretion and Action in Pancreatic β Cells*

    PubMed Central

    Isaac, Roi; Boura-Halfon, Sigalit; Gurevitch, Diana; Shainskaya, Alla; Levkovitz, Yechiel; Zick, Yehiel

    2013-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used for the treatment of mood and anxiety disorders. Here, we demonstrate that incubation (2 h) of murine islets or Min6 β cell line with the SSRIs paroxetine, fluoxetine, or sertraline inhibited insulin-induced Tyr phosphorylation of insulin receptor substrate (IRS)-2 protein and the activation of its downstream targets Akt and the ribosomal protein S6 kinase-1 (S6K1). Inhibition was dose-dependent with half-maximal effects at ∼15–20 μm. It correlated with a rapid dephosphorylation and activation of the IRS kinase GSK3β. Introduction of GSK3β siRNAs eliminated the inhibitory effects of the SSRIs. Inhibition of IRS-2 action by 30 μm SSRI was associated with a marked inhibition of glucose-stimulated insulin secretion from murine and human pancreatic islets. Secretion induced by basic secretagogues (KCl and Arg) was not affected by these drugs. Prolonged treatment (16 h) of Min6 cells with sertraline resulted in the induction of inducible nitric oxide synthase; activation of endoplasmic reticulum stress, and the initiation of the unfolded protein response, manifested by enhanced transcription of ATF4 and C/EBP homologous protein. This triggered an apoptotic process, manifested by enhanced caspase 3/7 activity, which resulted in β cell death. These findings implicate SSRIs as inhibitors of IRS protein function and insulin action through the activation of GSK3β. They further suggest that SSRIs inhibit insulin secretion; induce the unfolded protein response; activate an apoptotic process, and trigger β cell death. Given that SSRIs promote insulin resistance while inhibiting insulin secretion, these drugs might accelerate the transition from an insulin-resistant state to overt diabetes. PMID:23275337

  10. Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis.

    PubMed

    Taliaferro-Smith, LaTonia; Nagalingam, Arumugam; Knight, Brandi Brandon; Oberlick, Elaine; Saxena, Neeraj K; Sharma, Dipali

    2013-01-01

    The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients

  11. Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat.

    PubMed Central

    Buckingham, R. E.; Hamilton, T. C.; Howlett, D. R.; Mootoo, S.; Wilson, C.

    1989-01-01

    1. In rat isolated thoracic aortic rings pre-contracted with noradrenaline (10(-6) M), cromakalim (3 x 10(-7)-3 x 10(-5) M) produced concentration-related relaxation. This effect was progressively inhibited by increasing concentrations of the anti-diabetic sulphonylurea drug, glibenclamide (10(-6)-10(-5) M). 2. In rat isolated portal veins, cromakalim (3 x 10(-8)-10(-6) M) produced concentration-related inhibition of the spontaneous contractive activity and glibenclamide (3 x 10(-7)-3 x 10(-6) M) prevented this inhibitory action in a concentration-dependent manner. 3. In both rat aortic rings and portal veins, cromakalim (10(-5) M) stimulated 86Rb efflux. Prior exposure to glibenclamide (10(-7)-10(-6) M) produced a concentration-related inhibition of this response. 4. In conscious rats, cromakalim, 0.075 mg kg-1 i.v., produced a rapid and sustained fall in arterial blood pressure which was not influenced by pretreatment (2 h) with a large oral dose of glibenclamide (100 mg kg-1). 5. In conscious rats, the hypotensive action of cromakalim, 0.075 mg kg-1 i.v., was abolished by pretreatment (30 min) with glibenclamide, 20 mg kg-1, given by the intravenous route. 6. The results suggest that the vasorelaxant and hypotensive actions of cromakalim involve a K+ channel which can be inhibited by glibenclamide, but which may be distinct from the ATP-sensitive K+ channel of the pancreatic beta-cell. PMID:2497925

  12. Secondary Effects of Glyphosate Action in Phelipanche aegyptiaca: Inhibition of Solute Transport from the Host Plant to the Parasite.

    PubMed

    Shilo, Tal; Rubin, Baruch; Plakhine, Dina; Gal, Shira; Amir, Rachel; Hacham, Yael; Wolf, Shmuel; Eizenberg, Hanan

    2017-01-01

    It is currently held that glyphosate efficiently controls the obligate holoparasite Phelipanche aegyptiaca (Egyptian broomrape) by inhibiting its endogenous shikimate pathway, thereby causing a deficiency in aromatic amino acids (AAA). While there is no argument regarding the shikimate pathway being the primary site of the herbicide's action, the fact that the parasite receives a constant supply of nutrients, including proteins and amino acids, from the host does not fit with an AAA deficiency. This apparent contradiction implies that glyphosate mechanism of action in P. aegyptiaca is probably more complex and does not end with the inhibition of the AAA biosynthetic pathway alone. A possible explanation would lie in a limitation of the translocation of solutes from the host as a secondary effect. We examined the following hypotheses: (a) glyphosate does not affects P. aegyptiaca during its independent phase and (b) glyphosate has a secondary effect on the ability of P. aegyptiaca to attract nutrients, limiting the translocation to the parasite. By using a glyphosate-resistant host plant expressing the "phloem-mobile" green fluorescent protein (GFP), it was shown that glyphosate interacts specifically with P. aegyptiaca, initiating a deceleration of GFP translocation to the parasite within 24 h of treatment. Additionally, changes in the entire sugars profile (together with that of other metabolites) of P. aegyptiaca were induced by glyphosate. In addition, glyphosate did not impair germination or seedling development of P. aegyptiaca but begun to exert its action only after the parasite has established a connection to the host vascular system and became exposed to the herbicide. Our findings thus indicate that glyphosate does indeed have a secondary effect in P. aegyptiaca, probably as a consequence of its primary target inhibition-via inhibition of the translocation of phloem-mobile solutes to the parasite, as was simulated by the mobile GFP. The observed

  13. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation

    PubMed Central

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10−6 cm/sec, followed by amodiaquine around 20 x 10−6 cm/sec; both mefloquine and artesunate were around 10 x 10−6 cm/sec. Methylene blue was between 2 and 6 x 10−6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  14. Stress alters caffeine action on investigatory behaviour and behavioural inhibition in the mouse.

    PubMed

    Meyer, L; Caston, J

    2004-02-04

    A lot of studies have demonstrated that the physiological action of drugs can be modified by stressors. The present study investigates the effects of stressors on caffeine action on investigatory behaviour and behavioural inhibition in C57Bl6/J mice. For 6 consecutive days, the mice were subjected to one stressful procedure each day consisting on days 1 and 3 of immersion in cold water for 10 periods of 10s each, on days 2 and 5 of a restraint stress for 2 periods of 5 min each, and on days 3 and 6 of placing the animals in a lit openfield for a 10-min period. Saline or caffeine (30, 60 or 120 mgkg-1) were i.p. administered immediately after the last stressful experience, and the animals were tested behaviourally 10 min later. Their behaviour was compared to that of unstressed mice injected with either saline or caffeine. The results show that: (1) in saline-treated mice, stress decreased the investigatory behaviour and increased the behavioural inhibition; (2) in unstressed mice, caffeine decreased the investigatory behaviour in a dose-dependent manner; moreover, behavioural disinhibition, which appeared at low doses of the drug, did not at higher doses; (3) in stressed mice, the dose-dependent action of caffeine was almost abolished and the drug elicited, whatever the dose, a slight increase of the investigatory behaviour and a strong behavioural disinhibition. It is concluded that stress antagonizes the inhibitory action of caffeine on the investigatory behaviour and potentiates its action on behavioural disinhibition. The results are discussed in terms of interaction of stress and caffeine on the dopaminergic system.

  15. Neutrophil activation: an alternative to prostaglandin inhibition as the mechanism of action for NSAIDs.

    PubMed

    Altman, R D

    1990-02-01

    Experimental findings suggest that inhibition of neutrophil activation rather than suppression of prostaglandin formation may represent the principal mechanism of action of antiinflammatory drugs. This theory would account for the effectiveness of prostaglandin preserving agents, such as the nonacetylated salicylate salsalate, in the treatment of rheumatic disease. Results of the controlled clinical trials described in other papers contained in this supplement indicate that salsalate is equally effective as aspirin and the newer NSAID naproxen in relieving the signs and symptoms of rheumatoid arthritis. The damage to the gastric mucosa associated with NSAID use is believed to be attributable to impairment of mucosal defense mechanisms resulting from the inhibition of gastroprotective prostaglandins. Confirmation of neutrophil activation as the mechanism of action of NSAIDs would explain the efficacy of salsalate in light of its lower incidence of gastrointestinal side effects in controlled clinical trials with aspirin and naproxen. Establishment of such a mechanism would also suggest that the other adverse effects related to prostaglandin inhibition, such as hypersensitivity reactions, platelet dysfunction, and a reduction in renal function, are not necessary correlates of effective antiinflammatory therapy.

  16. Frequency-dependent inhibition of antidromic hippocampal compound action potentials by anti-convulsants.

    PubMed

    Teriakidis, Adrianna; Brown, Jon T; Randall, Andrew

    2006-01-01

    Using rat hippocampal slices, extracellularly recorded antidromic compound action potentials (cAP) were produced in CA1 pyramidal cell populations by electrical stimulation of the alveus at 0.5 Hz. These responses were additionally examined across a range of stimulus frequencies between 0.5 and 100 Hz. Anticonvulsant drugs in clinical use were applied via perfusion of the recording chamber. Three anticonvulsants produced a concentration-dependent inhibition of the cAP evoked at low frequency (0.5 Hz). The following IC(50) values were observed: lamotrigine, 210 microM (interpolated); carbamazepine, 210 microM (interpolated); phenytoin, 400 microM (extrapolated). The extent of inhibition produced was increased when trains of 30 cAPs were evoked at frequencies > or 30 Hz. This frequency dependence was quantified by measuring a response integral for a range of compound concentrations. Three other compounds valproate (5 mM), topiramate (500 microM) and levetiracetam (500 microM) produced no clear effect at any stimulus frequency tested. Using this simple neurophysiological assay it has been possible to compare the use-dependent inhibition of hippocampal action potentials by a range of anticonvulsants, providing a useful adjunct to patch clamp studies of such molecules at Na(+) channels. There is no clear correlation between the activity in this model and the clinical efficacy of these drugs in different forms of epilepsy.

  17. Milnacipran inhibits oxaliplatin-induced mechanical allodynia through spinal action in mice.

    PubMed

    Andoh, Tsugunobu; Kitamura, Ryo; Kuraishi, Yasushi

    2015-01-01

    We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, would have therapeutic effect on oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin (3 mg/kg) induced mechanical allodynia, which peaked on day 10 after injection and almost completely subsided by day 20. Ten days post-oxaliplatin injection, the intraperitoneal administration of milnacipran (3-30 mg/kg) significantly and dose-dependently inhibited the established mechanical allodynia. Intrathecal injections of milnacipran (2.1-21 µg/site) also significantly and dose-dependently inhibited mechanical allodynia, but intracisternal and intracereboventricular injections at the same doses did not. The present results suggest that milnacipran is effective against oxaliplatin-induced mechanical allodynia and that the antiallodynic effect is mainly mediated by actions on the spinal cord.

  18. Intravenous immunoglobulin inhibits BAFF production in chronic inflammatory demyelinating polyneuropathy - a new mechanism of action?

    PubMed

    Bick, Sandra; Tschernatsch, Marlene; Karg, Anne; Fuehlhuber, Verena; Trenczek, Tina E; Faltermeier, Kathrin; Hackstein, Holger; Kaps, Manfred; Blaes, Franz

    2013-03-15

    Chronic-inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disease treated with intravenous immunoglobulin (IVIg). The underlying mechanism of action remains incompletely understood. The B-cell activating factor BAFF contributes to B-cell homeostasis and (auto-)antibody production. BAFF was recently identified as one key molecule in the development of autoimmune diseases. Herein, we demonstrate that BAFF serum levels are elevated in CIDP patients. IVIg treatment resulted in a significant decrease of BAFF serum level. In vitro, IVIg inhibited BAFF in monocytes. Consequently, we identified BAFF as a new target for IVIg in CIDP treatment and provide a new, Fcγ-receptor independent, mechanism of action for IVIg.

  19. INHIBITION BY PHOSPHOLIPIDS OF THE ACTION OF SYNTHETIC DETERGENTS ON BACTERIA.

    PubMed

    Baker, Z; Harrison, R W; Miller, B F

    1941-11-30

    1. Lecithin, cephalin, and sphingomyelin prevent the inhibition of bacterial metabolism which is caused by synthetic anionic and cationic detergents. The phospholipids must be added either before or simultaneously with the detergent. Addition after the detergent is without effect. Bacteria still exhibit this phenomenon after they have been exposed to the phospholipid and thoroughly washed. 2. A similar action of the phospholipids has been demonstrated towards the bactericidal compounds isolated by Dubos and Hoogerheide from soil bacteria. There is very little effect with bactericidal mercury compounds. 3. The effect of lecithin against the bactericidal action of synthetic detergents was also determined. It was found that germicidal quantities of the detergents were not effective in the presence of the phospholipids.

  20. Antioxidant action of eugenol compounds: role of metal ion in the inhibition of lipid peroxidation.

    PubMed

    Ito, Masae; Murakami, Keiko; Yoshino, Masataka

    2005-03-01

    Antioxidant action of eugenol compounds was analyzed in relation to the role of transition metal. Iron-mediated lipid peroxidation and autooxidation of Fe2+ ion were inhibited markedly by isoeugenol, and less effectively by eugenol. Copper-dependent oxidation of low density lipoprotein (LDL) was potently inhibited by eugenol and isoeugenol to the same extent: eugenol compounds showed protective effects by prolonging lag phase and by suppressing propagation rate in the absence and presence of alpha-tocopherol. Inhibition of LDL oxidation by eugenol compounds was closely related to activities reducing copper and scavenging a stable radical, 1,1'-diphenyl-2-picrylhydrazyl (DPPH). Antioxidant properties of eugenol compounds can be explained by forming complexes with reduced metals. Potent inhibitory effect of isoeugenol on lipid peroxidation may be related to the decreased formation of perferryl ion or the iron-oxygen chelate complex as the initiating factor of lipid peroxidation by keeping iron at a reduced state. Inhibition of LDL oxidation by eugenol compounds is due to the suppression of free radical cascade of lipid peroxidation in LDL by reducing copper ion.

  1. Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase.

    PubMed

    Zhang, Lei; Chen, Xiaojie; Liu, Jun; Zhu, Qingzhang; Leng, Ying; Luo, Xiaomin; Jiang, Hualiang; Liu, Hong

    2012-12-01

    Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references.

  2. Secondary Effects of Glyphosate Action in Phelipanche aegyptiaca: Inhibition of Solute Transport from the Host Plant to the Parasite

    PubMed Central

    Shilo, Tal; Rubin, Baruch; Plakhine, Dina; Gal, Shira; Amir, Rachel; Hacham, Yael; Wolf, Shmuel; Eizenberg, Hanan

    2017-01-01

    It is currently held that glyphosate efficiently controls the obligate holoparasite Phelipanche aegyptiaca (Egyptian broomrape) by inhibiting its endogenous shikimate pathway, thereby causing a deficiency in aromatic amino acids (AAA). While there is no argument regarding the shikimate pathway being the primary site of the herbicide's action, the fact that the parasite receives a constant supply of nutrients, including proteins and amino acids, from the host does not fit with an AAA deficiency. This apparent contradiction implies that glyphosate mechanism of action in P. aegyptiaca is probably more complex and does not end with the inhibition of the AAA biosynthetic pathway alone. A possible explanation would lie in a limitation of the translocation of solutes from the host as a secondary effect. We examined the following hypotheses: (a) glyphosate does not affects P. aegyptiaca during its independent phase and (b) glyphosate has a secondary effect on the ability of P. aegyptiaca to attract nutrients, limiting the translocation to the parasite. By using a glyphosate-resistant host plant expressing the “phloem-mobile” green fluorescent protein (GFP), it was shown that glyphosate interacts specifically with P. aegyptiaca, initiating a deceleration of GFP translocation to the parasite within 24 h of treatment. Additionally, changes in the entire sugars profile (together with that of other metabolites) of P. aegyptiaca were induced by glyphosate. In addition, glyphosate did not impair germination or seedling development of P. aegyptiaca but begun to exert its action only after the parasite has established a connection to the host vascular system and became exposed to the herbicide. Our findings thus indicate that glyphosate does indeed have a secondary effect in P. aegyptiaca, probably as a consequence of its primary target inhibition—via inhibition of the translocation of phloem-mobile solutes to the parasite, as was simulated by the mobile GFP. The observed

  3. Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

    PubMed Central

    Calland, Noémie; Sahuc, Marie-Emmanuelle; Belouzard, Sandrine; Pène, Véronique; Bonnafous, Pierre; Mesalam, Ahmed Atef; Deloison, Gaspard; Descamps, Véronique; Sahpaz, Sevser; Wychowski, Czeslaw; Lambert, Olivier; Brodin, Priscille; Duverlie, Gilles; Meuleman, Philip; Rosenberg, Arielle R.; Dubuisson, Jean; Rouillé, Yves

    2015-01-01

    ABSTRACT Despite the validation of direct-acting antivirals for hepatitis C treatment, the discovery of new compounds with different modes of action may still be of importance for the treatment of special patient populations. We recently identified a natural molecule, epigallocatechin-3-gallate (EGCG), as an inhibitor of hepatitis C virus (HCV) targeting the viral particle. The aim of this work was to discover new natural compounds with higher anti-HCV activity than that of EGCG and determine their mode of action. Eight natural molecules with structure similarity to EGCG were selected. HCV JFH1 in cell culture and HCV pseudoparticle systems were used to determine the antiviral activity and mechanism of action of the compounds. We identified delphinidin, a polyphenol belonging to the anthocyanidin family, as a new inhibitor of HCV entry. Delphinidin inhibits HCV entry in a pangenotypic manner by acting directly on the viral particle and impairing its attachment to the cell surface. Importantly, it is also active against HCV in primary human hepatocytes, with no apparent cytotoxicity and in combination with interferon and boceprevir in cell culture. Different approaches showed that neither aggregation nor destruction of the particle occurred. Cryo-transmission electron microscopy observations of HCV pseudoparticles treated with delphinidin or EGCG showed a bulge on particles that was not observed under control conditions. In conclusion, EGCG and delphinidin inhibit HCV entry by a new mechanism, i.e., alteration of the viral particle structure that impairs its attachment to the cell surface. IMPORTANCE In this article, we identify a new inhibitor of hepatitis C virus (HCV) infection, delphinidin, that prevents HCV entry. This natural compound, a plant pigment responsible for the blue-purple color of flowers and berries, belongs to the flavonoid family, like the catechin EGCG, the major component present in green tea extract, which is also an inhibitor of HCV entry. We

  4. Inhibition of Androgen Receptor Transcriptional Activity as a Novel Mechanism of Action of Arsenic

    PubMed Central

    Rosenblatt, Adena E.; Burnstein, Kerry L.

    2009-01-01

    Environmental sodium arsenite is a toxin that is associated with male infertility due to decreased and abnormal sperm production. Arsenic trioxide (ATO), another inorganic trivalent semimetal, is an effective therapy for acute promyelocytic leukemia, and there is investigation of its possible efficacy in prostate cancer. However, the mechanism of arsenic action in male urogenital tract tissues is not clear. Because the androgen receptor (AR) plays an important role in spermatogenesis and prostate cancer, we explored the possibility that trivalent arsenic regulates AR function. We found that arsenic inhibited AR transcriptional activity in prostate cancer and Sertoli cells using reporter gene assays testing several androgen response element-containing regions and by assessing native target gene expression. Arsenic inhibition of AR activity was not due to down-regulation of AR protein levels, decreased hormone binding to AR, disruption of AR nuclear translocation, or interference with AR-DNA binding in vitro. However, chromatin immunoprecipitation studies revealed that arsenic inhibited AR recruitment to an AR target gene enhancer in vivo. Consistent with a deficiency in AR-chromatin binding, arsenic disrupted AR amino and carboxyl termini interaction. Furthermore, ATO caused a significant decrease in prostate cancer cell proliferation that was more pronounced in cells expressing AR compared with cells depleted of AR. In addition, inhibition of AR activity by ATO and by the AR antagonist, bicalutamide, was additive. Thus, arsenic-induced male infertility may be due to inhibition of AR activity. Further, because AR is an important target in prostate cancer therapy, arsenic may serve as an effective therapeutic option. PMID:19131511

  5. Inhibition of the compound action potentials of frog sciatic nerves by aroma oil compounds having various chemical structures.

    PubMed

    Ohtsubo, Sena; Fujita, Tsugumi; Matsushita, Akitomo; Kumamoto, Eiichi

    2015-03-01

    Plant-derived chemicals including aroma oil compounds have an ability to inhibit nerve conduction and modulate transient receptor potential (TRP) channels. Although applying aroma oils to the skin produces a local anesthetic effect, this has not been yet examined throughly. The aim of the present study was to know how nerve conduction inhibitions by aroma oil compounds are related to their chemical structures and whether these activities are mediated by TRP activation. Compound action potentials (CAPs) were recorded from the frog sciatic nerve by using the air-gap method. Citral (aldehyde), which activates various types of TRP channels, attenuated the peak amplitude of CAP with the half-maximal inhibitory concentration (IC50) value of 0.46 mmol/L. Another aldehyde (citronellal), alcohol (citronellol, geraniol, (±)-linalool, (-)-linalool, (+)-borneol, (-)-borneol, α-terpineol), ester (geranyl acetate, linalyl acetate, bornyl acetate), and oxide (rose oxide) compounds also reduced CAP peak amplitudes (IC50: 0.50, 0.35, 0.53, 1.7, 2.0, 1.5, 2.3, 2.7, 0.51, 0.71, 0.44, and 2.6 mmol/L, respectively). On the other hand, the amplitudes were reduced by a small extent by hydrocarbons (myrcene and p-cymene) and ketone (camphor) at high concentrations (2-5 mmol/L). The activities of citral and other TRP agonists ((+)-borneol and camphor) were resistant to TRP antagonist ruthenium red. An efficacy sequence for the CAP inhibitions was generally aldehydes ≥ esters ≥ alcohols > oxides > hydrocarbons. The CAP inhibition by the aroma oil compound was not related to its octanol-water partition coefficient. It is suggested that aroma oil compounds inhibit nerve conduction in a manner specific to their chemical structures without TRP activation.

  6. [Microbial metabolites that inhibit sterol biosynthesis, their chemical diversity and characteristics of mode of action].

    PubMed

    Trenin, A S

    2013-01-01

    Inhibitors of sterol biosynthesis (ISB) are widespread in nature and characterized by appreciable diversity both in their chemical structure and mode of action. Many of these inhibitors express noticeable biological activity and approved themselves in development of various pharmaceuticals. In this review there is a detailed description of biologically active microbial metabolites with revealed chemical structure that have ability to inhibit sterol biosynthesis. Inhibitors of mevalonate pathway in fungous and mammalian cells, exhibiting hypolipidemic or antifungal activity, as well as inhibitors of alternative non-mevalonate (pyruvate gliceraldehyde phosphate) isoprenoid pathway, which are promising in the development of affective antimicrobial or antiparasitic drugs, are under consideration in this review. Chemical formulas of the main natural inhibitors and their semi-synthetic derivatives are represented. Mechanism of their action at cellular and biochemical level is discussed. Special attention is given to inhibitors of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase (group of lovastatin) and inhibitors of acyl-CoA-cholesterol-acyl transferase (ACAT) that possess hypolipidemic activity and could be affective in the treatment of atherosclerosis. In case of inhibitors of late stages of sterol biosynthesis (after squalene formation) special attention is paid to compounds possessing evident antifungal and antitumoral activity. Explanation of mechanism of anticancer and antiviral action of microbial ISB, as well as the description of their ability to induce apoptosis is given.

  7. Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma.

    PubMed

    Diaz, Roberto Jose; Golbourn, Brian; Faria, Claudia; Picard, Daniel; Shih, David; Raynaud, Denis; Leadly, Michael; MacKenzie, Danielle; Bryant, Melissa; Bebenek, Matthew; Smith, Christian A; Taylor, Michael D; Huang, Annie; Rutka, James T

    2015-02-20

    Medulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYC- overexpressing medulloblastoma cells with AZD1152-HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152-HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma.

  8. Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma

    PubMed Central

    Faria, Claudia; Picard, Daniel; Shih, David; Raynaud, Denis; Leadly, Michael; MacKenzie, Danielle; Bryant, Melissa; Bebenek, Matthew; Smith, Christian A.; Taylor, Michael D.; Huang, Annie; Rutka, James T.

    2015-01-01

    Medulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYC-overexpressing medulloblastoma cells with AZD1152-HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152-HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma. PMID:25739120

  9. Corrective Action Investigation Plan for Corrective Action Unit 529: Area 25 Contaminated Materials, Nevada Test Site, Nevada, Rev. 0, Including Record of Technical Change No. 1

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office

    2003-02-26

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 529, Area 25 Contaminated Materials, Nevada Test Site (NTS), Nevada, under the Federal Facility Agreement and Consent Order. CAU 529 consists of one Corrective Action Site (25-23-17). For the purpose of this investigation, the Corrective Action Site has been divided into nine parcels based on the separate and distinct releases. A conceptual site model was developed for each parcel to address the translocation of contaminants from each release. The results of this investigation will be used to support a defensible evaluation of corrective action alternatives in the corrective action decision document.

  10. Cognitive control and right ventrolateral prefrontal cortex: reflexive reorienting, motor inhibition, and action updating

    PubMed Central

    Levy, Benjamin J.; Wagner, Anthony D.

    2011-01-01

    Delineating the functional organization of the prefrontal cortex is central to advancing models of goal-directed cognition. Considerable evidence indicates that specific forms of cognitive control are associated with distinct subregions of the left ventrolateral prefrontal cortex (VLPFC), but less is known about functional specialization within the right VLPFC. We report a functional MRI meta-analysis of two prominent theories of right VLPFC function: stopping of motor responses and reflexive orienting to abrupt perceptual onsets. Along with a broader review of right VLPFC function, extant data indicate that stopping and reflexive orienting similarly recruit the inferior frontal junction (IFJ), suggesting that IFJ supports the detection of behaviorally relevant stimuli. By contrast, other right VLPFC subregions are consistently active during motor inhibition, but not reflexive reorienting tasks, with posterior-VLPFC being active during the updating of action plans and mid-VLPFC responding to decision uncertainty. These results highlight the rich functional heterogeneity that exists within right VLPFC. PMID:21486295

  11. Corrective Action Investigation Plan for Corrective Action Unit 536: Area 3 Release Site, Nevada Test Site, Nevada (Rev. 0 / June 2003), Including Record of Technical Change No. 1

    SciTech Connect

    2003-06-27

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office's approach to collect the data necessary to evaluate corrective action alternatives (CAAs) appropriate for the closure of Corrective Action Unit (CAU) 536: Area 3 Release Site, Nevada Test Site, Nevada, under the Federal Facility Agreement and Consent Order. Corrective Action Unit 536 consists of a single Corrective Action Site (CAS): 03-44-02, Steam Jenny Discharge. The CAU 536 site is being investigated because existing information on the nature and extent of possible contamination is insufficient to evaluate and recommend corrective action alternatives for CAS 03-44-02. The additional information will be obtained by conducting a corrective action investigation (CAI) prior to evaluating CAAs and selecting the appropriate corrective action for this CAS. The results of this field investigation are to be used to support a defensible evaluation of corrective action alternatives in the corrective action decision document. Record of Technical Change No. 1 is dated 3-2004.

  12. Potentiation of Amitriptyline Anti-Hyperalgesic-Like Action By Astroglial Connexin 43 Inhibition in Neuropathic Rats

    PubMed Central

    Jeanson, Tiffany; Duchêne, Adeline; Richard, Damien; Bourgoin, Sylvie; Picoli, Christèle; Ezan, Pascal; Mouthon, Franck; Giaume, Christian; Hamon, Michel; Charvériat, Mathieu

    2016-01-01

    Antidepressants, prescribed as first line treatment of neuropathic pain, have a limited efficacy and poorly tolerated side effects. Because recent studies pointed out the implication of astroglial connexins (Cx) in both neuropathic pain and antidepressive treatment, we investigated whether their blockade by mefloquine could modulate the action of the tricyclic antidepressant amitriptyline. Using primary cultures, we found that both mefloquine and amitriptyline inhibited Cx43-containing gap junctions, and that the drug combination acted synergically. We then investigated whether mefloquine could enhance amitriptyline efficacy in a preclinical model of neuropathic pain. Sprague-Dawley rats that underwent chronic unilateral constriction injury (CCI) to the sciatic nerve (SN) were treated with either amitriptyline, mefloquine or the combination of both drugs. Whereas acute treatments were ineffective, chronic administration of amitriptyline reduced CCI-SN-induced hyperalgesia-like behavior, and this effect was markedly enhanced by co-administration of mefloquine, which was inactive on its own. No pharmacokinetic interactions between both drugs were observed and CCI-SN-induced neuroinflammatory and glial activation markers remained unaffected by these treatments in dorsal root ganglia and spinal cord. Mechanisms downstream of CCI-SN-induced neuroinflammation and glial activation might therefore be targeted. Connexin inhibition in astroglia could represent a promising approach towards improving neuropathic pain therapy by antidepressants. PMID:27941941

  13. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.

    PubMed

    Buggey, Jonathan; Mentz, Robert J; DeVore, Adam D; Velazquez, Eric J

    2015-09-01

    Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.

  14. Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition

    PubMed Central

    Pang, Tao; Wang, Juan; Benicky, Julius; Saavedra, Juan M.

    2012-01-01

    Background Minocycline exhibits anti-inflammatory properties independent of its antibiotic activity, ameliorating inflammatory responses in monocytes and macrophages. However, the mechanisms of minocycline anti-inflammatory effects are only partially understood. Methods Human circulating monocytes were cultured in the presence of lipopolysaccharide (LPS), 50 ng/ml, and minocycline (10–40 µM). Gene expression was determined by RT-PCR, cytokine and prostaglandin E2 (PGE2) release by ELISA, protein expression, phosphorylation and nuclear translocation by Western blotting. Results Minocycline significantly reduced the inflammatory response in LPS-challenged monocytes, decreasing LPS-induced transcription of pro-inflammatory tumor-necrosis factor alpha (TNF-α), interleukin-1 beta, interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), and the LPS-stimulated TNF-α, IL-6 and PGE2 release. Minocycline inhibited LPS-induced activation of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), NF-κB, LPS-induced TNF-α factor (LITAF) and the Nur77 nuclear receptor. Mechanisms involved in the anti-inflammatory effects of minocycline include a reduction of LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) activation and stimulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. Conclusions We provide novel evidence demonstrating that the anti-inflammatory effects of minocycline in human monocytes include, in addition to decreased NF-κB activation, abrogation of the LPS-stimulated LOX-1, LITAF, Nur77 pathways, p38 MAPK inhibition and PI3K/Akt activation. Our results reveal that minocycline inhibits points of convergence of distinct and interacting signaling pathways mediating multiple inflammatory signals which may influence monocyte activation, traffic and recruitment into the brain. General significance Our results in primary human monocytes contribute to explain the profound anti-inflammatory and protective effects of minocycline in

  15. Corrective Action Investigation Plan for Corrective Action Unit 516: Septic Systems and Discharge Points, Nevada Test Site, Nevada, Rev. 0, Including Record of Technical Change No. 1

    SciTech Connect

    2003-04-28

    This Corrective Action Investigation Plan (CAIP) contains the U.S. Department of Energy (DOE), National Nuclear Security Administration Nevada Sites Office's (NNSA/NSO's) approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 516, Septic Systems and Discharge Points, Nevada Test Site (NTS), Nevada, under the Federal Facility Agreement and Consent Order. CAU 516 consists of six Corrective Action Sites: 03-59-01, Building 3C-36 Septic System; 03-59-02, Building 3C-45 Septic System; 06-51-01, Sump Piping, 06-51-02, Clay Pipe and Debris; 06-51-03, Clean Out Box and Piping; and 22-19-04, Vehicle Decontamination Area. Located in Areas 3, 6, and 22 of the NTS, CAU 516 is being investigated because disposed waste may be present without appropriate controls, and hazardous and/or radioactive constituents may be present or migrating at concentrations and locations that could potentially pose a threat to human health and the environment. Existing information and process knowledge on the expected nature and extent of contamination of CAU 516 are insufficient to select preferred corrective action alternatives; therefore, additional information will be obtained by conducting a corrective action investigation. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document. Record of Technical Change No. 1 is dated 3/2004.

  16. Metabolic and vascular actions of endothelin-1 are inhibited by insulin-mediated vasodilation in perfused rat hindlimb muscle.

    PubMed

    Kolka, Cathryn M; Rattigan, Stephen; Richards, Stephen; Clark, Michael G

    2005-08-01

    Endothelin-1 (ET-1) is a potent endothelium-derived vasoactive peptide and may be involved in the microvascular actions of insulin for the normal delivery of nutrients to muscle, although higher levels may be antagonistic. Our aim was to observe the interaction between ET-1 and insulin. Initially, we attempted to distinguish the vascular from the metabolic effects of ET-1 in the constant-flow pump-perfused rat hindlimb by using various doses of ET-1 and measuring changes in perfusion pressure (PP), oxygen consumption (VO(2)), glucose uptake (GU) and lactate release (LR). Sodium nitroprusside (SNP) was used to block vasoconstriction and to thus assess the relationship between vascular and metabolic effects. Insulin was included in later experiments to determine the interaction between insulin and ET-1 on the above parameters. ET-1 caused a dose-dependent increase in PP. Effects on VO(2) were biphasic, with low doses increasing VO(2), and higher doses leading to a net inhibition. GU and LR were increased at lower doses (ET-1 < or =1 nM), but this effect was lost at higher doses (> or =10 nM ET-1). SNP (50 microM) fully blocked the increase in pressure and metabolism due to low-dose ET-1 and partly blocked both pressure and metabolic responses by the high dose. ET-1 vasodilatory activity was minimal at high or low dose. Insulin (15 nM) alone caused GU, which was not affected by ET-1. Of the other parameters measured, insulin behaved essentially the same as SNP, inhibiting the pressure and oxygen effects. Overall, these results show that ET-1 has a biphasic dose-dependent vasoconstrictor effect on hindlimb blood vessels, able to modulate flow to cause both the stimulation and inhibition of metabolism, although these effects are blocked by insulin, which is able to vasodilate against both low and high doses of ET-1.

  17. Inhibition of expression of the circadian clock gene Period causes metabolic abnormalities including repression of glycometabolism in Bombyx mori cells

    PubMed Central

    Tao, Hui; Li, Xue; Qiu, Jian-Feng; Cui, Wen-Zhao; Sima, Yang-Hu; Xu, Shi-Qing

    2017-01-01

    Abnormalities in the circadian clock system are known to affect the body’s metabolic functions, though the molecular mechanisms responsible remain uncertain. In this study, we achieved continuous knockdown of B. mori Period (BmPer) gene expression in the B. mori ovary cell line (BmN), and generated a Per-KD B. mori model with developmental disorders including small individual cells and slow growth. We conducted cell metabolomics assays by gas chromatography/liquid chromatography-mass spectrometry and showed that knockdown of BmPer gene expression resulted in significant inhibition of glycometabolism. Amino acids that used glucose metabolites as a source were also down-regulated, while lipid metabolism and nucleotide metabolism were significantly up-regulated. Metabolite correlation analysis showed that pyruvate and lactate were closely related to glycometabolism, as well as to metabolites such as aspartate, alanine, and xanthine in other pathways. Further validation experiments showed that the activities of the key enzymes of glucose metabolism, hexokinase, phosphofructokinase, and citrate synthase, were significantly decreased and transcription of their encoding genes, as well as that of pyruvate kinase, were also significantly down-regulated. We concluded that inhibition of the circadian clock gene BmPer repressed glycometabolism, and may be associated with changes in cellular amino acid metabolism, and in cell growth and development. PMID:28393918

  18. Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine.

    PubMed

    Vucicevic, Ljubica; Misirkic-Marjanovic, Maja; Paunovic, Verica; Kravic-Stevovic, Tamara; Martinovic, Tamara; Ciric, Darko; Maric, Nadja; Petricevic, Sasa; Harhaji-Trajkovic, Ljubica; Bumbasirevic, Vladimir; Trajkovic, Vladimir

    2014-01-01

    We investigated the role of autophagy, a controlled cellular self-digestion process, in regulating survival of neurons exposed to atypical antipsychotic olanzapine. Olanzapine induced autophagy in human SH-SY5Y neuronal cell line, as confirmed by the increase in autophagic flux and presence of autophagic vesicles, fusion of autophagosomes with lysosomes, and increase in the expression of autophagy-related (ATG) genes ATG4B, ATG5, and ATG7. The production of reactive oxygen species, but not modulation of the main autophagy repressor MTOR or its upstream regulators AMP-activated protein kinase and AKT1, was responsible for olanzapine-triggered autophagy. Olanzapine-mediated oxidative stress also induced mitochondrial depolarization and damage, and the autophagic clearance of dysfunctional mitochondria was confirmed by electron microscopy, colocalization of autophagosome-associated MAP1LC3B (LC3B henceforth) and mitochondria, and mitochondrial association with the autophagic cargo receptor SQSTM1/p62. While olanzapine-triggered mitochondrial damage was not overtly toxic to SH-SY5Y cells, their death was readily initiated upon the inhibition of autophagy with pharmacological inhibitors, RNA interference knockdown of BECN1 and LC3B, or biological free radical nitric oxide. The treatment of mice with olanzapine for 14 d increased the brain levels of autophagosome-associated LC3B-II and mRNA encoding Atg4b, Atg5, Atg7, Atg12, Gabarap, and Becn1. The administration of the autophagy inhibitor chloroquine significantly increased the expression of proapoptotic genes (Trp53, Bax, Bak1, Pmaip1, Bcl2l11, Cdkn1a, and Cdkn1b) and DNA fragmentation in the frontal brain region of olanzapine-exposed animals. These data indicate that olanzapine-triggered autophagy protects neurons from otherwise fatal mitochondrial damage, and that inhibition of autophagy might unmask the neurotoxic action of the drug.

  19. One mechanism of glucocorticoid action in asthma may involve the inhibition of IL-25 expression

    PubMed Central

    Lu, Wei; Lu, Chao; Zhang, Chengming; Zhang, Chenghao

    2017-01-01

    in asthma. One of the mechanisms of glucocorticoid action in asthma may involve inhibition of IL-25 expression.

  20. MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition

    PubMed Central

    Xu, Lei; Yates, Cecelia C.; Lockyer, Pamela; Xie, Liang; Bevilacqua, Ariana; He, Jun; Lander, Cynthia; Patterson, Cam; Willis, Monte

    2014-01-01

    The cell-permeant peptide inhibitor of MAPKAP kinase 2 (MK2), MMI-0100, inhibits MK2 and downstream fibrosis and inflammation. Recent studies have demonstrated that MMI-0100 reduces intimal hyperplasia in a mouse vein graft model, pulmonary fibrosis in a murine bleomycin-induced model and development of adhesions in conjunction with abdominal surgery. MK2 is critical to the pathogenesis of ischemic heart injury as MK2 −/− mice are resistant to ischemic remodeling. Therefore, we tested the hypothesis that inhibiting MK2 with MMI-0100 would protect the heart after acute myocardial infarction (AMI) in vivo. AMI was induced by placing a permanent LAD coronary ligation. When MMI-0100 peptide was given 30 minutes after permanent LAD coronary artery ligation, the resulting fibrosis was reduced/prevented ~50% at a 2 week time point, with a corresponding improvement in cardiac function and decrease in left ventricular dilation. In cultured cardiomyocytes and fibroblasts, MMI-0100 inhibited MK2 to reduce cardiomyocyte caspase 3/7 activity, while enhancing primary cardiac fibroblast caspase 3/7 activity, which may explain MMI-0100’s salvage of cardiac function and anti-fibrotic effects in vivo. These findings suggest that therapeutic inhibition of MK2 after acute MI, using rationally-designed cell-permeant peptides, inhibits cardiac fibrosis and maintains cardiac function by mechanisms that involve inhibiting cardiomyocyte apoptosis, while enhancing primary cardiac fibroblast cell death. PMID:25257914

  1. Glitazones inhibit human monoamine oxidase but their anti-inflammatory actions are not mediated by VAP-1/semicarbazide-sensitive amine oxidase inhibition.

    PubMed

    Carpéné, Christian; Bizou, Mathilde; Tréguer, Karine; Hasnaoui, Mounia; Grès, Sandra

    2015-09-01

    Glitazones are peroxisome proliferator-activated receptor gamma (PPARγ) agonists widely used as antidiabetic drugs also known as thiazolidinediones. Most of them exert other effects such as anti-inflammatory actions via mechanisms supposed to be independent from PPARγ activation (e.g., decreased plasma monocyte chemoattractant protein-1 (MCP-1) levels). Recently, pioglitazone has been shown to inhibit the B form of monoamine oxidase (MAO) in mouse, while rosiglitazone and troglitazone were described as non-covalent inhibitors of both human MAO A and MAO B. Since molecules interacting with MAO might also inhibit semicarbazide-sensitive amine oxidase (SSAO), known as vascular adhesion protein-1 (VAP-1), and since VAP-1/SSAO inhibitors exhibit anti-inflammatory activity, our aim was to elucidate whether VAP-1/SSAO inhibition could be a mechanism involved in the anti-inflammatory behaviour of glitazones. To this aim, MAO and SSAO activities were measured in human subcutaneous adipose tissue biopsies obtained from overweight women undergoing plastic surgery. The production of hydrogen peroxide, an end-product of amine oxidase activity, was determined in tissue homogenates using a fluorometric method. The oxidation of 1 mM tyramine was inhibited by pargyline and almost resistant to semicarbazide, therefore predominantly MAO-dependent. Rosiglitazone was more potent than pioglitazone in inhibiting tyramine oxidation. By contrast, benzylamine oxidation was only abolished by semicarbazide: hence SSAO-mediated. Pioglitazone hampered SSAO activity only when tested at 1 mM while rosiglitazone was inefficient. However, rosiglitazone exhibited anti-inflammatory activity in human adipocytes by limiting MCP-1 expression. Our observations rule out any involvement of VAP-1/SSAO inhibition and subsequent limitation of leukocyte extravasation in the anti-inflammatory action of glitazones.

  2. Fermentation and alternative oxidase contribute to the action of amino acid biosynthesis-inhibiting herbicides.

    PubMed

    Zulet, Amaia; Gil-Monreal, Miriam; Zabalza, Ana; van Dongen, Joost T; Royuela, Mercedes

    2015-03-01

    Acetolactate synthase inhibitors (ALS-inhibitors) and glyphosate (GLP) are two classes of herbicide that act by the specific inhibition of an enzyme in the biosynthetic pathway of branched-chain or aromatic amino acids, respectively. The physiological effects that are detected after application of these two classes of herbicides are not fully understood in relation to the primary biochemical target inhibition, although they have been well documented. Interestingly, the two herbicides' toxicity includes some common physiological effects suggesting that they kill the treated plants by a similar pattern despite targeting different enzymes. The induction of aerobic ethanol fermentation and alternative oxidase (AOX) are two examples of these common effects. The objective of this work was to gain further insight into the role of fermentation and AOX induction in the toxic consequences of ALS-inhibitors and GLP. For this, Arabidopsis T-DNA knockout mutants of alcohol dehydrogenase (ADH) 1 and AOX1a were used. The results found in wild-type indicate that both GLP and ALS-inhibitors reduce ATP production by inducing fermentation and alternative respiration. The main physiological effects in the process of herbicide activity upon treated plants were accumulation of carbohydrates and total free amino acids. The effects of the herbicides on these parameters were less pronounced in mutants compared to wild-type plants. The role of fermentation and AOX regarding pyruvate availability is also discussed.

  3. On the ability to inhibit thought and action: general and special theories of an act of control.

    PubMed

    Logan, Gordon D; Van Zandt, Trisha; Verbruggen, Frederick; Wagenmakers, Eric-Jan

    2014-01-01

    Response inhibition is an important act of control in many domains of psychology and neuroscience. It is often studied in a stop-signal task that requires subjects to inhibit an ongoing action in response to a stop signal. Performance in the stop-signal task is understood as a race between a go process that underlies the action and a stop process that inhibits the action. Responses are inhibited if the stop process finishes before the go process. The finishing time of the stop process is not directly observable; a mathematical model is required to estimate its duration. Logan and Cowan (1984) developed an independent race model that is widely used for this purpose. We present a general race model that extends the independent race model to account for the role of choice in go and stop processes, and a special race model that assumes each runner is a stochastic accumulator governed by a diffusion process. We apply the models to 2 data sets to test assumptions about selective influence of capacity limitations on drift rates and strategies on thresholds, which are largely confirmed. The model provides estimates of distributions of stop-signal response times, which previous models could not estimate. We discuss implications of viewing cognitive control as the result of a repertoire of acts of control tailored to different tasks and situations.

  4. Efficient inhibition of germination of coat-deficient bacterial spores by multivalent metal cations, including terbium (Tb³+).

    PubMed

    Yi, Xuan; Bond, Colton; Sarker, Mahfuzur R; Setlow, Peter

    2011-08-01

    Release of dipicolinic acid (DPA) and its fluorescence with terbium (Tb(3+)) allow rapid measurement of the germination and viability of spores of Bacillus and Clostridium species. However, germination of coat-deficient Bacillus spores was strongly inhibited by Tb(3+) and some other multivalent cations. Tb(3+) also inhibited germination of coat-deficient Clostridium perfringens spores.

  5. cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle.

    PubMed

    Genders, A J; Bradley, E A; Rattigan, S; Richards, S M

    2011-08-01

    There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulin-mediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan-cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic clamps (3 mU·min(-1)·kg(-1)) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity.

  6. Candida albicans biofilm inhibition by synergistic action of terpenes and fluconazole.

    PubMed

    Pemmaraju, Suma C; Pruthi, Parul A; Prasad, R; Pruthi, Vikas

    2013-11-01

    The current treatment options for Candida albicans biofilm-device related infections are very scarce due to their intrinsic increased tolerance to antimycotics. The aim of this work was to study synergistic action of terpenes (eugenol, menthol and thymol) with fluconazole (FLA) on C. albicans biofilm inhibition. The minimum inhibitory concentration (MIC) assayed using CLSI M27-A3 broth micro-dilution method showed antifungal activity against C. albicans MTCC 227 at a concentration of 0.12 % (v/v) for both thymol and eugenol as compared to 0.25 % (v/v) for menthol. FLA was taken as positive control. The effect of these terpenes on metabolic activity of preformed C. albicans biofilm cells was evaluated using 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay in 96-well polystyrene microtiter plate. Thymol and eugenol were more effective at lower concentrations of > or = 1.0 % (v/v) than menthol. Synergistic studies using checkerboard micro-dilution assay showed fractional inhibitory concentration index (sigma FIC = 0.31) between thymol/FLA followed by eugenol/FLA (sigma FIC = 0.37) and menthol/FLA (sigma FIC < 0.5) against pre-formed C. albicans biofilms. Thymol with fluconazole showed highest synergy in reduction of biofilm formation than eugenol and menthol which was not observed when their activities were observed independently. Adherence assay showed 30% viability of C. albicans cells after 2 h of treatment with 0.05 % (v/v) thymol/FLA. Effect of thymol/FLA on C. albicans adhesion visualized by SEM micrographs showed disruption in number of candidal cells and alteration in structural design of C. albicans. Thus, the study demonstrated synergistic effect of terpenes with fluconazole on C. albicans biofilm, which could be future medications for biofilm infections.

  7. 78 FR 42805 - HarperCollins Publishers Distribution Operations Including On-Site Leased Workers From Action...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-17

    ... Leased Workers From D's Packaging and Rennobs, Scranton, Pennsylvania; Amended Certification Regarding... also reports that workers leased from D's Packaging and Rennobs were employed off-site but were under..., Inc., Action Lift, Krayer Detective Agency, D's Packaging and Rennobs. The amended notice...

  8. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer.

    PubMed

    La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza; Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Brancale, Andrea; Novellino, Ettore; Dondio, Giulio; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano

    2014-08-14

    We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.

  9. New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

    PubMed Central

    La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza; Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Brancale, Andrea; Novellino, Ettore; Dondio, Giulio; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano

    2014-01-01

    We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. PMID:25025991

  10. Inhibition of aldose reductase and anti-cataract action of trans-anethole isolated from Foeniculum vulgare Mill. fruits.

    PubMed

    Dongare, Vandana; Kulkarni, Chaitanya; Kondawar, Manish; Magdum, Chandrakant; Haldavnekar, Vivek; Arvindekar, Akalpita

    2012-05-01

    Foeniculum vulgare fruits are routinely consumed for their carminative and mouth freshening effect. The plant was evaluated for aldose reductase inhibition and anti-diabetic action. Bioguided fractionation using silica gel column chromatography, HPLC, and GC-MS analysis revealed trans-anethole as the bioactive constituent possessing potent aldose reductase inhibitory action, with an IC50 value of 3.8μg/ml. Prolonged treatment with the pet ether fraction of the F. vulgare distillate demonstrated improvement in blood glucose, lipid profile, glycated haemoglobin and other parameters in streptozotocin-induced diabetic rats. Trans-anethole could effectively show anti-cataract activity through the increase in soluble lens protein, reduced glutathione, catalase and SOD activity on in vitro incubation of the eye lens with 55mM glucose. Trans-anethole demonstrated noncompetitive to mixed type of inhibition of lens aldose reductase using Lineweaver Burk plot.

  11. Multi-species nitrifying biofilm model (MSNBM) including free ammonia and free nitrous acid inhibition and oxygen limitation.

    PubMed

    Park, Seongjun; Bae, Wookeun; Rittmann, Bruce E

    2010-04-15

    A multi-species nitrifying biofilm model (MSNBM) is developed to describe nitrite accumulation by simultaneous free ammonia (FA) and free nitrous acid (FNA) inhibition, direct pH inhibition, and oxygen limitation in a biofilm. The MSNBM addresses the spatial gradient of pH with biofilm depth and how it induces changes of FA and FNA speciation and inhibition. Simulations using the MSNBM in a completely mixed biofilm reactor show that influent total ammonia nitrogen (TAN) concentration, bulk dissolved oxygen (DO) concentration, and buffer concentration exert significant control on the suppression of nitrite-oxidizing bacteria (NOB) and shortcut biological nitrogen removal (SBNR), but the pH in the bulk liquid has a weaker influence. Ammonium oxidation increases the nitrite concentration and decreases the pH, which together can increase FNA inhibition of NOB in the biofilm. Thus, a low buffer concentration can accentuate SBNR. DO and influent TAN concentrations are efficient means to enhance DO limitation, which affects NOB more than ammonia-oxidizing bacteria (AOB) inside the biofilm. With high influent TAN concentration, FA inhibition is dominant at an early phase, but finally DO limitation becomes more important as TAN degradation and biofilm growth proceed. MSNBM results indicate that oxygen depletion and FNA inhibition throughout the biofilm continuously suppress the growth of NOB, which helps achieve SBNR with a lower TAN concentration than in systems without concentration gradients.

  12. Multiple Molecular and Cellular Mechanisms of Action of Lycopene in Cancer Inhibition

    PubMed Central

    Trejo-Solís, Cristina; Pedraza-Chaverrí, Jose; Torres-Ramos, Mónica; Jiménez-Farfán, Dolores; Cruz Salgado, Arturo; Serrano-García, Norma; Osorio-Rico, Laura; Sotelo, Julio

    2013-01-01

    Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity. PMID:23970935

  13. Superoxide Inhibits Guanine Nucleotide Exchange Factor (GEF) Action on Ras, but not on Rho, through Desensitization of Ras to GEF

    PubMed Central

    2015-01-01

    Ras and Rho GTPases are molecular switches for various vital cellular signaling pathways. Overactivation of these GTPases often causes development of cancer. Guanine nucleotide exchange factors (GEFs) and oxidants function to upregulate these GTPases through facilitation of guanine nucleotide exchange (GNE) of these GTPases. However, the effect of oxidants on GEF functions, or vice versa, has not been known. We show that, via targeting Ras Cys51, an oxidant inhibits the catalytic action of Cdc25—the catalytic domain of RasGEFs—on Ras. However, the enhancement of Ras GNE by an oxidant continues regardless of the presence of Cdc25. Limiting RasGEF action by an oxidant may function to prevent the pathophysiological overactivation of Ras in the presence of both RasGEFs and oxidants. The continuous exposure of Ras to nitric oxide and its derivatives can form S-nitrosated Ras (Ras-SNO). This study also shows that an oxidant not only inhibits the catalytic action of Cdc25 on Ras-SNO but also fails to enhance Ras-SNO GNE. This lack of enhancement then populates the biologically inactive Ras-SNO in cells, which may function to prevent the continued redox signaling of the Ras pathophysiological response. Finally, this study also demonstrates that, unlike the case with RasGEFs, an oxidant does not inhibit the catalytic action of RhoGEF—Vav or Dbs—on Rho GTPases such as Rac1, RhoA, RhoC, and Cdc42. This result explains the results of the previous study in which, despite the presence of an oxidant, the catalytic action of Dbs in cells continued to enhance RhoC GNE. PMID:24422478

  14. Apple pomace, a by-product from the asturian cider industry, inhibits herpes simplex virus types 1 and 2 in vitro replication: study of its mechanisms of action.

    PubMed

    Alvarez, Angel L; Melón, Santiago; Dalton, Kevin P; Nicieza, Inés; Roque, Annele; Suárez, Belén; Parra, Francisco

    2012-06-01

    The anti-herpes simplex virus type 1 and anti-herpes simplex virus type 2 effects of apple pomace, a by-product from the cider-processing industry, were investigated. The mechanisms of antiviral action were assessed using a battery of experiments targeting sequential steps in the viral replication cycle. The anti-herpetic mechanisms of apple pomaces included the inhibition of virus attachment to the cell surface and the arrest of virus entry and uncoating. Quercitrin and procyanidin B2 were found to play a crucial role in the antiviral activity.

  15. Completion Report for Well ER-12-4, Corrective Action Unit 99: Rainier Mesa - Shoshone Mountain (includes Errata Sheet)

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office; Bechtel Nevada

    2006-05-01

    Well ER-12-4 was drilled for the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office, in support of the Nevada Environmental Restoration Project at the Nevada Test Site, Nye County, Nevada. This well was drilled in May 2005, as part of a hydrogeologic investigation program for the Rainier Mesa-Shoshone Mountain Corrective Action Unit in the north-central portion of the Nevada Test Site. The well is located on Rainier/Aqueduct Mesa, northwest of Yucca Flat, within Area 12 of the Nevada Test Site. The well provided information regarding the radiological and physical environment near underground nuclear tests conducted in U12t Tunnel, information on the pre-Tertiary rocks in the area, and depth to the regional water table.

  16. Nongenomic steroid action: Inhibiting effects on cell-to-cell communication between rat ventricular myocytes.

    PubMed

    Verrecchia, F; Sarrouilhe, D; Hervé, J C

    2001-01-01

    Numerous steroids are now believed to possess rapid membrane effects independent of the classical gene activation pathways and are potent modulators of membrane proteins, including voltage-and ligand-operated channels. The effects of steroids on the functional state of the intercellular channels clustered in gap junctions were compared by estimation of either the permeability for a fluorescent dye or the electrical conductance in cardiac myocytes of newborn rat. At 25 muM, the esters of 17beta-estradiol, testosterone and two other androgen hormones rapidly abolished cell-to-cell communication, whereas none of the longer chain steroids, belonging to pregnane (17alpha-hydroxypregnenolone, hydrocortisone), sterol (cholesterol, 25-hydroxycholesterol), bile acid (cholic and lithocholic acids) and vitamin (D3) families, lowered the junctional permeability. Altogether, no correlation with the presence or position of double bonds nor with the trans- or cis-fusion of the A and B rings was recognized. Esterification was a prerequisite for the activity of extracellularly applied steroids but the number, nature and position of ester chain(s) had no influence. 17beta-estradiol or testosterone effects were not prevented when cells were prein-cubated with blockers of the estrogen or androgen nuclear receptors (tamoxifen and cyproterone acetate, respectively). This, together with the rapid time course of the steroid effect (complete within a few minutes), in a rather high active concentration range, suggests a nongenomic mechanism of action. The reversible uncoupling effect of steroids appears to be independent of the shape of the molecules and more probably related to their size and lipo-solubility, which condition their insertion into the lipid bilayer and their subsequent disturbing effects.

  17. Psychosocial stress inhibits amplitude of gonadotropin-releasing hormone pulses independent of cortisol action on the type II glucocorticoid receptor.

    PubMed

    Wagenmaker, Elizabeth R; Breen, Kellie M; Oakley, Amy E; Tilbrook, Alan J; Karsch, Fred J

    2009-02-01

    Our laboratory has developed a paradigm of psychosocial stress (sequential layering of isolation, blindfold, and predator cues) that robustly elevates cortisol secretion and decreases LH pulse amplitude in ovariectomized ewes. This decrease in LH pulse amplitude is due, at least in part, to a reduction in pituitary responsiveness to GnRH, caused by cortisol acting via the type II glucocorticoid receptor (GR). The first experiment of the current study aimed to determine whether this layered psychosocial stress also inhibits pulsatile GnRH release into pituitary portal blood. The stress paradigm significantly reduced GnRH pulse amplitude compared with nonstressed ovariectomized ewes. The second experiment tested if this stress-induced decrease in GnRH pulse amplitude is mediated by cortisol action on the type II GR. Ovariectomized ewes were allocated to three groups: nonstress control, stress, and stress plus the type II GR antagonist RU486. The layered psychosocial stress paradigm decreased GnRH and LH pulse amplitude compared with nonstress controls. Importantly, the stress also lowered GnRH pulse amplitude to a comparable extent in ewes in which cortisol action via the type II GR was antagonized. Therefore, we conclude that psychosocial stress reduces the amplitude of GnRH pulses independent of cortisol action on the type II GR. The present findings, combined with our recent observations, suggest that the mechanisms by which psychosocial stress inhibits reproductive neuroendocrine activity at the hypothalamic and pituitary levels are fundamentally different.

  18. Contribution of Cage-Shaped Structure of Physalins to Their Mode of Action in Inhibition of NF-κB Activation

    PubMed Central

    2013-01-01

    A library of oxygenated natural steroids, including physalins, withanolides, and perulactones, coupled with the synthetic cage-shaped right-side structure of type B physalins, was constructed. SAR studies for inhibition of NF-κB activation showed the importance of both the B-ring and the oxygenated right-side partial structure. The 5β,6β-epoxy derivatives of both physalins and withanolides showed similar profiles of inhibition of NF-κB activation and appeared to act on NF-κB signaling via inhibition of phosphorylation and degradation of IκBα. In contrast, type B physalins with C5–C6 olefin functionality inhibited nuclear translocation and DNA binding of RelA/p50 protein dimer, which lie downstream of IκBα degradation, although withanolides having the same AB-ring functionality did not. These results indicated that the right-side partial structure of these steroids influences their mode of action. PMID:24900739

  19. Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress.

    PubMed

    Morita, Reiko; Yafune, Atsunori; Shiraki, Ayako; Itahashi, Megu; Ishii, Yuji; Akane, Hirotoshi; Nakane, Fumiyuki; Suzuki, Kazuhiko; Shibutani, Makoto; Mitsumori, Kunitoshi

    2013-01-01

    Orphenadrine (ORPH), an anticholinergic agent, is a cytochrome P450 (CYP) 2B inducer. CYP2B inducers are known to have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of ORPH and to clarify its possible mechanism of action. Male rats were given a single intraperitoneal injection of N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after DEN administration, rats were fed a diet containing ORPH (0, 750, or 1,500 ppm) for 6 weeks. One week after the ORPH-administration rats were subjected to two-thirds partial hepatectomy for the acceleration of hepatocellular proliferation. The number and area of glutathione S-transferase placental form-positive foci significantly increased in the DEN-ORPH groups. Real-time RT-PCR revealed increased mRNA expression levels of Cyp2b1/2, Mrp2 and Cyclin D1 in the DEN-ORPH groups and of Gpx2 and Gstm3 in the DEN-High ORPH group. Microsomal reactive oxygen species (ROS) production and oxidative stress markers such as thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine were increased in the DEN-High ORPH group. Immunohistochemically, constitutively active/androstane receptor (CAR) were clearly localized in the nuclei of hepatocytes in the DEN-ORPH groups. These results suggest that ORPH causes nuclear translocation of CAR resulting in the induction of the liver tumor-promoting activity. Furthermore, oxidative stress resulting from ROS production is also involved in the liver tumor-promoting activity of ORPH.

  20. 30 CFR 254.23 - What information must I include in the “Emergency response action plan” section?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OIL-SPILL RESPONSE REQUIREMENTS FOR FACILITIES LOCATED SEAWARD OF THE COAST LINE Oil-Spill Response Plans for Outer Continental Shelf... the oil spill reporting forms included in the Area Contingency Plan or an equivalent reporting...

  1. 30 CFR 254.23 - What information must I include in the “Emergency response action plan” section?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL-SPILL RESPONSE REQUIREMENTS FOR FACILITIES LOCATED SEAWARD OF THE COAST LINE Oil-Spill Response Plans for Outer Continental Shelf Facilities § 254.23 What information... for spill notification. The plan must provide for the use of the oil spill reporting forms included...

  2. Differential inhibition of aflatoxin B1 oxidation by gestodene action on human liver microsomes.

    PubMed

    Kim, B R; Oh, H S; Kim, D H

    1997-11-01

    Human cytochrome P450 (P450) 3A is known to be involved in the formation of both aflatoxin B1-exo-8,9-epoxide (exo-epoxidation) and aflatoxin Q1 (3 alpha-hydroxylation). Gestodene, a known inactivator of P450 3A4, inhibited the formation of AFB1 metabolites in a variety of ways depending on the incubation condition. Preincubation of gestodene with human liver microsomes prior to the addition of AFB1 inhibited both exo-epoxidation and 3 alpha-hydroxylation whereas simultaneous incubation of gestodene with AFB1 only inhibited 3 alpha-hydroxylation. These results suggest that two independent substrate binding sites exist in P450 3A4, and AFB1 binds to both of the binding sites. Gestodene selectively binds to one of the binding sites leading to the formation of AFQ1, whereas it does not affect the formation of exo-epoxide via the other binding site.

  3. Inhibition of Voltage-Gated Calcium Channels as Common Mode of Action for (Mixtures of) Distinct Classes of Insecticides

    PubMed Central

    Meijer, Marieke; Dingemans, Milou M.L.; van den Berg, Martin; Westerink, Remco H.S.

    2014-01-01

    Humans are exposed to distinct structural classes of insecticides with different neurotoxic modes of action. Because calcium homeostasis is essential for proper neuronal function and development, we investigated the effects of insecticides from different classes (pyrethroid: (α-)cypermethrin; organophosphate: chlorpyrifos; organochlorine: endosulfan; neonicotinoid: imidacloprid) and mixtures thereof on the intracellular calcium concentration ([Ca2+]i). Effects of acute (20 min) exposure to (mixtures of) insecticides on basal and depolarization-evoked [Ca2+]i were studied in vitro with Fura-2-loaded PC12 cells and high resolution single-cell fluorescence microscopy. The data demonstrate that cypermethrin, α-cypermethrin, endosulfan, and chlorpyrifos concentration-dependently decreased depolarization-evoked [Ca2+]i, with 50% (IC50) at 78nM, 239nM, 250nM, and 899nM, respectively. Additionally, acute exposure to chlorpyrifos or endosulfan (10μM) induced a modest increase in basal [Ca2+]i, amounting to 68 ± 8nM and 53 ± 8nM, respectively. Imidacloprid did not disturb basal or depolarization-evoked [Ca2+]i at 10μM. Following exposure to binary mixtures, effects on depolarization-evoked [Ca2+]i were within the expected effect additivity range, whereas the effect of the tertiary mixture was less than this expected additivity effect range. These results demonstrate that different types of insecticides inhibit depolarization-evoked [Ca2+]i in PC12 cells by inhibiting voltage-gated calcium channels (VGCCs) in vitro at concentrations comparable with human occupational exposure levels. Moreover, the effective concentrations in this study are below those for earlier described modes of action. Because inhibition of VGCCs appears to be a common and potentially additive mode of action of several classes of insecticides, this target should be considered in neurotoxicity risk assessment studies. PMID:24913802

  4. Inhibition of voltage-gated calcium channels as common mode of action for (mixtures of) distinct classes of insecticides.

    PubMed

    Meijer, Marieke; Dingemans, Milou M L; van den Berg, Martin; Westerink, Remco H S

    2014-09-01

    Humans are exposed to distinct structural classes of insecticides with different neurotoxic modes of action. Because calcium homeostasis is essential for proper neuronal function and development, we investigated the effects of insecticides from different classes (pyrethroid: (α-)cypermethrin; organophosphate: chlorpyrifos; organochlorine: endosulfan; neonicotinoid: imidacloprid) and mixtures thereof on the intracellular calcium concentration ([Ca(2+)]i). Effects of acute (20 min) exposure to (mixtures of) insecticides on basal and depolarization-evoked [Ca(2+)]i were studied in vitro with Fura-2-loaded PC12 cells and high resolution single-cell fluorescence microscopy. The data demonstrate that cypermethrin, α-cypermethrin, endosulfan, and chlorpyrifos concentration-dependently decreased depolarization-evoked [Ca(2+)]i, with 50% (IC50) at 78nM, 239nM, 250nM, and 899nM, respectively. Additionally, acute exposure to chlorpyrifos or endosulfan (10μM) induced a modest increase in basal [Ca(2+)]i, amounting to 68 ± 8nM and 53 ± 8nM, respectively. Imidacloprid did not disturb basal or depolarization-evoked [Ca(2+)]i at 10μM. Following exposure to binary mixtures, effects on depolarization-evoked [Ca(2+)]i were within the expected effect additivity range, whereas the effect of the tertiary mixture was less than this expected additivity effect range. These results demonstrate that different types of insecticides inhibit depolarization-evoked [Ca(2+)]i in PC12 cells by inhibiting voltage-gated calcium channels (VGCCs) in vitro at concentrations comparable with human occupational exposure levels. Moreover, the effective concentrations in this study are below those for earlier described modes of action. Because inhibition of VGCCs appears to be a common and potentially additive mode of action of several classes of insecticides, this target should be considered in neurotoxicity risk assessment studies.

  5. Pharmacological Inhibition of c-Jun N-terminal Kinase Reduces Food Intake and Sensitizes Leptin's Anorectic Signaling Actions.

    PubMed

    Gao, Su; Howard, Shannon; LoGrasso, Philip V

    2017-02-06

    The role for c-Jun N-terminal Kinase (JNK) in the control of feeding and energy balance is not well understood. Here, by use of novel and highly selective JNK inhibitors, we investigated the actions of JNK in the control of feeding and body weight homeostasis. In lean mice, intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of SR-3306, a brain-penetrant and selective pan-JNK (JNK1/2/3) inhibitor, reduced food intake and body weight. Moreover, i.p. and i.c.v. administrations of SR11935, a brain-penetrant and JNK2/3 isoform-selective inhibitor, exerted similar anorectic effects as SR3306, which suggests JNK2 or JNK3 mediates aspect of the anorectic effect by pan-JNK inhibition. Furthermore, daily i.p. injection of SR3306 (7 days) prevented the increases in food intake and weight gain in lean mice upon high-fat diet feeding, and this injection paradigm reduced high-fat intake and obesity in diet-induced obese (DIO) mice. In the DIO mice, JNK inhibition sensitized leptin's anorectic effect, and enhanced leptin-induced STAT3 activation in the hypothalamus. The underlying mechanisms likely involve the downregulation of SOCS3 by JNK inhibition. Collectively, our data suggest that JNK activity promotes positive energy balance, and the therapeutic intervention inhibiting JNK activities represents a promising approach to ameliorate diet-induced obesity and leptin resistance.

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

    PubMed Central

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

    2016-01-01

    ABSTRACT 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. PMID:26854859

  7. Ventral tegmental area neurons are either excited or inhibited by cocaine’s actions in the peripheral nervous system

    PubMed Central

    Mejías-Aponte, Carlos A.; Kiyatkin, Eugene A.

    2012-01-01

    Cocaine’s multiple pharmacological substrates are ubiquitously present in the peripheral and central nervous system. Thus, upon its administration, cocaine acts in the periphery before directly acting in the brain. We determined whether cocaine alters ventral tegmental area (VTA) neuronal activity via peripheral actions, and whether this precedes its central actions. In urethane-anesthetized rats, we recorded VTA neurons responses to intravenous injections of two cocaine analogs: cocaine-hydrochloride (HCl, 0.25 mg/kg) that readily cross the blood-brain barrier (BBB) and cocaine-methiodide (MI, 0.33 mg/kg) that does not cross the BBB. Both cocaine analogs produced sustained changes in discharge rates that began 5s after the initiation of a 10s drug infusion. Within the first 90s post-injection the magnitudes of neuronal responsive of both cocaine analogs were comparable, but later in time the effects of cocaine-HCl were stronger and persisted longer than those of cocaine-MI. The proportion of neurons responsive to cocaine-HCl was twice to that of cocaine-MI (74% and 35% respectively). Both analogs also differed in the response onsets. Cocaine-MI rarely evoked responses after 1 min whereas cocaine-HCl continued to evoke responses within 3 min post-injection. VTA neurons were either excited or inhibited by both cocaine analogs. Most units responsive to cocaine-MI, regardless of excitation or inhibition, had electrophysiological characteristics of putative DA neurons. Units inhibited by cocaine-HCl also had characteristic of DA neurons whereas excited neurons had widely varying action potential durations and discharge rates. Cocaine-MI and cocaine-HCl each produced changes in VTA neuron activity under full DA receptor blockade. However, the duration of inhibition was shortened, the number of excitations increased, and they occurred with an earlier onset during DA receptor blockade. These findings indicate that cocaine acts peripherally with a short latency and

  8. Effect of Aging on Motor Inhibition during Action Preparation under Sensory Conflict

    PubMed Central

    Duque, Julie; Petitjean, Charlotte; Swinnen, Stephan P.

    2016-01-01

    the MIB context was associated with an attenuated suppression of MEPs at the time of the imperative signal (i.e., before conflict is actually detected) in older individuals, suggesting altered motor inhibition, compared to young individuals. In addition, the behavioral analysis suggests that young and older adults rely on different strategies to cope with conflict, including a change in speed-accuracy tradeoff. PMID:28082896

  9. Action video gaming and cognitive control: playing first person shooter games is associated with improvement in working memory but not action inhibition.

    PubMed

    Colzato, Lorenza S; van den Wildenberg, Wery P M; Zmigrod, Sharon; Hommel, Bernhard

    2013-03-01

    The interest in the influence of videogame experience in our daily life is constantly growing. "First Person Shooter" (FPS) games require players to develop a flexible mindset to rapidly react and monitor fast moving visual and auditory stimuli, and to inhibit erroneous actions. This study investigated whether and to which degree experience with such videogames generalizes to other cognitive control tasks. Experienced video game players (VGPs) and individuals with little to no videogame experience (NVGPs) performed on a N-back task and a stop-signal paradigm that provide a relatively well-established diagnostic measure of the monitoring and updating of working memory (WM) and response inhibition (an index of behavioral impulsivity), respectively. VGPs were faster and more accurate in the monitoring and updating of WM than NVGPs, which were faster in reacting to go signals, but showed comparable stopping performance. Our findings support the idea that playing FPS games is associated with enhanced flexible updating of task-relevant information without affecting impulsivity.

  10. Insulin action is blocked by a monoclonal antibody that inhibits insulin receptor kinase

    SciTech Connect

    Morgan, D.O.; Ho, L.; Korn, L.J.; Roth, R.A.

    1986-01-01

    Thirty-six monoclonal antibodies to the human insulin receptor were produced. Thirty-four bound the intracellular domain of the receptor ..beta.. subunit, the domain containing the tyrosine-specific kinase activity. Of these 34 antibodies, 33 recognized the rat receptor and 1 was shown to precipitate the receptors from mice, chickens and frogs with high affinity. Another of the antibodies inhibited the kinase activities of the human and frog receptors with equal potencies. This antibody inhibited the kinase activities of these receptors by more than 90%, whereas others had no effect on either kinase activity. Microinjection of the inhibiting antibody into Xenopus oocytes blocked the ability of insulin to stimulate oocyte maturation. In contrast, this inhibiting antibody did not block the ability of progesterone to stimulate the same response. Furthermore, control immunoglobulin and a noninhibiting antibody to the receptor ..beta.. subunit did not block this response to insulin. These results strongly support a role for the tyrosine-specific kinase activity of the insulin receptor in mediating this biological effect of insulin.

  11. Corticospinal and reciprocal inhibition actions on human soleus motoneuron activity during standing and walking

    PubMed Central

    Hanna-Boutros, Berthe; Sangari, Sina; Giboin, Louis-Solal; El Mendili, Mohamed-Mounir; Lackmy-Vallée, Alexandra; Marchand-Pauvert, Véronique; Knikou, Maria

    2015-01-01

    Reciprocal Ia inhibition constitutes a key segmental neuronal pathway for coordination of antagonist muscles. In this study, we investigated the soleus H-reflex and reciprocal inhibition exerted from flexor group Ia afferents on soleus motoneurons during standing and walking in 15 healthy subjects following transcranial magnetic stimulation (TMS). The effects of separate TMS or deep peroneal nerve (DPN) stimulation and the effects of combined (TMS + DPN) stimuli on the soleus H-reflex were assessed during standing and at mid- and late stance phases of walking. Subthreshold TMS induced short-latency facilitation on the soleus H-reflex that was present during standing and at midstance but not at late stance of walking. Reciprocal inhibition was increased during standing and at late stance but not at the midstance phase of walking. The effects of combined TMS and DPN stimuli on the soleus H-reflex significantly changed between tasks, resulting in an extra facilitation of the soleus H-reflex during standing and not during walking. Our findings indicate that corticospinal inputs and Ia inhibitory interneurons interact at the spinal level in a task-dependent manner, and that corticospinal modulation of reciprocal Ia inhibition is stronger during standing than during walking. PMID:25825912

  12. Insulin Action is Blocked by a Monoclonal Antibody That Inhibits the Insulin Receptor Kinase

    NASA Astrophysics Data System (ADS)

    Morgan, David O.; Ho, Lisa; Korn, Laurence J.; Roth, Richard A.

    1986-01-01

    Thirty-six monoclonal antibodies to the human insulin receptor were produced. Thirty-four bound the intracellular domain of the receptor β subunit, the domain containing the tyrosine-specific kinase activity. Of these 34 antibodies, 33 recognized the rat receptor and 1 was shown to precipitate the receptors from mice, chickens, and frogs with high affinity. Another of the antibodies inhibited the kinase activities of the human and frog receptors with equal potencies. This antibody inhibited the kinase activities of these receptors by more than 90%, whereas others had no effect on either kinase activity. Microinjection of the inhibiting antibody into Xenopus oocytes blocked the ability of insulin to stimulate oocyte maturation. In contrast, this inhibiting antibody did not block the ability of progesterone to stimulate the same response. Furthermore, control immunoglobulin and a noninhibiting antibody to the receptor β subunit did not block this response to insulin. These results strongly support a role for the tyrosine-specific kinase activity of the insulin receptor in mediating this biological effect of insulin.

  13. Under What Conditions Do Young Children Have Difficulty Inhibiting Manual Actions?

    ERIC Educational Resources Information Center

    Simpson, Andrew; Riggs, Kevin J.

    2007-01-01

    Understanding how responses become prepotent is essential for understanding when inhibitory control is needed in everyday behavior. The authors investigated the conditions under which manual actions became prepotent in a go/no-go task. Children had to open boxes that contained stickers on go trials and leave shut boxes that were empty on no-go…

  14. Acquired Mitochondrial Abnormalities, Including Epigenetic Inhibition of Superoxide Dismutase 2, in Pulmonary Hypertension and Cancer: Therapeutic Implications.

    PubMed

    Archer, Stephen L

    2016-01-01

    There is no cure for non-small-cell lung cancer (NSCLC) or pulmonary arterial hypertension (PAH). Therapies lack efficacy and/or are toxic, reflecting a failure to target disease abnormalities that are distinct from processes vital to normal cells. NSCLC and PAH share reversible mitochondrial-metabolic abnormalities which may offer selective therapeutic targets. The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxide dismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α). (2) HIF-1α increases expression of pyruvate dehydrogenase kinase (PDK), which impairs oxidative metabolism and promotes a glycolytic metabolic state. (3) Mitochondrial fragmentation, partially due to mitofusin-2 downregulation, promotes proliferation. This review focuses on the recent discovery that decreased expression of SOD2, a putative tumor-suppressor gene and the major source of H2O2, results from hypermethylation of CpG islands. In cancer and PAH hypermethylation of a site in the enhancer region of intron 2 inhibits SOD2 transcription. In normal PASMC, SOD2 siRNA decreases H2O2 and activates HIF-1α. In PAH, reduced SOD2 expression decreases H2O2, reduces the cytosol and thereby activates HIF-1α. This causes a glycolytic shift in metabolism and increases the proliferation/apoptosis ratio by downregulating Kv1.5 channels, increasing cytosolic calcium, and inhibiting caspases. The DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, which restores SOD2 expression, corrects the proliferation/apoptosis imbalance in PAH and cancer cells. The specificity of PAH for lung vessels may relate to the selective upregulation of DNA methyltransferases that mediate CpG methylation in PASMC (DNA MT-1A and -3B). SOD2 augmentation inactivates HIF-1α in PAH

  15. Inhibition of carbonic anhydrase augments GABAA receptor-mediated analgesia via a spinal mechanism of action

    PubMed Central

    Asiedu, Marina N.; Mejia, Galo L.; Hübner, Christian A.; Kaila, Kai; Price, Theodore J.

    2014-01-01

    Peripheral nerve injury negatively influences spinal GABAergic networks via a reduction in the neuron-specific K+-Cl- cotransporter KCC2. This process has been linked to the emergence of neuropathic allodynia. In vivo pharmacological and modeling studies show that a loss of KCC2 function results in a decrease in the efficacy of GABAA -mediated spinal inhibition. One potential strategy to mitigate this effect entails inhibition of carbonic anhydrase activity to reduce HCO3- -dependent depolarization via GABAA receptors when KCC2 function is compromised. We have tested this hypothesis here. Our results show that, similarly to when KCC2 is pharmacologically blocked, peripheral nerve injury causes a loss of analgesic effect for neurosteroid GABAA allosteric modulators at maximally effective doses in naïve mice in the tail flick test. Remarkably, inhibition of carbonic anhydrase activity with intrathecal acetazolamide rapidly restores an analgesic effect for these compounds suggesting an important role of carbonic anhydrase activity in regulating GABAA -mediated analgesia after peripheral nerve injury. Moreover, spinal acetazolamide administration leads to a profound reduction in the mouse formalin pain test indicating that spinal carbonic anhydrase inhibition produces analgesia when primary afferent activity is driven by chemical mediators. Finally, we demonstrate that systemic administration of acetazolamide to rats with peripheral nerve injury produces an anti-allodynia effect by itself and an enhancement of the peak analgesic effect with a change in the shape of the dose response curve of the α1-sparing benzodiazepine L-838,417. Thus, carbonic anhydrase inhibition mitigates the negative effects of loss of KCC2 function after nerve injury in multiple species and through multiple administration routes resulting in an enhancement of analgesic effects for several GABAA allosteric modulators. We suggest that carbonic anhydrase inhibitors, many of which are clinically

  16. Anti-Proliferative Actions of T-Type Calcium Channel Inhibition in Thy1 Nephritis

    PubMed Central

    Cove-Smith, Andrea; Mulgrew, Christopher J.; Rudyk, Olena; Dutt, Neelanjana; McLatchie, Linda M.; Shattock, Michael J.; Hendry, Bruce M.

    2014-01-01

    Aberrant proliferation of mesangial cells (MCs) is a key finding in progressive glomerular disease. TH1177 is a small molecule that has been shown to inhibit low-voltage activated T-type Ca2+ channels (TCCs). The current study investigates the effect of TH1177 on MC proliferation in vitro and in vivo. The effect of Ca2+ channel inhibition on primary rat MC proliferation in vitro was studied using the microculture tetrazolium assay and by measuring bromodeoxyuridine incorporation. In vivo, rats with Thy1 nephritis were treated with TH1177 or vehicle. Glomerular injury and average glomerular cell number were determined in a blinded fashion. Immunostaining for Ki-67 and phosphorylated ERK were also performed. The expression of TCC isoforms in healthy and diseased tissue was investigated using quantitative real-time PCR. TCC blockade caused a significant reduction in rat MC proliferation in vitro, whereas L-type inhibition had no effect. Treatment of Thy1 nephritis with TH1177 significantly reduced glomerular injury (P < 0.005) and caused a 49% reduction in glomerular cell number (P < 0.005) compared to the placebo. TH1177 also reduced Ki-67-positive and pERK-positive cells per glomerulus by 52% (P < 0.01 and P < 0.005, respectively). These results demonstrate that TH1177 inhibits MC proliferation in vitro and in vivo, supporting the hypothesis that TCC inhibition may be a useful strategy for studying and modifying MC proliferative responses to injury. PMID:23746655

  17. Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance.

    PubMed

    Perez, Edith A

    2009-08-01

    Microtubules are important cellular targets for anticancer therapy because of their key role in mitosis. Microtubule inhibitors (MTI) such as taxanes, vinca alkaloids, and epothilones stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in apoptosis. In spite of their antitumor activity, innate or acquired drug resistance to MTIs such as the taxanes is common, limiting their overall clinical efficacy. Further insight into the mechanisms of action of microtubule-targeting drugs has lead to the discovery of novel agents that may provide higher efficacy with limited toxicity and help overcome resistance to conventional MTIs. This review will focus on the different mechanisms of action of MTIs, potential factors related to resistance and tolerability, and will discuss the recent approval as well as the development of new antineoplastic agents.

  18. Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation

    PubMed Central

    Harraz, Maged M.; Tyagi, Richa; Cortés, Pedro; Snyder, Solomon H.

    2016-01-01

    As traditional antidepressants act only after weeks/months, the discovery that ketamine, an antagonist of glutamate/NMDA receptors, elicits antidepressant actions in hours has been transformative. Its mechanism of action has been elusive, though enhanced mTOR signaling is a major feature. We report a novel signaling pathway wherein NMDA receptor activation stimulates generation of nitric oxide (NO), which S-nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb, a small G protein that activates mTOR. Siah1 degrades Rheb leading to reduced mTOR signaling, while ketamine, conversely, stabilizes Rheb which enhances mTOR signaling. Drugs selectively targeting components of this pathway may offer novel approaches to the treatment of depression. PMID:26782056

  19. Antimicrobial Mechanism of Action of Transferrins: Selective Inhibition of H+-ATPase ▿

    PubMed Central

    Andrés, María T.; Fierro, José F.

    2010-01-01

    Two bacterial species with different metabolic features, namely, Pseudomonas aeruginosa and Lactococcus lactis, were used as a comparative experimental model to investigate the antimicrobial target and mechanism of transferrins. In anaerobiosis, P. aeruginosa cells were not susceptible to lactoferrin (hLf) or transferrin (hTf). In aerobiosis, the cells were susceptible but O2 consumption was not modified, indicating that components of the electron transport chain (ETC) were not targeted. However, the respiratory chain inhibitor piericidin A significantly reduced the killing activity of both proteins. Moreover, 2,6-dichlorophenolindophenol (DCIP), a reducing agent that accepts electrons from the ETC coupled to H+ extrusion, made P. aeruginosa susceptible to hLf and hTf in anaerobiosis. These results indicated that active cooperation of the cell was indispensable for the antimicrobial effect. For L. lactis cells lacking an ETC, the absence of a detectable transmembrane electrical potential in hLf-treated cells suggested a loss of H+-ATPase activity. Furthermore, the inhibition of ATPase activity and H+ translocation (inverted membrane vesicles) provided direct evidence of the ability of hLf to inhibit H+-ATPase in L. lactis. Based on these data, we propose that hLf and hTf also inhibit the H+-ATPase of respiring P. aeruginosa cells. Such inhibition thereby interferes with reentry of H+ from the periplasmic space to the cytoplasm, resulting in perturbation of intracellular pH and the transmembrane proton gradient. Consistent with this hypothesis, periplasmic H+ accumulation was prevented by anaerobiosis or by piericidin A or was induced by DCIP in anaerobiosis. Collectively, these results indicate that transferrins target H+-ATPase and interfere with H+ translocation, yielding a lethal effect in vitro. PMID:20625147

  20. Insight into invertebrate defensin mechanism of action: oyster defensins inhibit peptidoglycan biosynthesis by binding to lipid II.

    PubMed

    Schmitt, Paulina; Wilmes, Miriam; Pugnière, Martine; Aumelas, André; Bachère, Evelyne; Sahl, Hans-Georg; Schneider, Tanja; Destoumieux-Garzón, Delphine

    2010-09-17

    Three oyster defensin variants (Cg-Defh1, Cg-Defh2, and Cg-Defm) were produced as recombinant peptides and characterized in terms of activities and mechanism of action. In agreement with their spectrum of activity almost specifically directed against Gram-positive bacteria, oyster defensins were shown here to be specific inhibitors of a bacterial biosynthesis pathway rather than mere membrane-active agents. Indeed, at lethal concentrations, the three defensins did not compromise Staphylococcus aureus membrane integrity but inhibited the cell wall biosynthesis as indicated by the accumulation of the UDP-N-acetylmuramyl-pentapeptide cell wall precursor. In addition, a combination of antagonization assays, thin layer chromatography, and surface plasmon resonance measurements showed that oyster defensins bind almost irreversibly to the lipid II peptidoglycan precursor, thereby inhibiting the cell wall biosynthesis. To our knowledge, this is the first detailed analysis of the mechanism of action of antibacterial defensins produced by invertebrates. Interestingly, the three defensins, which were chosen as representative of the oyster defensin molecular diversity, bound differentially to lipid II. This correlated with their differential antibacterial activities. From our experimental data and the analysis of oyster defensin sequence diversity, we propose that oyster defensin activity results from selective forces that have conserved residues involved in lipid II binding and diversified residues at the surface of oyster defensins that could improve electrostatic interactions with the bacterial membranes.

  1. Inhibition of Listeria monocytogenes on Ready-to-Eat Meats Using Bacteriocin Mixtures Based on Mode-of-Action

    PubMed Central

    Vijayakumar, Paul Priyesh; Muriana, Peter M.

    2017-01-01

    Bacteriocin-producing (Bac+) lactic acid bacteria (LAB) comprising selected strains of Lactobacillus curvatus, Lactococcus lactis, Pediococcus acidilactici, and Enterococcus faecium and thailandicus were examined for inhibition of Listeria monocytogenes during hotdog challenge studies. The Bac+ strains, or their cell-free supernatants (CFS), were grouped according to mode-of-action (MOA) as determined from prior studies. Making a mixture of as many MOAs as possible is a practical way to obtain a potent natural antimicrobial mixture to address L. monocytogenes contamination of RTE meat products (i.e., hotdogs). The heat resistance of the bacteriocins allowed the use of pasteurization to eliminate residual producer cells for use as post-process surface application or their inclusion into hotdog meat emulsion during cooking. The use of Bac+ LAB comprising 3× MOAs directly as co-inoculants on hotdogs was not effective at inhibiting L. monocytogenes. However, the use of multiple MOA Bac+ CFS mixtures in a variety of trials demonstrated the effectiveness of this approach by showing a >2-log decrease of L. monocytogenes in treatment samples and 6–7 log difference vs. controls. These data suggest that surface application of multiple mode-of-action bacteriocin mixtures can provide for an Alternative 2, and possibly Alternative 1, process category as specified by USDA-FSIS for control of L. monocytogenes on RTE meat products. PMID:28335414

  2. Inhibition of microtubule formation by uremic toxins: action mechanism and hypothesis about the active component.

    PubMed

    Braguer, D; Gallice, P; Monti, J P; Murisasco, A; Crevat, A

    1986-04-01

    We show in vitro inhibitory effect of a mixture of uremic toxins on tubulin 6S polymerization. It proves the existence of a direct interaction protein-toxin where micro-tubule associated proteins are not involved. A similar phenomenom could occur in uremic neuropathy. The action mechanism of this interaction is quite different from that of classical tubulin inhibitors: Vinca alcaloïdes and colchicine. Finally we hypothesize about the active molecule.

  3. Enkephalin inhibits the release and action of secretin on pancreatic secretion in the dog.

    PubMed Central

    Chey, W Y; Coy, D H; Konturek, S J; Schally, A V; Tasler, J

    1980-01-01

    1. Pancreatic bicarbonate and protein secretion as well as immuno-reactive plasma secretin concentration in response to a meal, duodenal acidification and exogenous secretin or octapeptide of cholecystokinin (OP-CCK) have been measured following administration of methionine-enkephalin in chronic pancreatic fistula dogs. 2. Methionine-enkephalin inhibited pancreatic responses to both exogenous hormones (secretin and OP-CCK) and to endogenous hormones released from the gut by food or duodenal acidification. 3. Naloxone, a potent opiate receptor antagonist, partly prevents this methionine-enkephalin-induced inhibition of pancreatic secretion suggesting that this effect might be mediated by opiate receptors. 4. The inhibitory effect of methionine-enkephalin on pancreatic response to endogenous stimulants was more pronounced than that to exogenous hormones and was accompanied by a significant reduction in plasma immuno-reactive secretin concentration. 5. This study indicates that methionine-enkephalin inhibits pancreatic secretion, at least in part, by suppressing the release of the intestinal hormones stimulating the exocrine pancreas. PMID:7359425

  4. Corrective Action Investigation Plan for Corrective Action Unit 214: Bunkers and Storage Areas Nevada Test Site, Nevada: Revision 0, Including Record of Technical Change No. 1 and No. 2

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office

    2003-05-16

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 214 under the Federal Facility Agreement and Consent Order. Located in Areas 5, 11, and 25 of the Nevada Test Site, CAU 214 consists of nine Corrective Action Sites (CASs): 05-99-01, Fallout Shelters; 11-22-03, Drum; 25-99-12, Fly Ash Storage; 25-23-01, Contaminated Materials; 25-23-19, Radioactive Material Storage; 25-99-18, Storage Area; 25-34-03, Motor Dr/Gr Assembly (Bunker); 25-34-04, Motor Dr/Gr Assembly (Bunker); and 25-34-05, Motor Dr/Gr Assembly (Bunker). These sites are being investigated because existing information on the nature and extent of potential contamination is insufficient to evaluate and recommend corrective action alternatives (CAAs). The suspected contaminants and critical analyte s for CAU 214 include oil (total petroleum hydrocarbons-diesel-range organics [TPH-DRO], polychlorinated biphenyls [PCBs]), pesticides (chlordane, heptachlor, 4,4-DDT), barium, cadmium, chronium, lubricants (TPH-DRO, TPH-gasoline-range organics [GRO]), and fly ash (arsenic). The land-use zones where CAU 214 CASs are located dictate that future land uses will be limited to nonresidential (i.e., industrial) activities. The results of this field investigation will support a defensible evaluation of viable corrective action alternatives that will be presented in the corrective action decision document.

  5. Tonic and phasic differential GABAergic inhibition of synaptic actions of joint afferents in the cat.

    PubMed

    Rudomin, P; Hernández, E; Lomelí, J

    2007-01-01

    The aim of this study was to examine the functional organization of the spinal neuronal networks activated by myelinated afferent fibers in the posterior articular nerve (PAN) of the anesthetized cat. Particular attention was given to the tonic and phasic GABAa inhibitory modulation of these networks. Changes in the synaptic effectiveness of the joint afferents were inferred from changes in the intraspinal focal potentials produced by electrical stimulation of the PAN. We found that conditioning stimulation of cutaneous nerves (sural, superficial peroneus and saphenous) and of the nucleus raphe magnus often inhibited, in a differential manner, the early and late components of the intraspinal focal potentials produced by stimulation of low and high threshold myelinated PAN afferents, respectively. The degree of the inhibition depended on the strength of both the conditioning and test stimuli and on the segmental level of recording. Conditioning stimulation of group I muscle afferents was less effective, but marked depression of the early and late focal potentials was produced by stimuli exceeding 5 xT. The i.v. injection of 1-2.5 mg/kg of picrotoxin, a GABAa blocker, had relatively minor effects on the early components of the PAN focal potentials, but was able to induce a significant increase of the late components. It also reduced the inhibitory effects of cutaneous and joint nerve conditioning on PAN focal responses. Conditioning autogenetic stimulation with high-frequency trains depressed the PAN focal potentials. The late components of the PAN responses remained depressed several minutes after discontinuing the conditioning train, even after picrotoxin administration. The present observations indicate that the neuronal networks activated by the low threshold PAN afferents show a relatively small post-activation depression and appear to be subjected to a minor tonic inhibitory GABAa control. In contrast, the pathways activated by stimulation of high threshold

  6. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036

    PubMed Central

    Chan, Wayne W.; Wise, Scott C.; Kaufman, Michael D.; Ahn, Yu Mi; Ensinger, Carol L.; Haack, Torsten; Hood, Molly M.; Jones, Jennifer; Lord, John W.; Lu, Wei Ping; Miller, David; Patt, William C.; Smith, Bryan D.; Petillo, Peter A.; Rutkoski, Thomas J.; Telikepalli, Hanumaiah; Vogeti, Lakshminarayana; Yao, Tony; Chun, Lawrence; Clark, Robin; Evangelista, Peter; Gavrilescu, L. Cristina; Lazarides, Katherine; Zaleskas, Virginia M.; Stewart, Lance J.; Van Etten, Richard A.; Flynn, Daniel L.

    2011-01-01

    Summary Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for chronic myeloid leukemia (CML) patients. Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead “switch-control” inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1T315I-expressing cell lines, prolongs survival in mouse models of T315I-mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph+ leukemia. PMID:21481795

  7. A Microplate Growth Inhibition Assay for Screening Bacteriocins against Listeria monocytogenes to Differentiate Their Mode-of-Action.

    PubMed

    Vijayakumar, Paul Priyesh; Muriana, Peter M

    2015-06-11

    Lactic acid bacteria (LAB) have historically been used in food fermentations to preserve foods and are generally-recognized-as-safe (GRAS) by the FDA for use as food ingredients. In addition to lactic acid; some strains also produce bacteriocins that have been proposed for use as food preservatives. In this study we examined the inhibition of Listeria monocytogenes 39-2 by neutralized and non-neutralized bacteriocin preparations (Bac+ preps) produced by Lactobacillus curvatus FS47; Lb. curvatus Beef3; Pediococcus acidilactici Bac3; Lactococcus lactis FLS1; Enterococcus faecium FS56-1; and Enterococcus thailandicus FS92. Activity differences between non-neutralized and neutralized Bac+ preps in agar spot assays could not readily be attributed to acid because a bacteriocin-negative control strain was not inhibitory to Listeria in these assays. When neutralized and non-neutralized Bac+ preps were used in microplate growth inhibition assays against L. monocytogenes 39-2 we observed some differences attributed to acid inhibition. A microplate growth inhibition assay was used to compare inhibitory reactions of wild-type and bacteriocin-resistant variants of L. monocytogenes to differentiate bacteriocins with different modes-of-action (MOA) whereby curvaticins FS47 and Beef3, and pediocin Bac3 were categorized to be in MOA1; enterocins FS92 and FS56-1 in MOA2; and lacticin FLS1 in MOA3. The microplate bacteriocin MOA assay establishes a platform to evaluate the best combination of bacteriocin preparations for use in food applications as biopreservatives against L. monocytogenes.

  8. Computational modeling of inhibition of voltage-gated Ca channels: identification of different effects on uterine and cardiac action potentials

    PubMed Central

    Tong, Wing-Chiu; Ghouri, Iffath; Taggart, Michael J.

    2014-01-01

    The uterus and heart share the important physiological feature whereby contractile activation of the muscle tissue is regulated by the generation of periodic, spontaneous electrical action potentials (APs). Preterm birth arising from premature uterine contractions is a major complication of pregnancy and there remains a need to pursue avenues of research that facilitate the use of drugs, tocolytics, to limit these inappropriate contractions without deleterious actions on cardiac electrical excitation. A novel approach is to make use of mathematical models of uterine and cardiac APs, which incorporate many ionic currents contributing to the AP forms, and test the cell-specific responses to interventions. We have used three such models—of uterine smooth muscle cells (USMC), cardiac sinoatrial node cells (SAN), and ventricular cells—to investigate the relative effects of reducing two important voltage-gated Ca currents—the L-type (ICaL) and T-type (ICaT) Ca currents. Reduction of ICaL (10%) alone, or ICaT (40%) alone, blunted USMC APs with little effect on ventricular APs and only mild effects on SAN activity. Larger reductions in either current further attenuated the USMC APs but with also greater effects on SAN APs. Encouragingly, a combination of ICaL and ICaT reduction did blunt USMC APs as intended with little detriment to APs of either cardiac cell type. Subsequent overlapping maps of ICaL and ICaT inhibition profiles from each model revealed a range of combined reductions of ICaL and ICaT over which an appreciable diminution of USMC APs could be achieved with no deleterious action on cardiac SAN or ventricular APs. This novel approach illustrates the potential for computational biology to inform us of possible uterine and cardiac cell-specific mechanisms. Incorporating such computational approaches in future studies directed at designing new, or repurposing existing, tocolytics will be beneficial for establishing a desired uterine specificity of action

  9. Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy.

    PubMed

    Yang, Lili; Rozenfeld, Raphael; Wu, Defeng; Devi, Lakshmi A; Zhang, Zhenfeng; Cederbaum, Arthur

    2014-03-01

    Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy.

  10. Activation of CpxRA in Haemophilus ducreyi primarily inhibits the expression of its targets, including major virulence determinants.

    PubMed

    Gangaiah, Dharanesh; Zhang, Xinjun; Fortney, Kate R; Baker, Beth; Liu, Yunlong; Munson, Robert S; Spinola, Stanley M

    2013-08-01

    Haemophilus ducreyi causes chancroid, a genital ulcer disease that facilitates the transmission of human immunodeficiency virus type 1. In humans, H. ducreyi is surrounded by phagocytes and must adapt to a hostile environment to survive. To sense and respond to environmental cues, bacteria frequently use two-component signal transduction (2CST) systems. The only obvious 2CST system in H. ducreyi is CpxRA; CpxR is a response regulator, and CpxA is a sensor kinase. Previous studies by Hansen and coworkers showed that CpxR directly represses the expression of dsrA, the lspB-lspA2 operon, and the flp operon, which are required for virulence in humans. They further showed that CpxA functions predominantly as a phosphatase in vitro to maintain the expression of virulence determinants. Since a cpxA mutant is avirulent while a cpxR mutant is fully virulent in humans, CpxA also likely functions predominantly as a phosphatase in vivo. To better understand the role of H. ducreyi CpxRA in controlling virulence determinants, here we defined genes potentially regulated by CpxRA by using RNA-Seq. Activation of CpxR by deletion of cpxA repressed nearly 70% of its targets, including seven established virulence determinants. Inactivation of CpxR by deletion of cpxR differentially regulated few genes and increased the expression of one virulence determinant. We identified a CpxR binding motif that was enriched in downregulated but not upregulated targets. These data reinforce the hypothesis that CpxA phosphatase activity plays a critical role in controlling H. ducreyi virulence in vivo. Characterization of the downregulated genes may offer new insights into pathogenesis.

  11. Inhibition of Oral Streptococci Growth Induced by the Complementary Action of Berberine Chloride and Antibacterial Compounds.

    PubMed

    Dziedzic, Arkadiusz; Wojtyczka, Robert D; Kubina, Robert

    2015-07-28

    Synergistic interactions between natural bioactive compounds from medicinal plants and antibiotics may exhibit therapeutic benefits, acting against oral cariogenic and opportunistic pathogens. The aim of the presented work was to assess the antibacterial activity of berberine chloride (BECl) in light of the effect exerted by common antibiotics on selected reference strains of oral streptococci (OST), and to evaluate the magnitude of interactions. Three representative oral microorganisms were investigated: Streptococcus mutans ATCC 25175 (SM), S. sanguinis ATCC 10556 (SS), S. oralis ATCC 9811 (SO) and microdilution tests, along with disc diffusion assays were applied. Here, we report that growth (viability) of all oral streptococci was reduced by exposure to BECl and was dependent primarily on exposure/ incubation time. A minimum inhibitory concentrations (MIC) of BECl against OST ranged from 512 µg/mL (SS) to 1024 µg/mL (SM, SO). The most noticeable antibacterial effects were observed for S. sanguinis (MIC 512 µg/mL) and the most significant synergistic action was found for the combinations BECl-penicillin, BECl-clindamycin and BECl-erythromycin. The S. oralis reflects the highest MBC value as assessed by the AlamarBlue assay (2058 µg/mL). The synergy between berberine and common antibiotics demonstrates its potential use as a novel antibacterial tool for opportunistic infections and also provides a rational basis for the use of berberine as an oral hygiene measure.

  12. Analgesic-antiinflammatory drugs inhibit orbicularis oculi reflexes in humans via a central mode of action.

    PubMed

    Ferracuti, S; Leardi, M G; Cruccu, G; Fabbri, A; Itil, T M

    1994-01-01

    1. A cross-over single blind study examined the possible central effects of non-opioid analgesic drugs on the trigeminal reflexes. 2. The corneal reflex and blink reflex (R1, R2) were recorded electromyographically and response areas measured in healthy volunteers before and after intramuscular injection of piroxicam (40 mg); and after intravenous injection of lysine acetylsalicylate (500 mg). After the last drug recording the subjects received intravenous naloxone (2 mg) followed 5 minutes later by further reflex testing. Saline was used as a placebo in control experiments. 3. Both analgesics reduced the corneal reflex: piroxicam induced a 27% and lysine acetylsalicylate a 21% a reduction that naloxone did not reverse. Neither drug reduced the early or the late component of the blink reflex. 4. The marked inhibitory changes that the two non-narcotic analgesics produced on the corneal reflex--a nociceptive response--indicate a centrally-mediated action. 5. Naloxone's failure to reverse the induced analgesia argues against opiate receptor mediation.

  13. Supercritical fluid extract of Lycium chinense Miller root inhibition of melanin production and its potential mechanisms of action

    PubMed Central

    2014-01-01

    Background The mode of action of Lycium chinense Miller root extract in skin care has never been explored. In the present study, Lycium chinense Miller root was extracted by the supercritical fluid CO2 extraction method. Methods In the present study, the components of the root extract were analyzed by HPLC. The effects of the extract on tyrosinase activity and melanin content were determined spectrophotometrically; the expression of melanogenesis-related proteins was determined by Western blotting; the possible signaling pathways involved in the root extract-mediated depigmentation were also investigated using specific inhibitors. Results The results revealed that the SFE of Lycium chinense Miller root (2.37-7.11 mg/mL) effectively suppressed intracellular tyrosinase activity and decreased the melanin content in B16F10 cells. The root extract also effectively decreased intracellular reactive oxygen species (ROS) levels. Furthermore, the root extract decreased the expression of melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein-1 (TRP-1) and then inhibited melanogenesis in B16F10 cells. The root extract also showed antioxidant capacities and depleted cellular ROS. Conclusions Our results indicate that the SFE of Lycium chinense Miller root inhibited melanogenesis in B16F10 cells by down-regulation of both mitogen-activated protein kinases (MAPK) and protein kinase A (PKA) signaling pathways or through its antioxidant properties. PMID:24972978

  14. Inhibition of Listeria monocytogenes on Ready-to-Eat Meats Using Bacteriocin Mixtures Based on Mode-of-Action.

    PubMed

    Vijayakumar, Paul Priyesh; Muriana, Peter M

    2017-03-14

    Bacteriocin-producing (Bac⁺) lactic acid bacteria (LAB) comprising selected strains of Lactobacillus curvatus, Lactococcus lactis, Pediococcus acidilactici, and Enterococcus faecium and thailandicus were examined for inhibition of Listeria monocytogenes during hotdog challenge studies. The Bac⁺ strains, or their cell-free supernatants (CFS), were grouped according to mode-of-action (MOA) as determined from prior studies. Making a mixture of as many MOAs as possible is a practical way to obtain a potent natural antimicrobial mixture to address L. monocytogenes contamination of RTE meat products (i.e., hotdogs). The heat resistance of the bacteriocins allowed the use of pasteurization to eliminate residual producer cells for use as post-process surface application or their inclusion into hotdog meat emulsion during cooking. The use of Bac⁺ LAB comprising 3× MOAs directly as co-inoculants on hotdogs was not effective at inhibiting L. monocytogenes. However, the use of multiple MOA Bac⁺ CFS mixtures in a variety of trials demonstrated the effectiveness of this approach by showing a >2-log decrease of L. monocytogenes in treatment samples and 6-7 log difference vs.

  15. A Survey of Parental Perception and Pattern of Action in Response to Influenza-like Illness in Their Children: Including Healthcare Use and Vaccination in Korea

    PubMed Central

    2017-01-01

    Seasonal influenza is a significant cause of morbidity and mortality of children in Korea. However, few data are available on parental perception and action toward childhood influenza. This study aimed to characterize parental perception and patterns of action in response to influenza and influenza-like illnesses (ILIs), including vaccination and healthcare use. This prospective study involved a random survey of parents whose children were aged 6–59 months. The survey was conducted in October 2014. The study included 638 parents of 824 children younger than 6 years. Most parental information of influenza came from mass media (28.2%) and social media (15.5%). The factor that most often motivated parents to vaccinate their children against influenza was promotion of the government or mass media (36.6%). Negative predictors of immunization included safety concerns about influenza vaccination (28.1%) and mistrust in the vaccine's effectiveness (23.3%). Therefore, correct information about influenza and vaccination from mass media will be one of the cornerstones for implementing a successful childhood immunization program and reducing morbidity and mortality in Korea. Furthermore, to enroll younger children in vaccination programs, and to minimize coverage gaps, public concerns about vaccine safety should be resolved. The demographic data in the present study will be used to provide a deeper insight into a parental perception and will help health care providers increase influenza immunization rate. PMID:28049230

  16. Environmental magnetic fields inhibit the antiproliferative action of tamoxifen and melatonin in a human breast cancer cell line.

    PubMed

    Harland, J D; Liburdy, R P

    1997-01-01

    We have previously reported that environmental-level magnetic fields (1.2 microT [12 milligauss], 60 Hz) block the growth inhibition of the hormone melatonin (10(-9) M) on MCF-7 human breast cancer cells in vitro. We now report that the same 1.2 microT, 60 Hz magnetic fields significantly block the growth inhibitory action of pharmacological levels of tamoxifen (10(-7) M). In biophysical studies we have taken advantage of Faraday's Law of Current Induction and tested whether the 1.2 microT magnetic field or the associated induced electric field is responsible for this field effect on melatonin and tamoxifen. We observe that the magnetic field component is associated with the field blocking effect on melatonin and tamoxifen function. To our knowledge the tamoxifen studies represent the first experimental evidence for an environmental-level magnetic field modification of drug interaction with human breast cancer cells. Together, these findings provide support to the theory that environmental-level magnetic fields can act to modify the action of a drug or hormone on regulation of cell proliferation. Melatonin and tamoxifen may act through different biological pathways to down-regulate cell growth, and further studies are required to identify a specific biological site of interaction for the 1.2 microT magnetic field.

  17. Antinociceptive and Anti-Inflammatory Effects of Ketamine and the Relationship to Its Antidepressant Action and GSK3 Inhibition.

    PubMed

    do Vale, Eduardo Mulato; Xavier, Cecília Coelho; Nogueira, Brenda Gomes; Campos, Bruna Caldas; de Aquino, Pedro Everson Alexandre; da Costa, Roberta Oliveira; Leal, Luzia Kalyne Almeida Moreira; de Vasconcelos, Silvânia Maria Mendes; Neves, Kelly Rose Tavares; de Barros Viana, Glauce Socorro

    2016-12-01

    Ketamine (KET), a NMDA antagonist, exerts an antidepressant effect at subanaesthetic doses and possesses analgesic and anti-inflammatory activities. We evaluated the involvement of KET antinociceptive and anti-inflammatory effects with its antidepressant action. Male Swiss mice were subjected to formalin, carrageenan-induced paw oedema and forced swimming tests, for assessing antinociceptive, anti-inflammatory and antidepressant effects. The treatment groups were as follows: control, KET (2, 5 and 10 mg/kg), lithium (LI: 5 mg/kg) and KET2 + LI5 combination. Immunohistochemistry analyses (TNF-α, iNOS, COX-2 and GSK3) in oedematous paws were performed. KET5 and KET10 reduced licking times in neurogenic (22 and 38%) and inflammatory (67 and 78%) phases of the formalin test, respectively, as related to controls. While LI5 inhibited the second phase by 24%, the licking time was inhibited by 26 and 59% in the KET2 + LI5 group (first and second phases). Furthermore, oedema volumes were reduced by 37 and 45% in the KET5 and KET10 groups, respectively. Oedema reductions were 29% in the LI5 group and 48% in the KET2 + LI5 group. In the forced swimming test, there were 23, 38 and 53% decreases in the immobility time in KET2, KET5 and KET10 groups, respectively. While LI5 caused no significant effect, decreases of 52% were observed with KET2 + LI5. KET also decreased TNF-α, iNOS, COX-2 and GSK3 immunostainings in oedematous paws, effects intensified with KET2 + LI5. We showed that KET presents antinociceptive and anti-inflammatory effects associated with its antidepressant response. Furthermore, our results indicate the close involvement of GSK3 inhibition and blockade of inflammatory responses, in the antidepressant drug effect.

  18. Central effects of growth hormone-releasing hexapeptide (GHRP-6) on growth hormone release are inhibited by central somatostatin action.

    PubMed

    Fairhall, K M; Mynett, A; Robinson, I C

    1995-03-01

    Growth hormone (GH) release is stimulated by a variety of synthetic secretagogues, of which growth hormone-releasing hexapeptide (GHRP-6) has been most thoroughly studied; it is thought to have actions at both pituitary and hypothalamic sites. To evaluate the central actions of this peptide, we have studied GH release in response to direct i.c.v. injections in anaesthetized guinea pigs. GHRP-6 (0.04-1 microgram) stimulated GH release > 10-fold 30-40 min after i.c.v. injection. The same GH response required > 20-fold more GHRP-6 when given by i.v. injection. GH release could also be elicited by a non-peptide GHRP analogue (L-692,585, 1 microgram i.c.v.), whereas a growth hormone-releasing factor (GRF) analogue (human GRF27Nle(1-29)NH2, 2 micrograms, i.c.v.) was ineffective. A long acting somatostatin analogue (Sandostatin, SMS 201-995, 10 micrograms i.c.v.) (SMS) given 20 min before 200 ng GHRP-6 blocked GH release. This was unlikely to be due to a direct effect of SMS leaking out to the pituitary, since central SMS injections did not affect basal GH release, nor did they block GH release in response to i.v. GRF injections. We conclude that the hypothalamus is a major target for GHRP-6 in vivo. Since the GH release induced by central GHRP-6 injections can be inhibited by a central action of somatostatin, and other data indicate that GHRP-6 activates GRF neurones, we suggest that somatostatin may block this activation via receptors known to be located on or near the GRF cells themselves. Somatostatin may therefore be a functional antagonist of GHRP-6 acting centrally, as well as at the pituitary gland.

  19. Corrective Action Investigation Plan for Corrective Action Unit 165: Areas 25 and 26 Dry Well and Washdown Areas, Nevada Test Site, Nevada (including Record of Technical Change Nos. 1, 2, and 3) (January 2002, Rev. 0)

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office

    2002-01-09

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 165 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 165 consists of eight Corrective Action Sites (CASs): CAS 25-20-01, Lab Drain Dry Well; CAS 25-51-02, Dry Well; CAS 25-59-01, Septic System; CAS 26-59-01, Septic System; CAS 25-07-06, Train Decontamination Area; CAS 25-07-07, Vehicle Washdown; CAS 26-07-01, Vehicle Washdown Station; and CAS 25-47-01, Reservoir and French Drain. All eight CASs are located in the Nevada Test Site, Nevada. Six of these CASs are located in Area 25 facilities and two CASs are located in Area 26 facilities. The eight CASs at CAU 165 consist of dry wells, septic systems, decontamination pads, and a reservoir. The six CASs in Area 25 are associated with the Nuclear Rocket Development Station that operated from 1958 to 1973. The two CASs in Area 26 are associated with facilities constructed for Project Pluto, a series of nuclear reactor tests conducted between 1961 to 1964 to develop a nuclear-powered ramjet engine. Based on site history, the scope of this plan will be a two-phased approach to investigate the possible presence of hazardous and/or radioactive constituents at concentrations that could potentially pose a threat to human health and the environment. The Phase I analytical program for most CASs will include volatile organic compounds, semivolatile organic compounds, Resource Conservation and Recovery Act metals, total petroleum hydrocarbons, polychlorinated biphenyls, and radionuclides. If laboratory data obtained from the Phase I investigation indicates the presence of contaminants of concern, the process will continue with a Phase II investigation to define the extent of contamination. Based on the results of

  20. Corrective Action Investigation Plan for Corrective Action Unit 5: Landfills, Nevada Test Site, Nevada (Rev. No.: 0) includes Record of Technical Change No. 1 (dated 9/17/2002)

    SciTech Connect

    IT Corporation, Las Vegas, NV

    2002-05-28

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 5 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 5 consists of eight Corrective Action Sites (CASs): 05-15-01, Sanitary Landfill; 05-16-01, Landfill; 06-08-01, Landfill; 06-15-02, Sanitary Landfill; 06-15-03, Sanitary Landfill; 12-15-01, Sanitary Landfill; 20-15-01, Landfill; 23-15-03, Disposal Site. Located between Areas 5, 6, 12, 20, and 23 of the Nevada Test Site (NTS), CAU 5 consists of unlined landfills used in support of disposal operations between 1952 and 1992. Large volumes of solid waste were produced from the projects which used the CAU 5 landfills. Waste disposed in these landfills may be present without appropriate controls (i.e., use restrictions, adequate cover) and hazardous and/or radioactive constituents may be present at concentrations and locations that could potentially pose a threat to human health and/or the environment. During the 1992 to 1995 time frame, the NTS was used for various research and development projects including nuclear weapons testing. Instead of managing solid waste at one or two disposal sites, the practice on the NTS was to dispose of solid waste in the vicinity of the project. A review of historical documentation, process knowledge, personal interviews, and inferred activities associated with this CAU identified the following as potential contaminants of concern: volatile organic compounds, semivolatile organic compounds, polychlorinated biphenyls, pesticides, petroleum hydrocarbons (diesel- and gasoline-range organics), Resource Conservation and Recovery Act Metals, plus nickel and zinc. A two-phase approach has been selected to collect information and generate data to satisfy needed resolution criteria

  1. The flavonoids luteolin and quercetagetin inhibit lipoteichoic acid actions on H9c2 cardiomyocytes.

    PubMed

    Gutiérrez-Venegas, Gloria; Bando-Campos, Carlos Giroshi

    2010-09-01

    Dental focal infections are infections in the mouth that cause subsequent infection and symptoms in other parts of the body. Dental conditions such as periodontitis have been associated with coronary heart disease. In this study, we investigated the effect of flavonoids on activation of mitogen-activated protein kinase (MAPK) family members, protein kinase B (AKT), and IL-1 beta expression by rat heart embryonic (H9c2) cells upon stimulation with LTA. Pretreatment with four flavonoids, including quercetin, genistein, quercetagetin, and luteolin diminished LTA-induced ERK1/2, JNK, p38, and AKT phosphorylation and IL-1 beta gene expression. Our findings indicate that flavonoids interfere with LTA signal transduction.

  2. Spermine Attenuates the Action of the DNA Intercalator, Actinomycin D, on DNA Binding and the Inhibition of Transcription and DNA Replication

    PubMed Central

    Chen, Jeremy J. W.; Wu, Wen-Lin; Yuann, Jeu-Ming P.; Su, Wang-Lin; Chuang, Show-Mei; Hou, Ming-Hon

    2012-01-01

    The anticancer activity of DNA intercalators is related to their ability to intercalate into the DNA duplex with high affinity, thereby interfering with DNA replication and transcription. Polyamines (spermine in particular) are almost exclusively bound to nucleic acids and are involved in many cellular processes that require nucleic acids. Until now, the effects of polyamines on DNA intercalator activities have remained unclear because intercalation is the most important mechanism employed by DNA-binding drugs. Herein, using actinomycin D (ACTD) as a model, we have attempted to elucidate the effects of spermine on the action of ACTD, including its DNA-binding ability, RNA and DNA polymerase interference, and its role in the transcription and replication inhibition of ACTD within cells. We found that spermine interfered with the binding and stabilization of ACTD to DNA. The presence of increasing concentrations of spermine enhanced the transcriptional and replication activities of RNA and DNA polymerases, respectively, in vitro treated with ActD. Moreover, a decrease in intracellular polyamine concentrations stimulated by methylglyoxal-bis(guanylhydrazone) (MGBG) enhanced the ACTD-induced inhibition of c-myc transcription and DNA replication in several cancer cell lines. The results indicated that spermine attenuates ACTD binding to DNA and its inhibition of transcription and DNA replication both in vitro and within cells. Finally, a synergistic antiproliferative effect of MGBG and ACTD was observed in a cell viability assay. Our findings will be of significant relevance to future developments in combination with cancer therapy by enhancing the anticancer activity of DNA interactors through polyamine depletion. PMID:23144800

  3. Industrial Sites Work Plan for Leachfield Corrective Action Units: Nevada Test Site and Tonopah Test Range, Nevada (including Record of Technical Change Nos. 1, 2, 3, and 4)

    SciTech Connect

    DOE /NV

    1998-12-18

    This Leachfield Corrective Action Units (CAUs) Work Plan has been developed in accordance with the Federal Facility Agreement and Consent Order (FFACO) that was agreed to by the U.S. Department of Energy, Nevada Operations Office (DOE/NV); the State of Nevada Division of Environmental Protection (NDEP); and the U.S. Department of Defense (FFACO, 1996). Under the FFACO, a work plan is an optional planning document that provides information for a CAU or group of CAUs where significant commonality exists. A work plan may be developed that can be referenced by leachfield Corrective Action Investigation Plans (CAIPs) to eliminate redundant CAU documentation. This Work Plan includes FFACO-required management, technical, quality assurance (QA), health and safety, public involvement, field sampling, and waste management documentation common to several CAUs with similar site histories and characteristics, namely the leachfield systems at the Nevada Test Site (NTS) and the Tonopah Test Range (TT R). For each CAU, a CAIP will be prepared to present detailed, site-specific information regarding contaminants of potential concern (COPCs), sampling locations, and investigation methods.

  4. Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation.

    PubMed

    Cotel, Florence; Exley, Richard; Cragg, Stephanie J; Perrier, Jean-François

    2013-03-19

    Motor fatigue induced by physical activity is an everyday experience characterized by a decreased capacity to generate motor force. Factors in both muscles and the central nervous system are involved. The central component of fatigue modulates the ability of motoneurons to activate muscle adequately independently of the muscle physiology. Indirect evidence indicates that central fatigue is caused by serotonin (5-HT), but the cellular mechanisms are unknown. In a slice preparation from the spinal cord of the adult turtle, we found that prolonged stimulation of the raphe-spinal pathway--as during motor exercise--activated 5-HT1A receptors that decreased motoneuronal excitability. Electrophysiological tests combined with pharmacology showed that focal activation of 5-HT1A receptors at the axon initial segment (AIS), but not on other motoneuronal compartments, inhibited the action potential initiation by modulating a Na(+) current. Immunohistochemical staining against 5-HT revealed a high-density innervation of 5-HT terminals on the somatodendritic membrane and a complete absence on the AIS. This observation raised the hypothesis that a 5-HT spillover activates receptors at this latter compartment. We tested it by measuring the level of extracellular 5-HT with cyclic voltammetry and found that prolonged stimulations of the raphe-spinal pathway increased the level of 5-HT to a concentration sufficient to activate 5-HT1A receptors. Together our results demonstrate that prolonged release of 5-HT during motor activity spills over from its release sites to the AIS of motoneurons. Here, activated 5-HT1A receptors inhibit firing and, thereby, muscle contraction. Hence, this is a cellular mechanism for central fatigue.

  5. Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation

    PubMed Central

    Cotel, Florence; Exley, Richard; Cragg, Stephanie J.; Perrier, Jean-François

    2013-01-01

    Motor fatigue induced by physical activity is an everyday experience characterized by a decreased capacity to generate motor force. Factors in both muscles and the central nervous system are involved. The central component of fatigue modulates the ability of motoneurons to activate muscle adequately independently of the muscle physiology. Indirect evidence indicates that central fatigue is caused by serotonin (5-HT), but the cellular mechanisms are unknown. In a slice preparation from the spinal cord of the adult turtle, we found that prolonged stimulation of the raphe-spinal pathway—as during motor exercise—activated 5-HT1A receptors that decreased motoneuronal excitability. Electrophysiological tests combined with pharmacology showed that focal activation of 5-HT1A receptors at the axon initial segment (AIS), but not on other motoneuronal compartments, inhibited the action potential initiation by modulating a Na+ current. Immunohistochemical staining against 5-HT revealed a high-density innervation of 5-HT terminals on the somatodendritic membrane and a complete absence on the AIS. This observation raised the hypothesis that a 5-HT spillover activates receptors at this latter compartment. We tested it by measuring the level of extracellular 5-HT with cyclic voltammetry and found that prolonged stimulations of the raphe-spinal pathway increased the level of 5-HT to a concentration sufficient to activate 5-HT1A receptors. Together our results demonstrate that prolonged release of 5-HT during motor activity spills over from its release sites to the AIS of motoneurons. Here, activated 5-HT1A receptors inhibit firing and, thereby, muscle contraction. Hence, this is a cellular mechanism for central fatigue. PMID:23487756

  6. Porcine epidemic diarrhea virus infection: inhibition by polysaccharide from Ginkgo biloba exocarp and mode of its action.

    PubMed

    Lee, Jung-Hee; Park, Jang-Soon; Lee, Seung-Woong; Hwang, Seock-Yeon; Young, Bae-Eun; Choi, Hwa-Jung

    2015-01-02

    Porcine epidemic diarrhea virus (PEDV) is the predominant cause of severe entero-pathogenic diarrhea in swine. Until now there is no recorded clinically effective antiviral chemotherapeutic agent for treatment of diseases caused by PEDV. This study aimed to investigate in vitro anti-PEDV effect of polysaccharide from Ginkgo biloba exocarp and mode of its action. The polysaccharide exhibited potent antiviral activity against PEDV reducing the formation of a visible CPE [a 50% inhibitory concentration (IC50)=1.7±1.3μg/mL], compared to positive control, ribavirin and it did not show cytotoxicity at 100μg/mL [a 50% cytotoxicity concentration (CC50)=100μg/mL]. Polysaccharide also showed effective inhibitory effects when added at the viral attachment and entry steps. Moreover, polysaccharide effectively inactivated PEDV infection in time-, dose- and temperature-dependent manners. Overall, this research revealed that polysaccharide could inhibit PEDV infection, and that polysaccharide may be involved in PEDV-Vero cell interactions, as the virus attachment and entry to the Vero cells was hindered by the polysaccharide. Therefore, polysaccharide possessing effective inhibitory effect on viral attachment and entry steps of PEDV life cycle is a good candidate for development of antivirals.

  7. Polyphenolics isolated from virgin coconut oil inhibits adjuvant induced arthritis in rats through antioxidant and anti-inflammatory action.

    PubMed

    Vysakh, A; Ratheesh, M; Rajmohanan, T P; Pramod, C; Premlal, S; Girish kumar, B; Sibi, P I

    2014-05-01

    We evaluated the protective efficacy of the polyphenolic fraction from virgin coconut oil (PV) against adjuvant induced arthritic rats. Arthritis was induced by intradermal injection of complete Freund's adjuvant. The activities of inflammatory, antioxidant enzymes and lipid peroxidation were estimated. PV showed high percentage of edema inhibition at a dose of 80mg/kg on 21st day of adjuvant arthritis and is non toxic. The expression of inflammatory genes such as COX-2, iNOS, TNF-α and IL-6 and the concentration of thiobarbituric acid reactive substance were decreased by treatment with PV. Antioxidant enzymes were increased and on treatment with PV. The increased level of total WBC count and C-reactive protein in the arthritic animals was reduced in PV treated rats. Synovial cytology showed that inflammatory cells and reactive mesothelial cells were suppressed by PV. Histopathology of paw tissue showed less edema formation and cellular infiltration on supplementation with PV. Thus the results demonstrated the potential beneficiary effect of PV on adjuvant induced arthritis in rats and the mechanism behind this action is due to its antioxidant and anti-inflammatory effects.

  8. Icaritin Inhibits Collagen Degradation-Related Factors and Facilitates Collagen Accumulation in Atherosclerotic Lesions: A Potential Action for Plaque Stabilization

    PubMed Central

    Zhang, Zong-Kang; Li, Jie; Yan, De-Xin; Leung, Wing-Nang; Zhang, Bao-Ting

    2016-01-01

    Most acute coronary syndromes result from rupture of vulnerable atherosclerotic plaques. The collagen content of plaques may critically affect plaque stability. This study tested whether Icaritin (ICT), an intestinal metabolite of Epimedium-derived flavonoids, could alter the collagen synthesis/degradation balance in atherosclerotic lesions. Rabbits were fed with an atherogenic diet for four months. Oral administration of ICT (10 mg·kg−1·day−1) was started after two months of an atherogenic diet and lasted for two months. The collagen degradation-related parameters, including macrophages accumulation, content and activity of interstitial collagenase-1 (MMP-1), and the collagen synthesis-related parameters, including amount and distribution of smooth muscle cells (SMC) and collagen mRNA/protein levels, were evaluated in the aorta. ICT reduced plasma lipid levels, inhibited macrophage accumulation, lowered MMP-1 mRNA and protein expression, and suppressed proteolytic activity of pro-MMP-1 and MMP-1 in the aorta. ICT changed the distribution of the SMCs towards the fibrous cap of lesions without increasing the amount of SMCs. Higher collagen protein content in lesions and aorta homogenates was observed with ICT treatment compared with the atherogenic diet only, without altered collagen mRNA level. These results suggest that ICT could inhibit the collagen degradation-related factors and facilitate collagen accumulation in atherosclerotic lesions, indicating a new potential of ICT in atherosclerotic plaques. PMID:26828485

  9. Icaritin Inhibits Collagen Degradation-Related Factors and Facilitates Collagen Accumulation in Atherosclerotic Lesions: A Potential Action for Plaque Stabilization.

    PubMed

    Zhang, Zong-Kang; Li, Jie; Yan, De-Xin; Leung, Wing-Nang; Zhang, Bao-Ting

    2016-01-28

    Most acute coronary syndromes result from rupture of vulnerable atherosclerotic plaques. The collagen content of plaques may critically affect plaque stability. This study tested whether Icaritin (ICT), an intestinal metabolite of Epimedium-derived flavonoids, could alter the collagen synthesis/degradation balance in atherosclerotic lesions. Rabbits were fed with an atherogenic diet for four months. Oral administration of ICT (10 mg·kg(-1)·day(-1)) was started after two months of an atherogenic diet and lasted for two months. The collagen degradation-related parameters, including macrophages accumulation, content and activity of interstitial collagenase-1 (MMP-1), and the collagen synthesis-related parameters, including amount and distribution of smooth muscle cells (SMC) and collagen mRNA/protein levels, were evaluated in the aorta. ICT reduced plasma lipid levels, inhibited macrophage accumulation, lowered MMP-1 mRNA and protein expression, and suppressed proteolytic activity of pro-MMP-1 and MMP-1 in the aorta. ICT changed the distribution of the SMCs towards the fibrous cap of lesions without increasing the amount of SMCs. Higher collagen protein content in lesions and aorta homogenates was observed with ICT treatment compared with the atherogenic diet only, without altered collagen mRNA level. These results suggest that ICT could inhibit the collagen degradation-related factors and facilitate collagen accumulation in atherosclerotic lesions, indicating a new potential of ICT in atherosclerotic plaques.

  10. Non-nucleosidic inhibition of Herpes simplex virus DNA polymerase: mechanistic insights into the anti-herpetic mode of action of herbal drug withaferin A

    PubMed Central

    2011-01-01

    Background Herpes Simplex Virus 1 and 2 causes several infections in humans including cold sores and encephalitis. Previous antiviral studies on herpes viruses have focussed on developing nucleoside analogues that can inhibit viral polymerase and terminate the replicating viral DNA. However, these drugs bear an intrinsic non-specificity as they can also inhibit cellular polymerase apart from the viral one. The present study is an attempt to elucidate the action mechanism of naturally occurring withaferin A in inhibiting viral DNA polymerase, thus providing an evidence for its development as a novel anti-herpetic drug. Results Withaferin A was found to bind very similarly to that of the previously reported 4-oxo-DHQ inhibitor. Withaferin A was observed binding to the residues Gln 617, Gln 618, Asn 815 and Tyr 818, all of which are crucial to the proper functioning of the polymerase. A comparison of the conformation obtained from docking and the molecular dynamics simulations shows that substantial changes in the binding conformations have occurred. These results indicate that the initial receptor-ligand interaction observed after docking can be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favoured. Conclusions We have performed docking and molecular dynamics simulation studies to elucidate the binding mechanism of prospective herbal drug withaferin A onto the structure of DNA polymerase of Herpes simplex virus. Our docking simulations results give high binding affinity of the ligand to the receptor. Long de novo MD simulations for 10 ns performed allowed us to evaluate the dynamic behaviour of the system studied and corroborate the docking results, as well as identify key residues in the enzyme-inhibitor interactions. The present MD simulations support the hypothesis that withaferin A is a potential ligand to target/inhibit DNA polymerase of the Herpes simplex

  11. Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action.

    PubMed

    Vonderlin, Nadine; Fischer, Fathima; Zitron, Edgar; Seyler, Claudia; Scherer, Daniel; Thomas, Dierk; Katus, Hugo A; Scholz, Eberhard P

    2015-01-01

    Midazolam is a short-acting benzodiazepine that is in wide clinical use as an anxiolytic, sedative, hypnotic, and anticonvulsant. Midazolam has been shown to inhibit ion channels, including calcium and potassium channels. So far, the effects of midazolam on cardiac human ether-à-go-go-related gene (hERG) channels have not been analyzed. The inhibitory effects of midazolam on heterologously expressed hERG channels were analyzed in Xenopus oocytes using the double-electrode voltage clamp technique. We found that midazolam inhibits hERG channels in a concentration-dependent manner, yielding an IC50 of 170 μM in Xenopus oocytes. When analyzed in a HEK 293 cell line using the patch-clamp technique, the IC50 was 13.6 μM. Midazolam resulted in a small negative shift of the activation curve of hERG channels. However, steady-state inactivation was not significantly affected. We further show that inhibition is state-dependent, occurring within the open and inactivated but not in the closed state. There was no frequency dependence of block. Using the hERG pore mutants F656A and Y652A we provide evidence that midazolam uses a classical binding site within the channel pore. Analyzing the subacute effects of midazolam on hERG channel trafficking, we further found that midazolam does not affect channel surface expression. Taken together, we show that the anesthetic midazolam is a low-affinity inhibitor of cardiac hERG channels without additional effects on channel surface expression. These data add to the current understanding of the pharmacological profile of the anesthetic midazolam.

  12. Parallel inhibition of amino acid efflux and growth of erythrocytic Plasmodium falciparum by mefloquine and non-piperidine analogs: Implication for the mechanism of antimalarial action.

    PubMed

    Ghavami, Maryam; Dapper, Christie H; Dalal, Seema; Holzschneider, Kristina; Klemba, Michael; Carlier, Paul R

    2016-10-01

    Despite the troubling psychiatric side-effects it causes in some patients, mefloquine (MQ) has been used for malaria prophylaxis and therapy, due to its activity against all Plasmodium species, its ease of dosing, and its relative safety in children and pregnant women. Yet at present there is no consensus on the mechanism of antimalarial action of MQ. Two leading hypotheses for the mechanism of MQ are inhibition of heme crystallization and inhibition of host cell hemoglobin endocytosis. In this report we show that MQ is a potent and rapid inhibitor of amino acid efflux from intact parasitized erythrocytes, which is a measure of the in vivo rate of host hemoglobin endocytosis and catabolism. To further explore the mechanism of action of MQ, we have compared the effects of MQ and 18 non-piperidine analogs on amino acid efflux and parasite growth. Among these closely related compounds, an excellent correlation over nearly 4 log units is seen for 50% inhibition concentration (IC50) values for parasite growth and leucine efflux. These data and other observations are consistent with the hypothesis that the antimalarial action of these compounds derives from inhibition of hemoglobin endocytosis.

  13. Effect of inhibition of glutathione synthesis on insulin action: in vivo and in vitro studies using buthionine sulfoximine.

    PubMed Central

    Khamaisi, M; Kavel, O; Rosenstock, M; Porat, M; Yuli, M; Kaiser, N; Rudich, A

    2000-01-01

    Decreased cellular GSH content is a common finding in experimental and human diabetes, in which increased oxidative stress appears to occur. Oxidative stress has been suggested to play a causative role in the development of impaired insulin action on adipose tissue and skeletal muscle. In this study we undertook to investigate the potential of GSH depletion to induce insulin resistance, by utilizing the GSH synthesis inhibitor, L-buthionine-[S,R]-sulfoximine (BSO). GSH depletion (20-80% in various tissues), was achieved in vivo by treating rats for 20 days with BSO, and in vitro (80%) by treating 3T3-L1 adipocytes with BSO for 18 h. No demonstrable change in the GSH/GSSG ratio was observed following BSO treatment. GSH depletion was progressively associated with abnormal glucose tolerance test, which could not be attributed to impaired insulin secretion. Skeletal muscle insulin responsiveness was unaffected by GSH depletion, based on normal glucose response to exogenous insulin, 2-deoxyglucose uptake measurements in isolated soleus muscle, and on normal skeletal muscle expression of GLUT4 protein. Adipocyte insulin responsiveness in vitro was assessed in 3T3-L1 adipocytes, which displayed decreased insulin-stimulated tyrosine phosphorylation of insulin-receptor-substrate proteins and of the insulin receptor, but exaggerated protein kinase B phosphorylation. However, insulin-stimulated glucose uptake was unaffected by GSH depletion. In accordance, normal adipose tissue insulin sensitivity was observed in BSO-treated rats in vivo, as demonstrated by normal inhibition of circulating non-esterified fatty acid levels by endogenous insulin secretion. In conclusion, GSH depletion by BSO results in impaired glucose tolerance, but preserved adipocyte and skeletal muscle insulin responsiveness. This suggests that alternative oxidation-borne factors mediate the induction of peripheral insulin resistance by oxidative stress. PMID:10880357

  14. Nitrous oxide directly inhibits action potential-dependent neurotransmission from single presynaptic boutons adhering to rat hippocampal CA3 neurons.

    PubMed

    Wakita, Masahito; Kotani, Naoki; Yamaga, Toshitaka; Akaike, Norio

    2015-09-01

    We evaluated the effects of N2O on synaptic transmission using a preparation of mechanically dissociated rat hippocampal CA3 neurons that allowed assays of single bouton responses evoked from native functional nerve endings. We studied the effects of N2O on GABAA, glutamate, AMPA and NMDA receptor-mediated currents (IGABA, IGlu, IAMPA and INMDA) elicited by exogenous application of GABA, glutamate, (S)-AMPA, and NMDA and spontaneous, miniature, and evoked GABAergic inhibitory and glutamatergic excitatory postsynaptic current (sIPSC, mIPSC, eIPSC, sEPSC, mEPSC and eEPSC) in mechanically dissociated CA3 neurons. eIPSC and eEPSC were evoked by focal electrical stimulation of a single bouton. Administration of 70% N2O altered neither IGABA nor the frequency and amplitude of both sIPSCs and mIPSCs. In contrast, N2O decreased the amplitude of eIPSCs, while increasing failure rates (Rf) and paired-pulse ratios (PPR) in a concentration-dependent manner. On the other hand, N2O decreased IGlu, IAMPA and INMDA. Again N2O did not change the frequency and amplitude of either sEPSCs of mEPSCs. N2O also decreased amplitudes of eEPSCs with increased Rf and PPR. The decay phases of all synaptic responses were unchanged. The present results indicated that N2O inhibits the activation of AMPA/KA and NMDA receptors and also that N2O preferentially depress the action potential-dependent GABA and glutamate releases but had little effects on spontaneous and miniature releases.

  15. Prepotency in action: does children's knowledge of an artifact affect their ability to inhibit acting on it?

    PubMed

    Simpson, Andrew; Carroll, Daniel J; Riggs, Kevin J

    2014-02-01

    Prepotent actions are actions that are strongly triggered by the environment and so tend to be carried out unless intentionally avoided. Understanding what makes an action prepotent is central to an understanding of inhibitory control. The current study investigated actions made on artifacts because in artifact-dense cultures much everyday behavior is focused on them. A total of 80 3-year-olds were tested on a Go/No-go task that required children to make an action on go trials and to withhold it on no-go trials. These actions were made on artifacts with which the actions were either associated (e.g., drawing with a crayon) or unassociated (e.g., drawing with a hammer). Failure to avoid the go action on no-go trials was taken as evidence that the action was prepotent. Results suggested that an action did not need to be associated with an artifact in order for it to be prepotent (so drawing with a hammer could be prepotent). However, associated actions were sometimes produced even when children had been instructed to make an unassociated action. Children sometimes drew with a crayon when told to hammer with it, but they never hammered when told to draw.

  16. Possible Involvement of the Inhibition of NF-κB Factor in Anti-Inflammatory Actions That Melatonin Exerts on Mast Cells.

    PubMed

    Maldonado, M D; García-Moreno, H; González-Yanes, C; Calvo, J R

    2016-08-01

    Melatonin is a molecule endogenously produced in a wide variety of immune cells, including mast cells (RBL-2H3). It exhibits immunomodulatory, anti-inflammatory and anti-apoptotic properties. The physiologic mechanisms underlying these activities of melatonin have not been clarified in mast cells. This work is designed to determine the anti-inflammatory effect and mechanism of action of melatonin on activated mast cells. RBL-2H3 were pre-treated with exogenous melatonin (MELx) at physiological (100nM) and pharmacological (1 mM) doses for 30 min, washed and activated with PMACI (phorbol 12-myristate 13-acetate plus calcium ionophore A23187) for 2 h and 12 h. The data shows that pre-treatment of MELx in stimulated mast cells, significantly reduced the levels of endogenous melatonin production (MELn), TNF-α and IL-6. These effects are directly related with the MELx concentration used. MELx also inhibited IKK/NF-κB signal transduction pathway in stimulated mast cells. These results indicate a molecular basis for the ability of melatonin to prevent inflammation and for the treatment of allergic inflammatory diseases through the down-regulation of mast cell activation. J. Cell. Biochem. 117: 1926-1933, 2016. © 2016 Wiley Periodicals, Inc.

  17. Biofilm inhibition and antimicrobial action of lipopeptide biosurfactant produced by heavy metal tolerant strain Bacillus cereus NK1.

    PubMed

    Sriram, Muthu Irulappan; Kalishwaralal, Kalimuthu; Deepak, Venkataraman; Gracerosepat, Raja; Srisakthi, Kandasamy; Gurunathan, Sangiliyandi

    2011-07-01

    Biosurfactants are worthful microbial amphiphilic molecules with efficient surface-active and biological properties applicable to several industries and processes. Among them lipopeptides represent a class of microbial surfactants with increasing scientific, therapeutic and biotechnological interests. A heavy metal tolerant Bacillus strain has been isolated and the biofilm inhibition and antimicrobial activity of biosurfactant produced by the strain have been studied. Biosurfactant production was confirmed by the conventional screening methods including hemolytic activity, drop collapsing test, oil displacement test, emulsification and lipase production assays. The biosurfactant produced by this strain was a lipopeptide and exhibited strong surface activity. The biosurfactant has been characterized using FTIR, TLC and HPLC. The minimum active dose of this biosurfactant when compared with the other chemical surfactants was found as 0.150±0.06 μg. The critical micelle concentration was found to be 45 mg/l. The biosurfactant was found to be stable and active over a wide range of pH, temperature and NaCl concentration. It was also able to emulsify a wide range of hydrocarbons and oils thereby extending its application for the bioremediation of oil contaminated sites. The biosurfactant exhibited significant reduction in biofilm formation by pathogens and showed potent antimicrobial activity against various gram positive, gram negative bacteria and fungi. Agar diffusion assay for heavy metal resistance showed that the isolate was resistant to ferrous, lead and zinc. Considering the biofilm inhibition and antimicrobial property of biosurfactant, it can be utilized as a potential therapeutic molecule for numerous microbial infections. The heavy metal resistance of the strain can also be harnessed as an invaluable biological tool for in situ bioremediation.

  18. Corrective Action Investigation Plan for Corrective Action Unit 322: Areas 1 and 3 Release Sites and Injection Wells, Nevada Test Site, Nevada: Revision 0, Including Record of Technical Change No. 1

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office

    2003-07-16

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office's approach to collect the data necessary to evaluate corrective action alternatives (CAAs) appropriate for the closure of Corrective Action Unit (CAU) 322, Areas 1 and 3 Release Sites and Injection Wells, Nevada Test Site, Nevada, under the Federal Facility Agreement and Consent Order. Corrective Action Unit 322 consists of three Corrective Action Sites (CASs): 01-25-01, AST Release (Area 1); 03-25-03, Mud Plant AST Diesel Release (Area 3); 03-20-05, Injection Wells (Area 3). Corrective Action Unit 322 is being investigated because existing information on the nature and extent of potential contamination is insufficient to evaluate and recommend corrective action alternatives. The investigation of three CASs in CAU 322 will determine if hazardous and/or radioactive constituents are present at concentrations and locations that could potentially pose a threat to human health and the environment. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document.

  19. Role of exogenously supplied ferulic and p-coumaric acids in mimicking the mode of action of acetolactate synthase inhibiting herbicides.

    PubMed

    Orcaray, Luis; Igal, María; Zabalza, Ana; Royuela, Mercedes

    2011-09-28

    Chlorsulfuron and imazethapyr (herbicides that inhibit acetolactate synthase; ALS, EC 4.1.3.18) produced a strong accumulation of hydroxycinnamic acids that was related to the induction of the first enzyme of the shikimate pathway, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (EC 2.5.2.54). The exogenous application of two hydroxycinnamic acids, ferulic and p-coumaric acids, to pea plants resulted in their internal accumulation, arrested growth, carbohydrate and quinate accumulation in the leaves, and the induction of ethanolic fermentation. These effects resemble some of the physiological effects detected after acetolactate synthase inhibition and suggest important roles for ferulic and p-coumaric acids in the mode of action of herbicides inhibiting the biosynthesis of branched chain amino acids.

  20. Mechanisms of growth inhibition of primary prostate epithelial cells following gamma irradiation or photodynamic therapy include senescence, necrosis, and autophagy, but not apoptosis.

    PubMed

    Frame, Fiona M; Savoie, Huguette; Bryden, Francesca; Giuntini, Francesca; Mann, Vincent M; Simms, Matthew S; Boyle, Ross W; Maitland, Norman J

    2016-01-01

    In comparison to more differentiated cells, prostate cancer stem-like cells are radioresistant, which could explain radio-recurrent prostate cancer. Improvement of radiotherapeutic efficacy may therefore require combination therapy. We have investigated the consequences of treating primary prostate epithelial cells with gamma irradiation and photodynamic therapy (PDT), both of which act through production of reactive oxygen species (ROS). Primary prostate epithelial cells were cultured from patient samples of benign prostatic hyperplasia and prostate cancer prior to treatment with PDT or gamma irradiation. Cell viability was measured using MTT and alamar blue assay, and cell recovery by colony-forming assays. Immunofluorescence of gamma-H2AX foci was used to quantify DNA damage, and autophagy and apoptosis were assessed using Western blots. Necrosis and senescence were measured by propidium iodide staining and beta-galactosidase staining, respectively. Both PDT and gamma irradiation reduced the colony-forming ability of primary prostate epithelial cells. PDT reduced the viability of all types of cells in the cultures, including stem-like cells and more differentiated cells. PDT induced necrosis and autophagy, whereas gamma irradiation induced senescence, but neither treatment induced apoptosis. PDT and gamma irradiation therefore inhibit cell growth by different mechanisms. We suggest these treatments would be suitable for use in combination as sequential treatments against prostate cancer.

  1. Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition.

    PubMed

    Gupta, Mamta; Gupta, Shiv Kumar; Hoffman, Barbara; Liebermann, Dan A

    2006-06-30

    Gadd45a, Gadd45b, and Gadd45g (Gadd45/MyD118/CR6) are genes that are rapidly induced by genotoxic stress and have been implicated in genotoxic stress-induced responses, notably in apoptosis. Recently, using myeloid-enriched bone marrow (BM) cells obtained from wild-type (WT), Gadd45a-deficient, and Gadd45b-deficient mice, we have shown that in hematopoietic cells Gadd45a and Gadd45b play a survival function to protect hematopoietic cells from DNA-damaging agents, including ultra violet (UV)-induced apoptosis. The present study was undertaken to decipher the molecular paths that mediate the survival functions of Gadd45a and Gadd45b against genotoxic stress induced by UV radiation. It is shown that in hematopoietic cells exposed to UV radiation Gaddd45a and Gadd45b cooperate to promote cell survival via two distinct signaling pathways involving activation of the GADD45a-p38-NF-kappaB-mediated survival pathway and GADD45b-mediated inhibition of the stress response MKK4-JNK pathway.

  2. Corrective Action Investigation Plan for Corrective Action Unit 527: Horn Silver Mine, Nevada Test Site, Nevada: Revision 1 (Including Records of Technical Change No.1, 2, 3, and 4)

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office

    2002-12-06

    This Corrective Action Investigation Plan contains the U.S. Department of Energy (DOE), National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 527, Horn Silver Mine, Nevada Test Site, Nevada, under the Federal Facility Agreement and Consent Order. Corrective Action Unit 527 consists of one Corrective Action Site (CAS): 26-20-01, Contaminated Waste Dump No.1. The site is located in an abandoned mine site in Area 26 (which is the most arid part of the NTS) approximately 65 miles northwest of Las Vegas. Historical documents may refer to this site as CAU 168, CWD-1, the Wingfield mine (or shaft), and the Wahmonie mine (or shaft). Historical documentation indicates that between 1959 and the 1970s, nonliquid classified material and unclassified waste was placed in the Horn Silver Mine's shaft. Some of the waste is known to be radioactive. Documentation indicates that the waste is present from 150 feet to the bottom of the mine (500 ft below ground surface). This CAU is being investigated because hazardous constituents migrating from materials and/or wastes disposed of in the Horn Silver Mine may pose a threat to human health and the environment as well as to assess the potential impacts associated with any potential releases from the waste. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document.

  3. Inhibition of a cAMP-dependent Ca-activated K conductance by forskolin prolongs Ca action potential duration in lamprey sensory neurons.

    PubMed

    Womble, M D; Wickelgren, W O

    1990-06-04

    Intracellular recordings from primary mechanosensory neurons (dorsal cells) of the lamprey spinal cord were made to test the membrane effects of forskolin, an activator of adenylate cyclase in these cells. At a concentration of 50 microM, forskolin was found to have a pronounced broadening effect on calcium action potentials (Ca APs) produced in the presence of voltage-activated K channel blockers (TEA, 3,4-DAP). Forskolin had no effect on passive membrane properties of the cells, such as resting potential or input resistance. Nor did it affect delayed rectification or Na APs and thus appeared not to block voltage-activated K channels. Forskolin's effect was evident only when a significant Ca component to the AP was present. It appeared not to increase the conductance of the Ca channel since its action was accompanied by a decrease in membrane conductance during the Ca AP, indicating instead an inhibition of a repolarizing Ca-activated conductance, other than a Ca-activated Cl conductance. The prolongation of Ca APs by forskolin, barium or the neurotransmitter GABA were all correlated in voltage-clamp with a decrease in outward current. Under the conductions used here, the major outward conductance in dorsal cells is a Ca-activated K conductance (gK(Ca]28, and it is concluded that the most probable mode of action for forskolin is via a cyclic AMP-mediated inhibition of this conductance. GABA has also been shown to prolong Ca APs in lamprey dorsal cells by inhibiting a repolarizing gK(Ca)28. Thus, the action of this transmitter may be mediated by an increase in intracellular cyclic AMP.

  4. Corrective Action Decision Document for Corrective Action Unit 168: Areas 25 and 26 Contaminated Materials and Waste Dumps, Nevada Test Site, Nevada: Revision 0, Including Record of Technical Change No. 1

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office

    2003-08-08

    This Corrective Action Decision Document identifies and rationalizes the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office's selection of recommended corrective action alternatives (CAAs) to facilitate the closure of Corrective Action Unit (CAU)168: Areas 25 and 26 Contaminated Materials and Waste Dumps, Nevada Test Site (NTS), Nevada, under the Federal Facility Agreement and Consent Order. Located in Areas 25 and 26 at the NTS in Nevada, CAU 168 is comprised of twelve Corrective Action Sites (CASs). Review of data collected during the corrective action investigation, as well as consideration of current and future operations in Areas 25 and 26 of the NTS, led the way to the development of three CAAs for consideration: Alternative 1 - No Further Action; Alternative 2 - Clean Closure; and Alternative 3 - Close in Place with Administrative Controls. As a result of this evaluation, a combination of all three CAAs is recommended for this CAU. Alternative 1 was the preferred CAA for three CASs, Alternative 2 was the preferred CAA for six CASs (and nearly all of one other CAS), and Alternative 3 was the preferred CAA for two CASs (and a portion of one other CAS) to complete the closure at the CAU 168 sites. These alternatives were judged to meet all requirements for the technical components evaluated as well as all applicable state and federal regulations for closure of the sites and elimination of potential future exposure pathways to the contaminated soils at CAU 168.

  5. A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells.

    PubMed

    Khalil, Hilal S; Langdon, Simon P; Goltsov, Alexey; Soininen, Tero; Harrison, David J; Bown, James; Deeni, Yusuf Y

    2016-11-15

    Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2.HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single antibody alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.

  6. Transforming growth factor beta is a potent inhibitor of interleukin 1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action

    PubMed Central

    1990-01-01

    Transforming growth factor beta (TGF-beta) acts as a potent inhibitor of the growth and functions of lymphoid and hemopoietic progenitor cells. Cell proliferation depends not only on the presence of growth factors, but also on the development of specific receptor-signal transducing complexes. We therefore investigated whether the inhibitory actions of TGF-beta could be mediated by inhibition of growth factor receptors. TGF-beta inhibited the constitutive level of interleukin 1 receptor (IL-1R) expression on several murine lymphoid and myeloid progenitor cell lines, as well as IL-1R expression induced by interleukin 3 (IL-3) on normal murine and human bone marrow cells. Furthermore, treatment of bone marrow progenitor cells with TGF-beta concomitantly inhibited the ability of IL-1 to promote high proliferative potential (HPP) colony formation as well as blocked IL-1- induced IL-2 production by EL-4 6.1 cells. These findings provide the first evidence that the inhibitory action of TGF-beta on the growth and functional activities of hematopoietic and T cells is associated with a reduction in the cell surface receptor expression for IL-1. PMID:2143773

  7. A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

    PubMed Central

    Khalil, Hilal S.; Langdon, Simon P.; Goltsov, Alexey; Soininen, Tero; Harrison, David J.; Bown, James; Deeni, Yusuf Y.

    2016-01-01

    Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single antibody alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target. PMID:27713148

  8. Dissociable Effects of Dopamine on the Initial Capture and the Reactive Inhibition of Impulsive Actions in Parkinson's Disease

    PubMed Central

    van Wouwe, Nelleke C.; Kanoff, Kristen E.; Claassen, Daniel O.; Spears, Charis A.; Neimat, Joseph; van den Wildenberg, Wery P. M.; Wylie, Scott A.

    2016-01-01

    Dopamine plays a key role in a range of action control processes. Here, we investigate how dopamine depletion caused by Parkinson disease (PD) and how dopamine restoring medication modulate the expression and suppression of unintended action impulses. Fifty-five PD patients and 56 healthy controls (HCs) performed an action control task (Simon task). PD patients completed the task twice, once withdrawn from dopamine medications and once while taking their medications. PD patients experienced similar susceptibility to making fast errors in conflict trials as HCs, but PD patients were less proficient compared with HCs at suppressing incorrect responses. Administration of dopaminergic medications had no effect on impulsive error rates but significantly improved the proficiency of inhibitory control in PD patients. We found no evidence that dopamine precursors and agonists affected action control in PD differently. Additionally, there was no clear evidence that individual differences in baseline action control (off dopamine medications) differentially responded to dopamine medications (i.e., no evidence for an inverted U-shaped performance curve). Together, these results indicate that dopamine depletion and restoration therapies directly modulate the reactive inhibitory control processes engaged to suppress interference from the spontaneously activated response impulses but exert no effect on an individual's susceptibility to act on impulses. PMID:26836515

  9. Mycelium of fungi isolated from mouldy foods inhibits Staphylococcus aureus including MRSA – A rationale for the re-introduction of mycotherapy?

    PubMed Central

    Alnaimat, Sulaiman; Alharbi, Naiyf S.; Alharbi, Sulaiman Ali; Salmen, Saleh H.; Chinnathambi, Arunachalam; Al-Johny, Bassam O.; Wainwright, M.

    2015-01-01

    Fungal mycelium capable of producing antibacterial agents was isolated from samples of apple, beetroot, lemon and orange; the mycelium of all isolates produced penicillin, while the apple and beetroot samples also produced the antibacterial mycotoxin patulin. The known penicillin-producing fungi were shown to produce penicillin, but not patulin. The mycelial discs of all of fruit and vegetable isolates, as well as the two known penicillin producing fungi, inhibited Staphylococcus aureus, and mycelium of all isolates inhibited MRSA, in contrast, only one of the two known penicillin-producers did so. The results are discussed in relation to the possibility of using the mycelium of Penicillium species in mycotherapy. PMID:26288565

  10. Prostaglandin E2 inhibition of secretagogue-stimulated (/sup 14/C)aminopyrine accumulation in rat parietal cells: a model for its mechanism of action

    SciTech Connect

    Rosenfeld, G.C.

    1986-05-01

    Prostaglandin E2 (PGE2) differentially inhibited histamine and isoproterenol stimulation of (/sup 14/C)aminopyrine accumulation in rat parietal cell preparations. Low concentrations of PGE2 decreased the maximum response to isoproterenol whereas higher concentrations increased the EC50 of histamine with only a modest effect on the maximum response. Also, PGE2 potentiated dibutyryl cyclic AMP stimulation of aminopyrine accumulation in either the absence or presence of carbachol. In contrast, PGE2 inhibited potentiation between carbachol and histamine due to its inhibitory effect on histamine and possibly also to an inhibitory effect on cholinergic activity. Islet activating protein prevented the inhibitory actions of PGE2. To account for these results a model is presented based on the recent proposal by Gilman of an interaction between components of adenylyl cyclase stimulatory and inhibitory guanine nucleotide binding proteins.

  11. The effects of action video game experience on the time course of inhibition of return and the efficiency of visual search.

    PubMed

    Castel, Alan D; Pratt, Jay; Drummond, Emily

    2005-06-01

    The ability to efficiently search the visual environment is a critical function of the visual system, and recent research has shown that experience playing action video games can influence visual selective attention. The present research examined the similarities and differences between video game players (VGPs) and non-video game players (NVGPs) in terms of the ability to inhibit attention from returning to previously attended locations, and the efficiency of visual search in easy and more demanding search environments. Both groups were equally good at inhibiting the return of attention to previously cued locations, although VGPs displayed overall faster reaction times to detect targets. VGPs also showed overall faster response time for easy and difficult visual search tasks compared to NVGPs, largely attributed to faster stimulus-response mapping. The findings suggest that relative to NVGPs, VGPs rely on similar types of visual processing strategies but possess faster stimulus-response mappings in visual attention tasks.

  12. Anti-Fatigue Effect by Peptide Fraction from Protein Hydrolysate of Croceine Croaker (Pseudosciaena crocea) Swim Bladder through Inhibiting the Oxidative Reactions including DNA Damage

    PubMed Central

    Zhao, Yu-Qin; Zeng, Li; Yang, Zui-Su; Huang, Fang-Fang; Ding, Guo-Fang; Wang, Bin

    2016-01-01

    The swim bladder of the croceine croaker (Pseudosciaena crocea) was believed to have good curative effects in various diseases, including amnesia, insomnia, dizziness, anepithymia, and weakness after giving birth, in traditional Chinese medicine. However, there is no research focusing on the antioxidant and anti-fatigue peptides from croceine croaker swim bladders at present. Therefore, the purpose of this study was to investigate the bioactivities of peptide fractions from the protein hydrolysate of croceine croaker related to antioxidant and anti-fatigue effects. In the study, swim bladder peptide fraction (SBP-III-3) was isolated from the protein hydrolysate of the croceine croaker, and its antioxidant and anti-fatigue activities were measured using in vitro and in vivo methods. The results indicated that SBP-III-3 exhibited good scavenging activities on hydroxyl radicals (HO•) (EC50 (the concentration where a sample caused a 50% decrease of the initial concentration of HO•) = 0.867 mg/mL), 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH•) (EC50 = 0.895 mg/mL), superoxide anion radical (O2−•) (EC50 = 0.871 mg/mL), and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical (ABTS+•) (EC50 = 0.346 mg/mL). SBP-III-3 also showed protective effects on DNA damage in a concentration-effect manner and prolonged the swimming time to exhaustion of Institute of Cancer Research (ICR) mice by 57.9%–107.5% greater than that of the control. SBP-III-3 could increase the levels of muscle glucose (9.4%–115.2% increase) and liver glycogen (35.7%–157.3%), and decrease the levels of blood urea nitrogen (BUN), lactic acid (LA), and malondialdehyde (MDA) by 16.4%–22.4%, 13.9%–20.1%, and 28.0%–53.6%, respectively. SBP-III-3 also enhanced the activity of lactic dehydrogenase to scavenge excessive LA for slowing the development of fatigue. In addition, SBP-III-3 increased the activities superoxide dismutase, catalase, and glutathione peroxidase to reduce the

  13. Pharmacological Inhibition of c-Jun N-terminal Kinase Reduces Food Intake and Sensitizes Leptin’s Anorectic Signaling Actions

    PubMed Central

    Gao, Su; Howard, Shannon; LoGrasso, Philip V.

    2017-01-01

    The role for c-Jun N-terminal Kinase (JNK) in the control of feeding and energy balance is not well understood. Here, by use of novel and highly selective JNK inhibitors, we investigated the actions of JNK in the control of feeding and body weight homeostasis. In lean mice, intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of SR-3306, a brain-penetrant and selective pan-JNK (JNK1/2/3) inhibitor, reduced food intake and body weight. Moreover, i.p. and i.c.v. administrations of SR11935, a brain-penetrant and JNK2/3 isoform-selective inhibitor, exerted similar anorectic effects as SR3306, which suggests JNK2 or JNK3 mediates aspect of the anorectic effect by pan-JNK inhibition. Furthermore, daily i.p. injection of SR3306 (7 days) prevented the increases in food intake and weight gain in lean mice upon high-fat diet feeding, and this injection paradigm reduced high-fat intake and obesity in diet-induced obese (DIO) mice. In the DIO mice, JNK inhibition sensitized leptin’s anorectic effect, and enhanced leptin-induced STAT3 activation in the hypothalamus. The underlying mechanisms likely involve the downregulation of SOCS3 by JNK inhibition. Collectively, our data suggest that JNK activity promotes positive energy balance, and the therapeutic intervention inhibiting JNK activities represents a promising approach to ameliorate diet-induced obesity and leptin resistance. PMID:28165482

  14. Evaluation of organic cation transporter 3 (SLC22A3) inhibition as a potential mechanism of antidepressant action.

    PubMed

    Zhu, Hao-Jie; Appel, David I; Gründemann, Dirk; Richelson, Elliott; Markowitz, John S

    2012-04-01

    Organic cation transporter 3 (OCT3, SLC22A3) is a low-affinity, high-capacity transporter widely expressed in the central nervous system (CNS) and other major organs in both humans and rodents. It is postulated that OCT3 has a role in the overall regulation of neurotransmission and maintenance of homeostasis within the CNS. It is generally believed that all antidepressant drugs in current clinical use exert their primary therapeutic effects through inhibition of one or more of the high-affinity neuronal plasma membrane monoamine transporters, such as the norepinephrine transporter and the serotonin transporter. In the present study, we investigated the inhibitory effects of selected antidepressants on OCT3 activity in OCT3-transfected cells to evaluate whether OCT3 inhibition may at least in part contribute to the pharmacological effects of tested antidepressants. The studies demonstrated that all examined antidepressants inhibited OCT3-mediated uptake of the established OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in a concentration-dependent manner. The IC(50) values were determined to be 4.7 μM, 7.4 μM, 12.0 μM, 18.6 μM, 11.2 μM, and 21.9 μM for desipramine, sertraline, paroxetine, amitriptyline, imipramine, and fluoxetine, respectively. Additionally, desipramine had an IC(50) value of 0.7 μM for the uptake of NE by OCT3, while the IC(50) value of sertraline was 2.3 μM for 5-HT uptake. Both desipramine and sertraline appeared to inhibit OCT3 activity via a non-competitive mechanism. In vivo studies are warranted to determine whether such effects on OCT3 inhibition are of sufficient magnitude to contribute to the overall therapeutic effects of antidepressants.

  15. Tonic Inhibition of Accumbal Spiny Neurons by Extrasynaptic α4βδ GABAA Receptors Modulates the Actions of Psychostimulants

    PubMed Central

    Maguire, Edward P.; Macpherson, Tom; Swinny, Jerome D.; Dixon, Claire I.; Herd, Murray B.; Belelli, Delia; Stephens, David N.

    2014-01-01

    Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/− or α4−/− mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/− mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the α4 deletion specific to D1-expressing neurons (α4D1−/−) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4−/− or α4D1−/− mice, blocked cocaine enhancement of CPP. In comparison, α4D2−/− mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward. Therefore, α4βδ GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors. PMID:24431441

  16. Comparison of the inhibition of biliary excretion produced by certain inducing agents including 2,3,7,8-tetrachlorodibenzo-p-dioxin

    SciTech Connect

    Berman, E.F.; Schaus, P.; Fujimoto, J.M.

    1986-01-01

    Rats were treated with chlordecone, mirex, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and respective solvent vehicle. Under urethane or pentobarbital anesthesia, the bile duct was cannulated and radioactive morphine, imipramine, or ouabain was given by segmented retrograde intrabiliary injection. The spectrum of inhibition of biliary excretion by chlordecone and mirex were similar in that morphine glucuronide and in part polar imipramine metabolite recoveries in bile were decreased; ouabain recovery was unaffected. TCDD was different in that it markedly decreased the recovery of ouabain. Thus, it appears that chlordecone, mirex, and TCDD inhibit the canalicular transport of the glucuronide metabolites of morphine and imipramine into bile, and TCDD affects in addition the canalicular transport of ouabain into bile.

  17. Platyphylloside Isolated From Betula platyphylla Inhibit Adipocyte Differentiation and Induce Lipolysis Via Regulating Adipokines Including PPARγ in 3T3-L1 Cells

    PubMed Central

    Lee, Mina; Sung, Sang Hyun

    2016-01-01

    Background: Obesity causes or aggravates many health problems, both independently and in association with several pathological disorders, including Type II diabetes, hypertension, atherosclerosis, and cancer. Therefore, we screened small compounds isolated from natural products for the development of anti-obesity drugs. Objective: The purpose of this study was to investigate the anti-adipogenic activities of platyphylloside, diarylheptanoid isolated from Betula platyphylla, which was selected based on the screening using 3T3-L1 cells. Materials and Methods: To evaluate the inhibition of adipocyte differentiation and lipolysis, lipid contents of BPP on were measured using Oil Red O staining in 3T3-L1 cells. The mRNA and protein expression levels of various adipokines were measured by Quantitative real-time PCR and Western blotting analysis, respectively. Results: Platyphylloside showed significant inhibitory activity on adipocyte differentiation in 3T3-L1 cells and suppressed adipocyte differentiation even in the presence of troglitazone, a PPARγ agonist. Platyphylloside might suppress adipocyte differentiation through PPARγ, C/EBPα, and SREBP1-induced adipogenesis, which is synergistically associated with downstream adipocyte-specific gene promoters such as aP2, FAS, SCD-1, LPL, and Adiponectin. In addition, platyphylloside affected lipolysis by down-regulating perilipin and HSL and up-regulating TNFα. Conclusion: Taken together, the results reveal that platyphylloside has anti-adipogenic activity and highlight its potential in the prevention and treatment of obesity. SUMMARY The extract of B. platyphylla bark and its isolate, BPP, had anti-adipogenic activity in 3T3-L1 cells via suppression of adipocyte differentiation from preadipocytes.Treatment with BPP significantly down-regulated the expression of PPARγ, C/EBP, C/EBPβ, C/EBPδ, SREBP1c, SCD-1, FAS, aP2 and LPL.BPP induced a lipolytic response in mature adipocytes via up-regulation krof TNFá and down

  18. Cool-1-mediated inhibition of c-Cbl modulates multiple critical properties of glioblastomas, including the ability to generate tumors in vivo.

    PubMed

    Stevens, Brett M; Folts, Christopher J; Cui, Wanchang; Bardin, Addie L; Walter, Kevin; Carson-Walter, Eleanor; Vescovi, Angelo; Noble, Mark

    2014-05-01

    We discovered that glioblastoma (GBM) cells use Cool-1/β-pix to inhibit normal activation of the c-Cbl ubiquitin ligase via the redox/Fyn/c-Cbl pathway and that c-Cbl inhibition is critical for GBM cell function. Restoring normal c-Cbl activity by Cool-1 knockdown in vitro reduced GBM cell division, almost eliminated generation of adhesion-independent spheroids, reduced the representation of cells expressing antigens thought to identify tumor initiating cells (TICs), reduced levels of several proteins of critical importance in TIC function (such as Notch-1 and Sox2), and increased sensitivity to BCNU (carmustine) and temozolomide (TMZ). In vivo, Cool-1 knockdown greatly suppressed the ability of GBM cells to generate tumors, an outcome that was c-Cbl dependent. In contrast, Cool-1 knockdown did not reduce division or increase BCNU or TMZ sensitivity in primary glial progenitor cells and Cool-1/c-Cbl complexes were not found in normal brain tissue. Our studies provide the first evidence that Cool-1 may be critical in the biology of human tumors, that suppression of c-Cbl by Cool-1 may be critical for generation of at least a subset of GBMs and offer a novel target that appears to be selectively necessary for TIC function and modulates chemoresistance in GBM cells. Targeting such proteins that inhibit c-Cbl offers potentially attractive opportunities for therapeutic development.

  19. Action Spectra for the Inhibition of Hypocotyl Growth by Continuous Irradiation in Light and Dark-Grown Sinapis alba L. Seedlings 1

    PubMed Central

    Beggs, Christopher J.; Holmes, M. Geoffrey; Jabben, Merten; Schäfer, Eberhard

    1980-01-01

    Action spectra for the inhibition by continuous (24-hour) irradiation of hypocotyl growth in 54-hour-old Sinapis alba L. seedlings were measured using seedlings which had had four different pretreatments. These seedlings were either (a) dark-grown with a high total phytochrome level, (b) dark-grown with a low total phytochrome level, (c) light-grown with chlorophyll, or (d) light-grown with no chlorophyll [treated with 4-chloro-5-(methylamino)-2-(α,α,α-trifluoro-m-tolyl)-3(2H) -pyridazinone (San 9789)]. The resulting action spectra show that the blue, red, and far-red (716 nm) wavebands are most inhibitory for dark-grown plants with high phytochrome content, whereas hypocotyl growth in dark-grown plants with a low phytochrome content are only slightly inhibited by blue and far-red radiation. In light-grown plants, the effectiveness of blue and far-red light almost disappears. The position of red light effectiveness in chlorophyll-containing plants is shifted to lower wavelengths compared with those containing no chlorophyll. PMID:16661489

  20. Action of silver nanoparticles towards biological systems: cytotoxicity evaluation using hen's egg test and inhibition of Streptococcus mutans biofilm formation.

    PubMed

    Freire, Priscila L L; Stamford, Thayza C M; Albuquerque, Allan J R; Sampaio, Fabio C; Cavalcante, Horacinna M M; Macedo, Rui O; Galembeck, André; Flores, Miguel A P; Rosenblatt, Aronita

    2015-02-01

    This study aimed to evaluate the cytotoxicity and bactericidal properties of four silver nanoparticle (AgNP) colloids and their ability to inhibit Streptococcus mutans biofilm formation on dental enamel. The cytotoxicity of AgNPs was evaluated based on signs of vascular change on the chorioallantoic membrane using the hen's egg test (HET-CAM). Bactericidal properties and inhibition of S. mutans biofilm formation were determined using a parallel-flow cell system and a dichromatic fluorescent stain. The percentage of viable cells was calculated from regression data generated from a viability standard. AgNP colloids proved to be non-irritating, as they were unable to promote vasoconstriction, haemorrhage or coagulation. AgNP colloids inhibited S. mutans biofilm formation on dental enamel, and cell viability measured by fluorescence was 0% for samples S1, S2, S3 and S4 and 36.5% for the positive control (diluted 30% silver diamine fluoride). AgNPs are new products with a low production cost because they have a lower concentration of silver, with low toxicity and an effective bactericidal effect against a cariogenic oral bacterium. Moreover, they do not promote colour change in dental enamel, which is an aesthetic advantage compared with traditional silver products.

  1. Synergistic action of auxin and ethylene on root elongation inhibition is caused by a reduction of epidermal cell length

    PubMed Central

    Alarcón, M Victoria; Lloret, Pedro G; Salguero, Julio

    2014-01-01

    Auxin and ethylene have been largely reported to reduce root elongation in maize primary root. However the effects of auxin are greater than those caused by ethylene. Although auxin stimulates ethylene biosynthesis through the specific increase of ACC synthase, the auxin inhibitory effect on root elongation is not mediated by the auxin-induced increase of ethylene production. Recently it has been demonstrated that root inhibition by the application of the synthetic auxin NAA (1-naphtalenacetic acid) is increased if combined with the ethylene precursor ACC (1-aminocyclopropane-1-carboxilic acid) when both compounds are applied at very low concentrations. Root elongation is basically the result of two processes: a) cell divisions in the meristem where meristematic cells continuously generate new cells and b) subsequently polarized growth by elongation along the root axis as cells leave the meristem and enter the root elongation zone. Our results indicate that exogenous auxin reduced both root elongation and epidermal cell length. In a different way, ethylene at very low concentrations only inhibited root elongation without affecting significantly epidermal cell length. However, these concentrations of ethylene increased the inhibitory effect of auxin on root elongation and cell length. Consequently the results support the hypothesis that ethylene acts synergistically with auxin in the regulation of root elongation and that inhibition by both hormones is due, at least partially, to the reduction of cell length in the epidermal layer. PMID:24598313

  2. Synergistic action of auxin and ethylene on root elongation inhibition is caused by a reduction of epidermal cell length.

    PubMed

    Alarcón, M Victoria; Lloret, Pedro G; Salguero, Julio

    2014-01-01

    Auxin and ethylene have been largely reported to reduce root elongation in maize primary root. However the effects of auxin are greater than those caused by ethylene. Although auxin stimulates ethylene biosynthesis through the specific increase of ACC synthase, the auxin inhibitory effect on root elongation is not mediated by the auxin-induced increase of ethylene production. Recently it has been demonstrated that root inhibition by the application of the synthetic auxin NAA (1-naphtalenacetic acid) is increased if combined with the ethylene precursor ACC (1-aminocyclopropane-1-carboxilic acid) when both compounds are applied at very low concentrations.   Root elongation is basically the result of two processes: a) cell divisions in the meristem where meristematic cells continuously generate new cells and b) subsequently polarized growth by elongation along the root axis as cells leave the meristem and enter the root elongation zone. Our results indicate that exogenous auxin reduced both root elongation and epidermal cell length. In a different way, ethylene at very low concentrations only inhibited root elongation without affecting significantly epidermal cell length. However, these concentrations of ethylene increased the inhibitory effect of auxin on root elongation and cell length. Consequently the results support the hypothesis that ethylene acts synergistically with auxin in the regulation of root elongation and that inhibition by both hormones is due, at least partially, to the reduction of cell length in the epidermal layer.

  3. Inhibition of programmed cell death by cyclosporin A; preferential blocking of cell death induced by signals via TCR/CD3 complex and its mode of action.

    PubMed Central

    Yasutomi, D; Odaka, C; Saito, S; Niizeki, H; Kizaki, H; Tadakuma, T

    1992-01-01

    Cyclosporin A (CsA) is reported to inhibit programmed cell death. We confirmed this by using T-cell hybridomas which are inducible to programmed cell death by activation with immobilized anti-CD3 antibody or with anti-Thy 1.2 antibody. Cell death and DNA fragmentation, characteristic features of programmed cell death, were almost completely blocked by CsA or FK506. To investigate whether CsA inhibits only the cell death through the signals via the TCR/CD3 complex or all of the programmed cell death induced by various reagents, we further established CD4+8+ thymic lymphomas which result in programmed cell death after activation with calcium ionophore, dexamethasone, cyclic AMP or anti-CD3 antibody. It was revealed that CsA could block only the cell death mediated by the TCR/CD3 complex. For the clarification of the site of action of CsA, Ca2+ influx and endocytosis of receptors after stimulation with anti-CD3 antibody were monitored in the presence of CsA, and no significant effects of CsA were observed. Furthermore, prevention of cell death was examined by adding CsA at various periods of time after initiation of culture. CsA was found to exert its effect even when added after 4 h of cultivation, and the kinetic pattern of suppression was similar to that of the suppressive effect on IL-2 production. These observations indicate that in the events of programmed cell death, the major site of action of CsA will not be the inhibition of the immediate membrane events after activation of the TCR/CD3 complex but rather the interference in the function of molecules that transmit signals between membrane events and the activation of genes in the nucleus. Images Figure 2 Figure 3 PMID:1383138

  4. Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir.

    PubMed

    Carbajo-Lozoya, Javier; Ma-Lauer, Yue; Malešević, Miroslav; Theuerkorn, Martin; Kahlert, Viktoria; Prell, Erik; von Brunn, Brigitte; Muth, Doreen; Baumert, Thomas F; Drosten, Christian; Fischer, Gunter; von Brunn, Albrecht

    2014-05-12

    Until recently, there were no effective drugs available blocking coronavirus (CoV) infection in humans and animals. We have shown before that CsA and FK506 inhibit coronavirus replication (Carbajo-Lozoya, J., Müller, M.A., Kallies, S., Thiel, V., Drosten, C., von Brunn, A. Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506. Virus Res. 2012; Pfefferle, S., Schöpf, J., Kögl, M., Friedel, C., Müller, M.A., Stellberger, T., von Dall'Armi, E., Herzog, P., Kallies, S., Niemeyer, D., Ditt, V., Kuri, T., Züst, R., Schwarz, F., Zimmer, R., Steffen, I., Weber, F., Thiel, V., Herrler, G., Thiel, H.-J., Schwegmann-Weßels, C., Pöhlmann, S., Haas, J., Drosten, C. and von Brunn, A. The SARS-Coronavirus-host interactome: identification of cyclophilins as target for pan-Coronavirus inhibitors. PLoS Pathog., 2011). Here we demonstrate that CsD Alisporivir, NIM811 as well as novel non-immunosuppressive derivatives of CsA and FK506 strongly inhibit the growth of human coronavirus HCoV-NL63 at low micromolar, non-cytotoxic concentrations in cell culture. We show by qPCR analysis that virus replication is diminished up to four orders of magnitude to background levels. Knockdown of the cellular Cyclophilin A (CypA/PPIA) gene in Caco-2 cells prevents replication of HCoV-NL63, suggesting that CypA is required for virus replication. Collectively, our results uncover Cyclophilin A as a host target for CoV infection and provide new strategies for urgently needed therapeutic approaches.

  5. Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments

    PubMed Central

    Theron, Grant; Peter, Jonny; Calligaro, Greg; Meldau, Richard; Hanrahan, Colleen; Khalfey, Hoosain; Matinyenya, Brian; Muchinga, Tapuwa; Smith, Liezel; Pandie, Shaheen; Lenders, Laura; Patel, Vinod; Mayosi, Bongani M.; Dheda, Keertan

    2014-01-01

    The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to-positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific CT values, and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with CT values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC CT > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7–16) versus 22 (18–33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF CT is a poor surrogate of load in extrapulmonary specimens. PMID:25014250

  6. Leucas aspera inhibits the Dalton's ascitic lymphoma in Swiss albino mice: A preliminary study exploring possible mechanism of action

    PubMed Central

    Augustine, Bibin Baby; Dash, Suvakanta; Lahkar, Mangala; Sarma, Usha; Samudrala, Pavan Kumar; Thomas, Jaya Mary

    2014-01-01

    Background: North East India is a rich source of medicinal plants and a number of plant extracts are used by tribal peoples living in this area for various disorders. L.aspera is such a plant, traditionally used as an antitumor agent. Aim: In the present study, aerial parts of L.aspera were investigated for antitumor activity in Dalton's lymphoma (DAL) bearing mice. The ability of plant extract in free radical scavenging, neoangiogenesis inhibition and macrophage stimulation were also checked. Materials and Methods: Based on the preliminary in vitro cytotoxicity studies ethyl acetate fraction of L.aspera (EALA) was selected for the detailed study. DAL ascites tumor model was performed to check the antitumor activity of EALA (200 and 400mg/kg of body weight). Hematological and histopathological parameters were estimated. Antioxidant levels, neoangiogenesis and peritoneal macrophage count were also determined. Results: In vitro MTT and Trypan blue assay results showed the cytotoxic effect of EALA in DAL cells lines. EALA treatment resulted in significant decrease in ascites tumor volume and viable cell count. Hematological and liver antioxidant parameters were normalised by EALA treatment. It was also found that EALA treatment inhibits neovascularisation and produce macrophage stimulation in treated mice. Conclusion: The results showed that EALA is a promising anticancer agent and its activity is comparable to the standard drug 5-Flouro uracil (5-FU). PMID:24914276

  7. Ketanserin, an antidepressant, exerts its antileishmanial action via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme of Leishmania donovani.

    PubMed

    Singh, Sushma; Dinesh, Neeradi; Kaur, Preet Kamal; Shamiulla, Baigadda

    2014-06-01

    Leishmaniasis is one of the major health problems existing globally. The current chemotherapy for leishmaniasis presents several drawbacks like toxicity and increased resistance to existing drugs, and hence, there is a necessity to look out for the novel drug targets and new chemical entities. Current trend in drug discovery arena is the "repurposing" of old drugs for the treatment of diseases. In the present study, an antidepressant, ketanserin, was found lethal to both Leishmania donovani promastigotes and intracellular amastigotes with no apparent toxicity to the cells. Ketanserin killed promastigotes and amastigotes with an IC50 value of 37 μM and 28 μM respectively, in a dose-dependent manner. Ketanserin was found to inhibit L. donovani recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme with an IC50 value of 43 μM. Ketanserin treated promastigotes were exogenously supplemented with sterols like ergosterol and cholesterol to rescue cell death. Ergosterol could recover the inhibition partially, whereas cholesterol supplementation completely failed to rescue the inhibited parasites. Further, HMGR-overexpressing parasites were generated by transfecting Leishmania promastigotes with an episomal pspα hygroα-HMGR construct. Wild-type and HMGR overexpressors of L. donovani were used to study the effect and mode of action of this inhibitor. The HMGR overexpressors showed twofold resistance to ketanserin. These observations suggest that the lethal effect of ketanserin is due to inhibition of HMGR, the rate-limiting enzyme of the ergosterol biosynthetic pathway. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present study may have implications in treatment of leishmaniasis.

  8. Inhibition of spoilage mould conidia by acetic acid and sorbic acid involves different modes of action, requiring modification of the classical weak-acid theory.

    PubMed

    Stratford, Malcolm; Plumridge, Andrew; Nebe-von-Caron, Gerhardt; Archer, David B

    2009-11-30

    Fungal spoilage of many foods is prevented by weak-acid preservatives such as sorbic acid or acetic acid. We show that sorbic and acetic acids do not both inhibit cells by lowering of internal pH alone and that the "classical weak-acid theory" must be revised. The "classical weak-acid theory" suggests that all lipophilic acids with identical pK(a) values are equally effective as preservatives, causing inhibition by diffusion of molecular acids into the cell, dissociation, and subsequent acidification of the cytoplasm. Using a number of spoilage fungi from different genera, we have shown that sorbic acid was far more toxic than acetic acid, and no correlation existed between resistance to acetic acid and resistance to sorbic acid. The molar ratio of minimum inhibitory concentrations (MICs) (acetic: sorbic) was 58 for Paecilomyces variotii and 14 for Aspergillus phoenicis. Using flow cytometry on germinating conidia of Aspergillusniger, acetic acid at pH 4.0 caused an immediate decline in the mean cytoplasmic pH (pH(i)) falling from neutrality to approximately pH 4.7 at the MIC (80 mM). Sorbic acid also caused a rapid but far smaller drop in pH(i), at the MIC (4.5 mM); the pH remained above pH 6.3. Over 0-5 mM, a number of other weak acids caused a similar fall in cytoplasmic pH. It was concluded that while acetic acid inhibition of A. niger conidia was due to cytoplasmic acidification, inhibition by sorbic acid was not. A possible membrane-mediated mode of action of sorbic acid is discussed.

  9. Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments.

    PubMed

    Theron, Grant; Peter, Jonny; Calligaro, Greg; Meldau, Richard; Hanrahan, Colleen; Khalfey, Hoosain; Matinyenya, Brian; Muchinga, Tapuwa; Smith, Liezel; Pandie, Shaheen; Lenders, Laura; Patel, Vinod; Mayosi, Bongani M; Dheda, Keertan

    2014-07-11

    The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to-positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific C(T) values, and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with C(T) values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC C(T) > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7-16) versus 22 (18-33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF C(T) is a poor surrogate of load in extrapulmonary specimens.

  10. Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials.

    PubMed Central

    Loria, P; Miller, S; Foley, M; Tilley, L

    1999-01-01

    The malaria parasite feeds by degrading haemoglobin in an acidic food vacuole, producing free haem moieties as a by-product. The haem in oxyhaemoglobin is oxidized from the Fe(II) state to the Fe(III) state with the consequent production of an equimolar concentration of H2O2. We have analysed the fate of haem molecules in Plasmodium falciparum-infected erythrocytes and have found that only about one third of the haem is polymerized to form haemozoin. The remainder appears to be degraded by a non-enzymic process which leads to an accumulation of iron in the parasite. A possible route for degradation of the haem is by reacting with H2O2, and we show that, under conditions designed to resemble those found in the food vacuole, i.e., at pH5.2 in the presence of protein, free haem undergoes rapid peroxidative decomposition. Chloroquine and quinacrine are shown to be efficient inhibitors of the peroxidative destruction of haem, while epiquinine, a quinoline compound with very low antimalarial activity, has little inhibitory effect. We also show that chloroquine enhances the association of haem with membranes, while epiquinine inhibits this association, and that treatment of parasitized erythrocytes with chloroquine leads to a build-up of membrane-associated haem in the parasite. We suggest that chloroquine exerts its antimalarial activity by causing a build-up of toxic membrane-associated haem molecules that eventually destroy the integrity of the malaria parasite. We have further shown that resistance-modulating compounds, such as chlorpromazine, interact with haem and efficiently inhibit its degradation. This may explain the weak antimalarial activities of these compounds. PMID:10191268

  11. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection.

    PubMed

    Meng, Zhongji; Zhang, Xiaoyong; Pei, Rongjuan; Zhang, Ejuan; Kemper, Thekla; Vollmer, Jörg; Davis, Heather L; Glebe, Dieter; Gerlich, Wolfram; Roggendorf, Michael; Lu, Mengji

    2016-01-01

    CpG oligodeoxynucleotides (ODNs) stimulate immune cells via TLR9 and are potentially useful immunomodulators for the treatment of chronic viral infections. In the present study, different classes of CpGs were tested for their capacities for innate immune activation and antiviral activities in the woodchuck model. A class P CpG ODN was found to stimulate interferon (IFN) production in woodchuck peripheral blood mononuclear cells (PBMCs) in vitro, and following subcutaneous administration in vivo, it was observed to induce IFN and MxA expression in woodchuck PBMCs. Combination treatment with CpG ODN and entecavir (ETV) led to effective suppression of the woodchuck hepatitis virus (WHV) load in the woodchucks, with early viral responses and inhibition of replication. The woodchuck hepatitis surface antigen (WHsAg) serum concentrations were strongly decreased by CpG and ETV together but not by either agent alone, indicating synergistic effects. However, viral control post-treatment was still transient, similar to that observed with ETV alone. Significantly elevated levels of serum aspartate aminotransferase (AST) but not of alanine aminotransferase (ALT) in some of the woodchucks receiving CpG ODN were noted, but these increases were resolved before the completion of treatment and were not associated with an elevated serum bilirubin level or coagulation disorders, suggesting the absence of a significant safety concern.

  12. Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action

    SciTech Connect

    Zhang, Haimou; Qin, Gangjian; Liang, Gang; Li, Jinan; Chiu, Isaac; Barrington, Robert A.; Liu, Dongxu . E-mail: dxliu001@yahoo.com

    2007-07-13

    Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanism of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-{kappa}B activation and nuclear translocation in an I{kappa}B{alpha}-dependent manner. The inhibitory effects were associated with reduction of inhibitor I{kappa}B kinase activity and stabilization of the NF-{kappa}B inhibitor I{kappa}B. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations.

  13. Theoretical study of the deposition and adsorption of bisphosphonates on the 001 hydroxyapatite surface: Implications in the pathological crystallization inhibition and the bone antiresorptive action

    NASA Astrophysics Data System (ADS)

    Fernández, David; Ortega-Castro, Joaquín; Frau, Juan

    2017-01-01

    The effect of different side chain groups of bisphosphonates (BPs) on the adsorption on the hydroxyapatite (HAP) is still a controversial issue. In this work, we studied the deposition and adsorption of a set of 26 BPs on the HAP (001) surface by using density functional theory (DFT) in which has been shown that the charge, the length or the presence of different functional groups at R2 side chain can modulate the adsorption energy of the BP. It was observed that negative charged groups at R2 enhanced the favourable electrostatic interactions between the BP and the HAP surface, but also that the length of R2 was important to enable the formation of the favorable electrostatic interactions between the functional group at R2 and the surface. A crossover study between the HAP/BP model (3D-QSAR/DFT) and the inhibition of the human farnesyl pyrophosphate synthase (FPPS) (3D-QSAR) pointed out that the electrostatic character of the R2 side chain provokes contrary effects in the inhibition of pathological crystallization and in the bone antiresorptive action of BPs.

  14. Fir honeydew honey flavonoids inhibit TNF-α-induced MMP-9 expression in human keratinocytes: a new action of honey in wound healing.

    PubMed

    Majtan, Juraj; Bohova, Jana; Garcia-Villalba, Rocio; Tomas-Barberan, Francisco A; Madakova, Zuzana; Majtan, Tomas; Majtan, Viktor; Klaudiny, Jaroslav

    2013-09-01

    Matrix metalloproteinase-9 (MMP-9) appears to be a major protease responsible for the degradation of matrix and growth-promoting agents in chronic wounds. Honey has been successfully used for treating non-healing wounds associated with infections. However, the mechanisms of its action at the cellular level have remained poorly understood. The aim of this study was to investigate the effect of fir honeydew honey on TNF-α-induced MMP-9 expression and secretion from human keratinocytes (HaCaT) and to identify the honey component(s) responsible for a discovered effect. A C18 solid-phase column was used for preparation of honey aqueous extract (HAE). Expression and production of MMP-9 by HaCaT cells were determined by reverse transcription-PCR, gelatine zymography and Western blot analysis using a polyclonal antibody against MMP-9. We found that HAE inhibited TNF-α-induced production of MMP-9 in keratinocytes in a dose-dependent manner at both the mRNA and protein levels. Apigenin and kaempferol, identified flavonoids in HAE, markedly inhibited MMP-9 production from HaCaT and epidermal keratinocytes. Taken together, fir honeydew honey, which contains certain flavonoids, prevents TNF-α-induced proteolytic activity in cutaneous inflammation. Thus, our findings provide clear evidence that honey may serve as a natural treatment for dermatological problems associated with a persistent inflammation.

  15. Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

    PubMed Central

    Chiba, Tomohiro; Sakurada, Tsuyoshi; Watanabe, Rie; Yamaguchi, Kohji; Kimura, Yasuhisa; Kioka, Noriyuki; Kawagishi, Hirokazu; Matsuo, Michinori; Ueda, Kazumitsu

    2014-01-01

    Hypercholesterolemia is one of the key risk factors for coronary heart disease, a major cause of death in developed countries. Suppression of NPC1L1-mediated dietary and biliary cholesterol absorption is predicted to be one of the most effective ways to reduce the risk of hypercholesterolemia. In a screen for natural products that inhibit ezetimibe glucuronide binding to NPC1L1, we found a novel compound, fomiroid A, in extracts of the mushroom Fomitopsis nigra. Fomiroid A is a lanosterone derivative with molecular formula C30H48O3. Fomiroid A inhibited ezetimibe glucuronide binding to NPC1L1, and dose-dependently prevented NPC1L1-mediated cholesterol uptake and formation of esterified cholesterol in NPC1L1-expressing Caco2 cells. Fomiroid A exhibited a pharmacological chaperone activity that corrected trafficking defects of the L1072T/L1168I mutant of NPC1L1. Because ezetimibe does not have such an activity, the binding site and mode of action of fomiroid A are likely to be distinct from those of ezetimibe. PMID:25551765

  16. C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

    PubMed Central

    Aoki, Manabu; Hayashi, Hironori; Yedidi, Ravikiran S.; Martyr, Cuthbert D.; Takamatsu, Yuki; Aoki-Ogata, Hiromi; Nakamura, Teruya; Nakata, Hirotomo; Das, Debananda; Yamagata, Yuriko; Ghosh, Arun K.

    2015-01-01

    ABSTRACT We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1WT), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 μM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRVRP51); the three compounds remained active against HIV-1DRVRP51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR. IMPORTANCE Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1 strains and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1 strains (HIVDRVR) has recently been observed in vivo and in

  17. Actions of adenosine A1 and A2 receptor antagonists on CFTR antibody-inhibited β-adrenergic mucin secretion response

    PubMed Central

    Pereira, M M C; Lloyd Mills, C; Dormer, R L; McPherson, M A

    1998-01-01

    The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated β-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited β-adrenergic response and whether excessive cyclic AMP rise is required.CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured.The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion.DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion.CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism.DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not.Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of β-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis. PMID:9831904

  18. GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance.

    PubMed

    Heppner, Kristy M; Baquero, Arian F; Bennett, Camdin M; Lindsley, Sarah R; Kirigiti, Melissa A; Bennett, Baylin; Bosch, Martha A; Mercer, Aaron J; Rønnekleiv, Oline K; True, Cadence; Grove, Kevin L; Smith, M Susan

    2017-01-01

    Kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARC) are key components of the hypothalamic-pituitary-gonadal axis, as they regulate the basal pulsatile release of gonadotropin releasing hormone (GnRH). ARC Kiss1 action is dependent on energy status, and unmasking metabolic factors responsible for modulating ARC Kiss1 neurons is of great importance. One possible factor is glucagon-like peptide 1 (GLP-1), an anorexigenic neuropeptide produced by brainstem preproglucagon neurons. Because GLP fiber projections and the GLP-1 receptor (GLP-1R) are abundant in the ARC, we hypothesized that GLP-1R signaling could modulate ARC Kiss1 action. Using ovariectomized mice, we found that GLP-producing fibers come in close apposition with ARC Kiss1 neurons; these neurons also contain Glp1r mRNA. Electrophysiological recordings revealed that liraglutide (a long-acting GLP-1R agonist) increased action potential firing and caused a direct membrane depolarization of ARC Kiss1 cells in brain slices. We determined that brainstem preproglucagon mRNA is decreased after a 48-h fast in mice, a negative energy state in which ARC Kiss1 expression and downstream GnRH/luteinizing hormone (LH) release are potently suppressed. However, activation of GLP-1R signaling in fasted mice with liraglutide was not sufficient to prevent LH inhibition. Furthermore, chronic central infusions of the GLP-1R antagonist, exendin(9-39), in ad libitum-fed mice did not alter ARC Kiss1 mRNA or plasma LH. As a whole, these data identify a novel interaction of the GLP-1 system with ARC Kiss1 neurons but indicate that CNS GLP-1R signaling alone is not critical for the maintenance of LH during fasting or normal feeding.

  19. GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance

    PubMed Central

    Heppner, Kristy M.; Baquero, Arian F.; True, Cadence; Grove, Kevin L.

    2017-01-01

    Abstract Kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARC) are key components of the hypothalamic-pituitary-gonadal axis, as they regulate the basal pulsatile release of gonadotropin releasing hormone (GnRH). ARC Kiss1 action is dependent on energy status, and unmasking metabolic factors responsible for modulating ARC Kiss1 neurons is of great importance. One possible factor is glucagon-like peptide 1 (GLP-1), an anorexigenic neuropeptide produced by brainstem preproglucagon neurons. Because GLP fiber projections and the GLP-1 receptor (GLP-1R) are abundant in the ARC, we hypothesized that GLP-1R signaling could modulate ARC Kiss1 action. Using ovariectomized mice, we found that GLP-producing fibers come in close apposition with ARC Kiss1 neurons; these neurons also contain Glp1r mRNA. Electrophysiological recordings revealed that liraglutide (a long-acting GLP-1R agonist) increased action potential firing and caused a direct membrane depolarization of ARC Kiss1 cells in brain slices. We determined that brainstem preproglucagon mRNA is decreased after a 48-h fast in mice, a negative energy state in which ARC Kiss1 expression and downstream GnRH/luteinizing hormone (LH) release are potently suppressed. However, activation of GLP-1R signaling in fasted mice with liraglutide was not sufficient to prevent LH inhibition. Furthermore, chronic central infusions of the GLP-1R antagonist, exendin(9–39), in ad libitum–fed mice did not alter ARC Kiss1 mRNA or plasma LH. As a whole, these data identify a novel interaction of the GLP-1 system with ARC Kiss1 neurons but indicate that CNS GLP-1R signaling alone is not critical for the maintenance of LH during fasting or normal feeding. PMID:28144621

  20. Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumour actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis.

    PubMed

    Zheng, Yu; Zhou, Hong; Brennan, Karen; Blair, Julie M; Modzelewski, James R K; Seibel, Markus J; Dunstan, Colin R

    2007-02-01

    than either agent alone; and that (ii) inhibition of bone resorption, rather than direct anti-tumour action, mediates the effects of these agents on tumour growth in this in vivo model.

  1. Inhibition of recombinant N-type and native high voltage-gated neuronal Ca{sup 2+} channels by AdGABA: Mechanism of action studies

    SciTech Connect

    Martinez-Hernandez, Elizabeth; Sandoval, Alejandro; Gonzalez-Ramirez, Ricardo; Zoidis, Grigoris; Felix, Ricardo

    2011-02-01

    High-voltage activated Ca{sup 2+} (Ca{sub V}) channels play a key role in the regulation of numerous physiological events by causing transient changes in the intracellular Ca{sup 2+} concentration. These channels consist of a pore-forming Ca{sub V}{alpha}{sub 1} protein and three auxiliary subunits (Ca{sub V}{beta}, Ca{sub V}{alpha}{sub 2}{delta} and Ca{sub V}{gamma}). Ca{sub V}{alpha}{sub 2}{delta} is an important component of Ca{sub V} channels in many tissues and of great interest as a drug target. It is well known that anticonvulsant agent gabapentin (GBP) binds to Ca{sub V}{alpha}{sub 2}{delta} and reduces Ca{sup 2+} currents by modulating the expression and/or function of the Ca{sub V}{alpha}{sub 1} subunit. Recently, we showed that an adamantane derivative of GABA, AdGABA, has also inhibitory effects on Ca{sub V} channels. However, the importance of the interaction of AdGABA with the Ca{sub V}{alpha}{sub 2}{delta} subunit has not been conclusively demonstrated and the mechanism of action of the drug has yet to be elucidated. Here, we describe studies on the mechanism of action of AdGABA. Using a combined approach of patch-clamp recordings and molecular biology we show that AdGABA inhibits Ca{sup 2+} currents acting on Ca{sub V}{alpha}{sub 2}{delta} only when applied chronically, both in a heterologous expression system and in dorsal root-ganglion neurons. AdGABA seems to require uptake and be acting intracellularly given that its effects are prevented by an inhibitor of the L-amino acid transport system. Interestingly, a mutation in the Ca{sub V}{alpha}{sub 2}{delta} that abolishes GBP binding did not affect AdGABA actions, revealing that its mechanism of action is similar but not identical to that of GBP. These results indicate that AdGABA is an important Ca{sub V}{alpha}{sub 2}{delta} ligand that regulates Ca{sub V} channels.

  2. Myeloid-derived suppressor cells in murine AIDS inhibit B-cell responses in part via soluble mediators including reactive oxygen and nitrogen species, and TGF-β.

    PubMed

    Rastad, Jessica L; Green, William R

    2016-12-01

    Monocytic myeloid-derived suppressor cells (M-MDSCs) were increased during LP-BM5 retroviral infection, and were capable of suppressing not only T-cell, but also B-cell responses. In addition to previously demonstrating iNOS- and VISTA-dependent M-MDSC mechanisms, in this paper, we detail how M-MDSCs utilized soluble mediators, including the reactive oxygen and nitrogen species superoxide, peroxynitrite, and nitric oxide, and TGF-β, to suppress B cells in a predominantly contact-independent manner. Suppression was independent of cysteine-depletion and hydrogen peroxide production. When two major mechanisms of suppression (iNOS and VISTA) were eliminated in double knockout mice, M-MDSCs from LP-BM5-infected mice were able to compensate using other, soluble mechanisms in order to maintain suppression of B cells. The IL-10 producing regulatory B-cell compartment was among the targets of M-MDSC-mediated suppression.

  3. American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction

    PubMed Central

    Visvanathan, Kala; Chlebowski, Rowan T.; Hurley, Patricia; Col, Nananda F.; Ropka, Mary; Collyar, Deborah; Morrow, Monica; Runowicz, Carolyn; Pritchard, Kathleen I.; Hagerty, Karen; Arun, Banu; Garber, Judy; Vogel, Victor G.; Wade, James L.; Brown, Powel; Cuzick, Jack; Kramer, Barnett S.; Lippman, Scott M.

    2009-01-01

    Purpose To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. Methods A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) –positive invasive tumors. Women ≤ 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making. PMID:19470930

  4. Sphingosine-1-phosphate inhibits high glucose-mediated ERK1/2 action in endothelium through induction of MAP kinase phosphatase-3

    PubMed Central

    Whetzel, Angela M.; Bolick, David T.; Hedrick, Catherine C.

    2009-01-01

    Endothelial activation is a key early event in vascular complications of Type 1 diabetes. The nonobese diabetic (NOD) mouse is a well-characterized model of Type 1 diabetes. We previously reported that Type 1 diabetic NOD mice have increased endothelial activation, with increased production of monocyte chemoattractant protein (MCP)-1 and IL-6, and a 30% increase of surface VCAM-1 expression leading to a fourfold increase in monocyte adhesion to the endothelium. Sphingosine-1-phosphate (S1P) prevents monocyte:endothelial interactions in these diabetic NOD mice. Incubation of diabetic NOD endothelial cells (EC) with S1P (100 nmol/l) reduced ERK1/2 phosphorylation by 90%, with no significant changes in total ERK1/2 protein. In the current study, we investigated the mechanism of S1P action on ERK1/2 to reduce activation of diabetic endothelium. S1P caused a significant threefold increase in mitogen-activated kinase phosphatase-3 (MKP-3) expression in EC. MKP-3 selectively regulates ERK1/2 activity through dephosphorylation. Incubation of diabetic NOD EC with S1P and the S1P1-selective agonist SEW2871 significantly increased expression of MKP-3 and reduced ERK1/2 phosphorylation, while incubation with the S1P1/S1P3 antagonist VPC23019 decreased the expression of MKP-3, both results supporting a role for S1P1 in MKP-3 regulation. To mimic the S1P-mediated induction of MKP-3 diabetic NOD EC, we overexpressed MKP-3 in human aortic endothelial cells (HAEC) cultured in elevated glucose (25 mmol/l). Overexpression of MKP-3 in glucose-cultured HAEC decreased ERK1/2 phosphorylation and resulted in decreased monocyte:endothelial interactions in a static monocyte adhesion assay. Finally, we used small interfering RNA to MKP-3 and observed increased monocyte adhesion. Moreover, S1P was unable to inhibit monocyte adhesion in the absence of MKP-3. Thus, one mechanism for the anti-inflammatory action of S1P in diabetic EC is inhibition of ERK1/2 phosphorylation through induction of

  5. Enhanced latent inhibition in dopamine receptor-deficient mice is sex-specific for the D1 but not D2 receptor subtype: implications for antipsychotic drug action.

    PubMed

    Bay-Richter, Cecilie; O'Tuathaigh, Colm M P; O'Sullivan, Gerard; Heery, David M; Waddington, John L; Moran, Paula M

    2009-04-01

    Latent inhibition (LI) is reduced learning to a stimulus that has previously been experienced without consequence. It is an important model of abnormal allocation of salience to irrelevant information in patients with schizophrenia. In rodents LI is abolished by psychotomimetic drugs and in experimental conditions where LI is low in controls, its expression is enhanced by antipsychotic drugs with activity at dopamine (DA) receptors. It is however unclear what the independent contributions of DA receptor subtypes are to these effects. This study therefore examined LI in congenic DA D1 and D2 receptor knockout (D1 KO and D2 KO) mice. Conditioned suppression of drinking was used as the measure of learning in the LI procedure. Both male and female DA D2 KO mice showed clear enhancement of LI reproducing antipsychotic drug effects in the model. Unexpectedly, enhancement was also seen in D1 KO female mice but not in D1 KO male mice. This sex-specific pattern was not replicated in locomotor or motor coordination tasks nor in the effect of DA KOs on baseline learning in control groups indicating some specificity of the effect to LI. These data suggest that the dopaminergic mechanism underlying LI potentiation and possibly antipsychotic action may differ between the sexes, being mediated by D2 receptors in males but by both D1 and D2 receptors in females. These data suggest that the DA D1 receptor may prove an important target for understanding sex differences in the mechanisms of action of antipsychotic drugs and in the aetiology of aberrant salience allocation in schizophrenia.

  6. Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies.

    PubMed

    Hu-Lowe, Dana D; Chen, Enhong; Zhang, Lianglin; Watson, Katherine D; Mancuso, Patrizia; Lappin, Patrick; Wickman, Grant; Chen, Jeffrey H; Wang, Jianying; Jiang, Xin; Amundson, Karin; Simon, Ronald; Erbersdobler, Andreas; Bergqvist, Simon; Feng, Zheng; Swanson, Terri A; Simmons, Brett H; Lippincott, John; Casperson, Gerald F; Levin, Wendy J; Stampino, Corrado Gallo; Shalinsky, David R; Ferrara, Katherine W; Fiedler, Walter; Bertolini, Francesco

    2011-02-15

    Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin(+) perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.

  7. A mechanistic model for enzymatic saccharification of cellulose using continuous distribution kinetics II: cooperative enzyme action, solution kinetics, and product inhibition.

    PubMed

    Griggs, Andrew J; Stickel, Jonathan J; Lischeske, James J

    2012-03-01

    The projected cost for the enzymatic hydrolysis of cellulosic biomass continues to be a barrier for the commercial production of liquid transportation fuels from renewable feedstocks. Predictive models for the kinetics of the enzymatic reactions will enable an improved understanding of current limitations, such as the slow-down of the overall conversion rate, and may point the way for more efficient utilization of the enzymes in order to achieve higher conversion yields. A mechanistically based kinetic model for the enzymatic hydrolysis of cellulose was recently reported in Griggs et al. (2011) (Part I). In this article (Part II), the enzyme system is expanded to include solution-phase kinetics, particularly cellobiose-to-glucose conversion by β-glucosidase (βG), and novel adsorption and product inhibition schemes have been incorporated, based on current structural knowledge of the component enzymes. Model results show cases of cooperative and non-cooperative hydrolysis for an enzyme system consisting of EG(I) and CBH(I). The model is used to explore various potential rate-limiting phenomena, such as substrate accessibility, product inhibition, sterically hindered enzyme adsorption, and the molecular weight of the cellulose substrate.

  8. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells.

    PubMed

    Sen, C K; Khanna, S; Roy, S; Packer, L

    2000-04-28

    HT4 hippocampal neuronal cells were studied to compare the efficacy of tocopherols and tocotrienol to protect against glutamate-induced death. Tocotrienols were more effective than alpha-tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of alpha-tocopherol. Vitamin E molecules have potent antioxidant properties. Results show that at low concentrations, tocotrienols may have protected cells by an antioxidant-independent mechanism. Examination of signal transduction pathways revealed that protein tyrosine phosphorylation processes played a central role in the execution of death. Activation of pp60(c-Src) kinase and phosphorylation of ERK were observed in response to glutamate treatment. Nanomolar amounts of alpha-tocotrienol, but not alpha-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase. Overexpression of kinase-active c-Src sensitized cells to glutamate-induced death. Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. alpha-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains. This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4-10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.

  9. Observation-execution matching and action inhibition in human primary motor cortex during viewing of speech-related lip movements or listening to speech.

    PubMed

    Murakami, Takenobu; Restle, Julia; Ziemann, Ulf

    2011-06-01

    One influential theory posits that language has evolved from gestural communication through observation-execution matching processes in the mirror neuron system (MNS). This theory predicts that observation of speech-related lip movements or even listening to speech would result in effector and task specific increase of the excitability of the corresponding motor representations in the primary motor cortex (M1), since actual movement execution is known be effector and task specific. In addition, effector and task specific inhibitory control mechanisms should be important to prevent overt motor activation during observation of speech-related lip movements or listening to speech. We tested these predictions by applying focal transcranial magnetic stimulation to the left M1 of 12 healthy right-handed volunteers and measuring motor evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) in a lip muscle, the right orbicularis oris (OO), vs. a hand muscle, the right first dorsal interosseus (FDI). We found that MEP and SICI increased only in the OO but not in the FDI during viewing of speech-related lip movements or listening to speech. These changes were highly task specific because they were absent when lip movements non-related to speech were viewed. Finally, the increase in MEP amplitude in the OO correlated inversely with accuracy of speech perception, i.e. the MEP increase was directly related to task difficulty. The MEP findings support the notion that observation-execution matching is an operating process in the putative human MNS that might have been fundamental for evolution of language. Furthermore, the SICI findings provide evidence that inhibitory mechanisms are recruited to prevent unwanted overt motor activation during action observation.

  10. Corrective Action Investigation Plan for Corrective Action Unit 168: Areas 25 and 26 Contaminated Materials and Waste Dumps, Nevada Test Site, Nevada (Rev. 0) includes Record of Technical Change No. 1 (dated 8/28/2002), Record of Technical Change No. 2 (dated 9/23/2002), and Record of Technical Change No. 3 (dated 6/2/2004)

    SciTech Connect

    U.S. Department of Energy, National Nuclear Security Administration Nevada

    2001-11-21

    This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit 168 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 168 consists of a group of twelve relatively diverse Corrective Action Sites (CASs 25-16-01, Construction Waste Pile; 25-16-03, MX Construction Landfill; 25-19-02, Waste Disposal Site; 25-23-02, Radioactive Storage RR Cars; 25-23-18, Radioactive Material Storage; 25-34-01, NRDS Contaminated Bunker; 25-34-02, NRDS Contaminated Bunker; CAS 25-23-13, ETL - Lab Radioactive Contamination; 25-99-16, USW G3; 26-08-01, Waste Dump/Burn Pit; 26-17-01, Pluto Waste Holding Area; 26-19-02, Contaminated Waste Dump No.2). These CASs vary in terms of the sources and nature of potential contamination. The CASs are located and/or associated wit h the following Nevada Test Site (NTS) facilities within three areas. The first eight CASs were in operation between 1958 to 1984 in Area 25 include the Engine Maintenance, Assembly, and Disassembly Facility; the Missile Experiment Salvage Yard; the Reactor Maintenance, Assembly, and Disassembly Facility; the Radioactive Materials Storage Facility; and the Treatment Test Facility Building at Test Cell A. Secondly, the three CASs located in Area 26 include the Project Pluto testing area that operated from 1961 to 1964. Lastly, the Underground Southern Nevada Well (USW) G3 (CAS 25-99-16), a groundwater monitoring well located west of the NTS on the ridgeline of Yucca Mountain, was in operation during the 1980s. Based on site history and existing characterization data obtained to support the data quality objectives process, contaminants of potential concern (COPCs) for CAU 168 are primarily radionuclide; however, the COPCs for several CASs were not defined. To address COPC uncertainty

  11. Anti-carcinogenic action of curcumin by activation of antioxidant defence system and inhibition of NF-κB signalling in lymphoma-bearing mice.

    PubMed

    Das, Laxmidhar; Vinayak, Manjula

    2012-04-01

    NF-κB (nuclear factor κB) plays a significant role in inflammation, immunity, cell proliferation, apoptosis and malignancy. ROS (reactive oxygen species) are among the most important regulating factors of NF-κB. Intracellular ROS are mainly regulated by an endogenous antioxidant defence system. Any disruption of redox balance leads to oxidative stress, which causes a number of pathological conditions including inflammation and malignancy. Increased metabolic activity in cancerous cells leads to oxidative stress, which is further enhanced due to depletion of the endogenous antioxidant defence system. However, the activation and signalling of NF-κB are reported to be inhibited by overexpression and induced activity of antioxidant enzymes. Therefore the present study focuses on the correlation between the endogenous antioxidant defence system, ROS and NF-κB activation during lymphoma growth in mice. The study highlights the anti-carcinogenic role of curcumin by modulation of NF-κB activation and oxidative stress via the endogenous antioxidant defence system. Oxidative stress was monitored by lipid peroxidation, protein carbonylation and antioxidant enzyme activity. NF-κB-mediated signalling was tested by DNA-binding activity. The results reflect that intracellular production of H2O2 in oxidative tumour micro-environment regulates NF-κB activation. Curcumin inhibits oxidative state in the liver of lymphoma-bearing mice by enhancing the transcription and activities of antioxidant enzymes, which in turn modulate activation of NF-κB, leading to a decrease in lymphoma growth. Morphological changes as well as cell proliferation and cell survival assays confirmed reduced lymphoma growth. Thus curcumin contributes to cancer prevention by disrupting the vicious cycle of constant ROS production, responsible for a high oxidative micro-environment for tumour growth.

  12. Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPARgamma ligand-like action as a novel mechanism.

    PubMed

    Park, Jun-Young; Kawada, Teruo; Han, In-Seob; Kim, Byung-Sam; Goto, Tsuyoshi; Takahashi, Nobuyuki; Fushiki, Tohru; Kurata, Tadao; Yu, Rina

    2004-08-13

    Capsaicin, a major ingredient of hot pepper, is considered to exhibit anti-inflammatory properties. Our previous study demonstrated that capsaicin inhibited the production of pro-inflammatory mediators through NF-kappaB inactivation in LPS-stimulated macrophages. In order to further clarify the mechanism underlying the anti-inflammatory action of capsaicin, we investigated whether capsaicin alters PPARgamma activity, which regulates the production of the pro-inflammatory cytokine TNFalpha. Capsaicin significantly inhibited the production of TNFalpha by macrophages in a dose-dependent manner. Simultaneous exposure of the cells to capsaicin and PPARgamma agonist troglitazone or RXR agonist LG100268 resulted in stronger inhibition of TNFalpha production compared to the cells treated with either capsaicin, troglitazone, or LG100268 alone. Luciferase reporter assay revealed that capsaicin induced GAL4/PPARgamma chimera and full length PPARgamma (PPRE) transactivations in a dose-dependent manner. Furthermore, a specific PPARgamma antagonist T0070907 abrogated the inhibitory action of capsaicin on LPS-induced TNFalpha production by RAW 264.7 cells, indicating that capsaicin acts like a ligand for PPARgamma. Our data demonstrate for the first time that the anti-inflammatory action of capsaicin may be mediated by PPARgamma activation in LPS-stimulated RAW 264.7 cells.

  13. A highly acid-resistant novel strain of Lactobacillus johnsonii No. 1088 has antibacterial activity, including that against Helicobacter pylori, and inhibits gastrin-mediated acid production in mice

    PubMed Central

    Aiba, Yuji; Nakano, Yasuhiro; Koga, Yasuhiro; Takahashi, Kenji; Komatsu, Yasuhiko

    2015-01-01

    A novel strain of Lactobacillus johnsonii No. 1088 was isolated from the gastric juice of a healthy Japanese male volunteer, and characterized for its effectiveness in the stomach environment. Lactobacillus johnsonii No. 1088 was found to have the strongest acid resistance among several lactobacilli examined (>10% of cells survived at pH 1.0 after 2 h), and such a high acid resistance property was a specific characteristic of this strain of L. johnsonii. When cultured with various virulent bacteria, L. johnsonii No. 1088 inhibited the growth of Helicobacter pylori,Escherichia coli O-157, Salmonella Typhimurium, and Clostridium difficile, in which case its effectiveness was more potent than that of a type strain of L. johnsonii,JCM2012. In addition to its effect in vitro, L. johnsonii No. 1088 inhibited the growth of H. pylori in human intestinal microbiota-associated mice in both its live and lyophilized forms. Moreover, L. johnsonii No. 1088 suppressed gastric acid secretion in mice via decreasing the number of gastrin-positive cells in the stomach. These results taken together suggest that L. johnsonii No. 1088 is a unique lactobacillus having properties beneficial for supporting H. pylori eradication by triple therapy including the use of a proton pump inhibitor (PPI) and also for prophylaxis of gastroesophageal reflux disease possibly caused after H. pylori eradication as a side effect of PPI. PMID:25771812

  14. The complete genome sequence of the Alphaentomopoxvirus Anomala cuprea entomopoxvirus, including its terminal hairpin loop sequences, suggests a potentially unique mode of apoptosis inhibition and mode of DNA replication.

    PubMed

    Mitsuhashi, Wataru; Miyamoto, Kazuhisa; Wada, Sanae

    2014-03-01

    Complete genome sequence of Anomala cuprea entomopoxvirus, which belongs to the genus Alphaentomopoxvirus, including its terminal hairpin loop sequences, is reported. This is the first genome sequence of Alphaentomopoxvirus reported, and hairpin loops in entomopoxviruses have not previously been sequenced. The genome is 245,717 bp, which is smaller than had previously been estimated for Alphaentomopoxvirus. The inverted terminal repeats are quite long, and experimental results suggest that one genome molecule has one type of hairpin at one end and another type at the other end. The genome contains unexpected ORFs, e.g., that for the ubiquitin-conjugating enzyme E2 of eukaryotes. The BIR and RING domains found in a single ORF for an inhibitor of apoptosis in baculoviruses and entomopoxviruses occurred in two different, widely separated ORFs. Furthermore, an ORF in the genome contains a serpin domain that was previously found in vertebrate poxviruses for apoptosis inhibition but not in insect viruses.

  15. Lehrerbelastungsforschung -- Erweiterung durch ein handlungpsychologisches Belastungskonzept (Research on Teacher's Ability To Cope with Stress -- A Broadening of the Approach by Including a Psychology of Action-Concept of Stress).

    ERIC Educational Resources Information Center

    Krause, Andreas

    2003-01-01

    Reveals that most research on teacher stress relies on personal accounts. Presents a psychology of action-concept of stress and that has been transferred to teacher's instructional activities. Argues that this psychology of action concept of stress helps develop an understanding of teachers' work and what may lead to psychological stress. (CAJ)

  16. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors).

    PubMed

    Stahl, Stephen M

    2015-04-01

    Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites--or nodes--where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks.

  17. Botulinum toxin: mechanisms of action.

    PubMed

    Dressler, Dirk; Adib Saberi, Fereshte

    2005-01-01

    Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BT's therapeutic potential suddenly became apparent. We wish to give an overview over BT's mechanisms of action relevant for understanding its therapeutic use. BT's molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide.

  18. THE POSSIBLE MEDIATION BY CYCLIC AMP OF THE STIMULATION OF THYMOCYTE PROLIFERATION BY VASOPRESSIN AND THE INHIBITION OF THIS MITOGENIC ACTION BY THYROCALCITONIN,

    DTIC Science & Technology

    LYMPHOCYTES, MITOSIS), (*MITOSIS, INHIBITION), (* HORMONES , MITOSIS), CELLS(BIOLOGY), PHYSIOLOGY, THYMUS, ADENOSINE PHOSPHATES, STIMULATION...PHYSIOLOGY), GROWTH(PHYSIOLOGY), DEOXYRIBONUCLEIC ACIDS, PURINE ALKALOIDS, PITUITARY HORMONES , THYROID HORMONES , IN VITRO ANALYSIS, CANADA

  19. Inhibition of the plasma membrane Ca2+ pump by CD44 receptor activation of tyrosine kinases increases the action potential afterhyperpolarization in sensory neurons.

    PubMed

    Ghosh, Biswarup; Li, Yan; Thayer, Stanley A

    2011-02-16

    The cytoplasmic Ca(2+) clearance rate affects neuronal excitability, plasticity, and synaptic transmission. Here, we examined the modulation of the plasma membrane Ca(2+) ATPase (PMCA) by tyrosine kinases. In rat sensory neurons grown in culture, the PMCA was under tonic inhibition by a member of the Src family of tyrosine kinases (SFKs). Ca(2+) clearance accelerated in the presence of selective tyrosine kinase inhibitors. Tonic inhibition of the PMCA was attenuated in cells expressing a dominant-negative construct or shRNA directed to message for the SFKs Lck or Fyn, but not Src. SFKs did not appear to phosphorylate the PMCA directly but instead activated focal adhesion kinase (FAK). Expression of constitutively active FAK enhanced and dominant-negative or shRNA knockdown of FAK attenuated tonic inhibition. Antisense knockdown of PMCA isoform 4 removed tonic inhibition of Ca(2+) clearance, indicating that FAK acts on PMCA4. The hyaluronan receptor CD44 activates SFK-FAK signaling cascades and is expressed in sensory neurons. Treating neurons with a CD44-blocking antibody or short hyaluronan oligosaccharides, which are produced during injury and displace macromolecular hyaluronan from CD44, attenuated tonic PMCA inhibition. Ca(2+)-activated K(+) channels mediate a slow afterhyperpolarization in sensory neurons that was inhibited by tyrosine kinase inhibitors and enhanced by knockdown of PMCA4. Thus, we describe a novel kinase cascade in sensory neurons that enables the extracellular matrix to alter Ca(2+) signals by modulating PMCA-mediated Ca(2+) clearance. This signaling pathway may influence the excitability of sensory neurons following injury.

  20. Streamlined Approach for Environmental Restoration (SAFER) Plan for Corrective Action Unit 357: Mud Pits and Waste Dump, Nevada Test Site, Nevada: Revision 0, Including Record of Technical Change No. 1

    SciTech Connect

    2003-06-25

    This Streamlined Approach for Environmental Restoration (SAFER) plan was prepared as a characterization and closure report for Corrective Action Unit (CAU) 357, Mud Pits and Waste Dump, in accordance with the Federal Facility Agreement and Consent Order. The CAU consists of 14 Corrective Action Sites (CASs) located in Areas 1, 4, 7, 8, 10, and 25 of the Nevada Test Site (NTS). All of the CASs are found within Yucca Flat except CAS 25-15-01 (Waste Dump). Corrective Action Site 25-15-01 is found in Area 25 in Jackass Flat. Of the 14 CASs in CAU 357, 11 are mud pits, suspected mud pits, or mud processing-related sites, which are by-products of drilling activities in support of the underground nuclear weapons testing done on the NTS. Of the remaining CASs, one CAS is a waste dump, one CAS contains scattered lead bricks, and one CAS has a building associated with Project 31.2. All 14 of the CASs are inactive and abandoned. Clean closure with no further action of CAU 357 will be completed if no contaminants are detected above preliminary action levels. A closure report will be prepared and submitted to the Nevada Division of Environmental Protection for review and approval upon completion of the field activities. Record of Technical Change No. 1 is dated 3/2004.

  1. [Modes of action of IUDs].

    PubMed

    Janaud, A

    1982-05-01

    There are between 14-17 million women in the world, excluding China, who wear an IUD, or about 3-5% of all married women younger than 45. Studies on the mode of action of IUDs have been conducted mostly on laboratory animals; they show that ovulation and fecundation are not inhibited by the presence of an IUD. Contrary to what was generally believed, the latest studies have shown that the principle mode of action of the IUD is not its anti-implantation effect, but it depends on the adjustment inside the uterine cavity between the size of the uterine cavity itself, and the size and shape of the device. Endometrial modifications caused by IUDs include inflammatory phenomena, and inhibition of endometrial maturation. Moreover, copper IUDs act directly on spermatozoa and on endometrial steroid receptors. It is still not clear what role prostaglandins play in the mechanism of action of IUDs. Incidence of ectopic pregnancy is not greater in IUD wearers than in women who do not use contraception. Follicle stimulating hormone and luteinizing hormone levels also are comparable in IUD wearers and in nonwearers. IUD wearers have a shorter luteal phase, which entails an earlier menstrual bleeding due to the antifibrinolytic action of the IUD; progesterone levels are identical in users and in nonusers of IUDs.

  2. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA.

    PubMed

    Yik, Jasper H N; Chen, Ruichuan; Nishimura, Rieko; Jennings, Jennifer L; Link, Andrew J; Zhou, Qiang

    2003-10-01

    The positive transcriptional elongation factor b (P-TEFb), consisting of CDK9 and cyclin T, stimulates transcription by phosphorylating RNA polymerase II. It becomes inactivated when associated with the abundant 7SK snRNA. Here, we show that the 7SK binding alone was not sufficient to inhibit P-TEFb. P-TEFb was inhibited by the HEXIM1 protein in a process that specifically required 7SK for mediating the HEXIM1:P-TEFb interaction. This allowed HEXIM1 to inhibit transcription both in vivo and in vitro. P-TEFb dissociated from HEXIM1 and 7SK in cells undergoing stress response, increasing the level of active P-TEFb for stress-induced transcription. P-TEFb was the predominant HEXIM1-associated protein factor, and thus likely to be the principal target of inhibition coordinated by HEXIM1 and 7SK. Since HEXIM1 expression is induced in cells treated with hexamethylene bisacetamide, a potent inducer of cell differentiation, targeting the general transcription factor P-TEFb by HEXIM1/7SK may contribute to the global control of cell growth and differentiation.

  3. Cellular Localization of Protoporphyrinogen-Oxidizing Activities of Etiolated Barley (Hordeum vulgare L.) Leaves (Relationship to Mechanism of Action of Protoporphyrinogen Oxidase-Inhibiting Herbicides).

    PubMed Central

    Lee, H. J.; Duke, M. V.; Duke, S. O.

    1993-01-01

    Seven-day-old, etiolated barley (Hordeum vulgare L. var Post) leaves were fractionated into crude and purified etioplast, microsomal, and plasma membrane (PM) fractions. Protoporphyrinogen oxidase (Protox) specific activities of crude etioplast, purified etioplast, microsome, and PM fractions were approximately 29, 26, 23, and 12 nmol h-1 mg-1 of protein, respectively. The herbicide acifluorfen-methyl (AFM), at 1 [mu]M, inhibited Protox activity from crude etioplasts, purified etioplasts, microsomes, and PM by 58, 59, 23, and 0% in the absence of reductants. Reductants (ascorbate, glutathione [GSH], dithiothreitol [DTT], and NADPH) individually reduced the Protox activity of all fractions, except that microsomal Protox activity was slightly stimulated by NADPH. Ascorbate, GSH, or a combination of the two reductants enhanced Protox inhibition by AFM, and AFM inhibition of Protox was greatest in all fractions with DTT. NADPH enhanced AFM inhibition significantly only in etioplast fractions. Uroporphyrinogen I (Urogen I) and coproporphyrinogen I (Coprogen I) oxidase activities were found in all fractions; however, etioplast fractions had significantly more substrate specificity for protoporphyrinogen IX (Protogen IX) than the other fractions. Urogen I and Coprogen I oxidase activities were unaffected by AFM in all fractions, and 2 mM DTT almost completely inhibited these activities from all fractions. Diethyldithiocarbamate inhibited PM Protox activity by 62% but had less effect on microsome and little or no effect on etioplast Protox. Juglone and duroquinone stimulated microsomal and PM Protox activity, whereas the lesser effect of these quinones on etioplast Protox activity was judged to be due to PM and/or microsomal contaminants. These data indicate that there are microsomal and PM Protogen IX-oxidizing activities that are not the same as those associated with the etioplast and that these activities are not inhibited in vivo by AFM. In summary, these data support

  4. Eplerenone inhibits the intracrine and extracellular actions of angiotensin II on the inward calcium current in the failing heart. On the presence of an intracrine renin angiotensin aldosterone system

    PubMed Central

    De Mello, Walmor C.; Gerena, Yamil

    2009-01-01

    The influence of chronic administration of eplerenone on the intracrine as well as on the extracellular action of angiotensin II (Ang II) on L-type inward calcium current was investigated in the failing heart of cardiomyopathic hamsters (TO-2).For this, eplerenone (200 mg/kg/day) was administered orally to 2 month-old cardiomyopathic hamsters for a period of 3 months. Measurements of the peak inward calcium current (ICa) was performed in single cells under voltage clamp using the whole cell configuration. The results indicated that eplerenone suppressed the intracrine action of Ang II (10−8 M) on peak ICa density. Moreover, the intracellular dialysis of the peptide did not change the time course of ICa inactivation in animals treated chronically with eplerenone. The extracellular administration of Ang II (10−8 M) incremented the peak ICa density by only 20±8% (n=30) compared with 38±4% (n=35) (P<0.05) obtained in age-matched cardiomyopathic hamsters not exposed to eplerenone. Interestingly, the inhibitory of eplerenone (10− 7 M) on the intracrine action of Ang II was also found, in vitro, but required an incubation period of, at least, 24 h. The inhibitory action of eplerenone on the intracellular action of Ang II was partially reversed by exposing the eplerenone-treated cells to aldosterone (10 nM) for a period of 24 h what supports the view that: a) the mineralocorticoid receptor(MR) was involved in the modulation of the intracrine action of the peptide; b) the effect of eplerenone on the intracrine as well as on the extracellular action of Ang II was related ,in part, to a decreased expression of membrane-bound and intracellular AT1 receptors. In conclusion: a) eplerenone inhibits the intracrine action of Ang II on inward calcium current and reduces drastically the effect of extracellular Ang II on ICa; b) aldosterone is able to revert the effect of eplerenone; c) the mineralocorticoid receptor is an essential component of the intracrine renin

  5. Prediction of enzyme inhibition and mode of inhibitory action based on calculation of distances between hydrogen bond donor/acceptor groups of the molecule and docking analysis: An application on the discovery of novel effective PTP1B inhibitors.

    PubMed

    Eleftheriou, P; Petrou, A; Geronikaki, A; Liaras, K; Dirnali, S; Anna, M

    2015-01-01

    PTP1B is a protein tyrosine phosphatase involved in insulin receptor desensitization. PTP1B inhibition prolongs the activated state of the receptor, practically enhancing the effect of insulin. Thus PTP1B has become a drug target for the treatment of type II diabetes. PTP1b is an enzyme with multiple binding sites for competitive and allosteric inhibitors. Prediction of inhibitory action using docking analysis has limited success in case of enzymes with multiple binding sites, since the selection of the right crystal structure depends on the kind of inhibitor. In the present study, a two-step strategy for the prediction of PTP1b inhibitory action was applied to 12 compounds. Based on the study of known inhibitors, we isolated the structural characteristics required for binding to each binding site. As a first step, 3D-structures of the molecules were produced and their structural parameters were measured and used for prediction of the binding site of the compound. These results were used for the selection of the appropriate crystal structure for docking analysis of each compound, and the final prediction was based on the estimated binding energies. This strategy effectively predicted the activity of all compounds. A linear correlation was found between estimated binding energy and inhibition measured in vitro (r = -0.894).

  6. Inhibition of MAP kinase promotes the recruitment of corepressor SMRT by tamoxifen-bound estrogen receptor alpha and potentiates tamoxifen action in MCF-7 cells

    SciTech Connect

    Hong, Wei; Chen, Linfeng; Li, Juan; Yao, Zhi

    2010-05-28

    Estrogen receptor alpha (ER{alpha}), a ligand controlled transcription factor, plays an important role in breast cancer growth and endocrine therapy. Tamoxifen (TAM) antagonizes ER{alpha} activity and has been applied in breast cancer treatment. TAM-bound ER{alpha} associates with nuclear receptor-corepressors. Mitogen-activated protein kinase (MAPK) has been elucidated to result in cross-talk between growth factor and ER{alpha} mediated signaling. We show that activated MAPK represses interaction of TAM-bound ER{alpha} with silencing mediator for retinoid and thyroid hormone receptors (SMRT) and inhibits the recruitment of SMRT by ER{alpha} to certain estrogen target genes. Blockade of MAPK signaling cascade with MEK inhibitor U0126 promotes the interaction and subsequently inhibits ER{alpha} activity via enhanced recruitment of SMRT, leading to reduced expression of ER{alpha} target genes. The growth rate of MCF-7 cells was decelerated when treated with both TAM and U0126. Moreover, the growth of MCF-7 cells stably expressing SMRT showed a robust repression in the presence of TAM and U0126. These results suggest that activated MAPK signaling cascade attenuates antagonist-induced recruitment of SMRT to ER{alpha}, suggesting corepressor mediates inhibition of ER{alpha} transactivation and breast cancer cell growth by antagonist. Taken together, our finding indicates combination of antagonist and MAPK inhibitor could be a helpful approach for breast cancer therapy.

  7. Bisphenol A and Related Alkylphenols Exert Nongenomic Estrogenic Actions Through a G Protein-Coupled Estrogen Receptor 1 (Gper)/Epidermal Growth Factor Receptor (Egfr) Pathway to Inhibit Meiotic Maturation of Zebrafish Oocytes1

    PubMed Central

    Fitzgerald, Amanda C.; Peyton, Candace; Dong, Jing; Thomas, Peter

    2015-01-01

    Xenobiotic estrogens, such as bisphenol A (BPA), disrupt a wide variety of genomic estrogen actions, but their nongenomic estrogen actions remain poorly understood. We investigated nongenomic estrogenic effects of low concentrations of BPA and three related alkylphenols on the inhibition of zebrafish oocye maturation (OM) mediated through a G protein-coupled estrogen receptor 1 (Gper)-dependent epidermal growth factor receptor (Egfr) pathway. BPA (10–100 nM) treatment for 3 h mimicked the effects of estradiol-17beta (E2) and EGF, decreasing spontaneous maturation of defolliculated zebrafish oocytes, an effect not blocked by coincubation with actinomycin D, but blocked by coincubation with a Gper antibody. BPA displayed relatively high binding affinity (15.8% that of E2) for recombinant zebrafish Gper. The inhibitory effects of BPA were attenuated by inhibition of upstream regulators of Egfr, intracellular tyrosine kinase (Src) with PP2, and matrix metalloproteinase with ilomastat. Treatment with an inhibitor of Egfr transactivation, AG1478, and an inhibitor of the mitogen-activated protein kinase (MAPK) 3/1 pathway, U0126, increased spontaneous OM and blocked the inhibitory effects of BPA, E2, and the selective GPER agonist, G-1. Western blot analysis showed that BPA (10–200 nM) mimicked the stimulatory effects of E2 and EGF on Mapk3/1 phosphorylation. Tetrabromobisphenol A, 4-nonylphenol, and tetrachlorobisphenol A (5–100 nM) also inhibited OM, an effect blocked by cotreatment with AG1478, as well as with the GPER antagonist, G-15, and displayed similar binding affinities as BPA to zebrafish Gper. The results suggest that BPA and related alkylphenols disrupt zebrafish OM by a novel nongenomic estrogenic mechanism involving activation of the Gper/Egfr/Mapk3/1 pathway. PMID:26490843

  8. Inhibition of murine renal carcinoma pulmonary metastases by systemic administration of interferon gamma: mechanism of action and potential for combination with interleukin 4.

    PubMed

    Hillman, G G; Younes, E; Visscher, D; Hamzavi, F; Kim, S; Lam, J S; Montecillo, E J; Ali, E; Pontes, J E; Puri, R K; Haas, G P

    1997-10-01

    We have previously demonstrated that IFN-gamma causes cell growth inhibition and up-regulation of MHC antigens in human renal cell carcinoma cell lines. In this study, we have investigated the therapeutic potential of IFN-gamma for the treatment of 5-day established pulmonary metastases induced by i.v. injection of Renca cells, a murine renal adenocarcinoma. We found that systemic injections of IFN-gamma significantly reduced the number of lung metastases in a dose-dependent manner and increased mouse survival. Histological evaluation of IFN-gamma-treated lungs showed residual small tumor nodules containing extensive necrosis and mononuclear infiltrates. Immunohistochemistry studies on lung sections showed macrophage infiltration into tumor nodules, and in vivo depletion of macrophages partially inhibited IFN-gamma antitumor effect, suggesting a role for the macrophages in tumor destruction. Lymphocyte depletion of either natural killer (NK) cells or CD4+ or CD8+ T-cell subsets or both T-cell subsets did not affect the IFN-gamma effect, whereas depletion of both NK and T cells decreased the antitumor activity of IFN-gamma. These data indicate that neither T cells nor NK cells are essential for this activity but that either lymphocyte population can contribute to the IFN-gamma effect. An optimal dose of IFN-gamma inhibited by 60% the growth of Renca cells treated for 3 days in vitro, but this effect was transient and less pronounced in a long-term colony assay, suggesting that IFN-gamma direct growth inhibition may play a role but may not be sufficient to mediate its antitumor effect in vivo. In vitro, IFN-gamma caused up-regulation of class I MHC antigens and induction of class II antigen expression in Renca cells, an effect that may enhance Renca immunogenicity but may be relevant only when a T-cell response is elicited. A sequential administration of IFN-gamma followed by interleukin 4 was therapeutically better than IFN-gamma alone for the treatment of advanced

  9. OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

    PubMed Central

    Ma, Shan-yao; Ning, Meng-meng; Zou, Qing-an; Feng, Ying; Ye, Yang-liang; Shen, Jian-hua; Leng, Ying

    2016-01-01

    Aim: TGR5 agonists stimulate intestinal glucagon-like peptide-1 (GLP-1) release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dual function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. Methods: TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in ICR and diabetic ob/ob mice. Results: OL3 activated human and mouse TGR5 with an EC50 of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells (3–30 μmol/L). OL3 inhibited human and mouse DPP-4 with IC50 values of 18.44 and 69.98 μmol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 (150 mg/kg), the serum OL3 concentration was 101.10 ng/mL at 1 h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. Conclusion: OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the

  10. Antibacterial Compounds of Canadian Honeys Target Bacterial Cell Wall Inducing Phenotype Changes, Growth Inhibition and Cell Lysis That Resemble Action of β-Lactam Antibiotics

    PubMed Central

    Brudzynski, Katrina; Sjaarda, Calvin

    2014-01-01

    Honeys show a desirable broad spectrum activity against Gram-positive and negative bacteria making antibacterial activity an intrinsic property of honey and a desirable source for new drug development. The cellular targets and underlying mechanism of action of honey antibacterial compounds remain largely unknown. To facilitate the target discovery, we employed a method of phenotypic profiling by directly comparing morphological changes in Escherichia coli induced by honeys to that of ampicillin, the cell wall-active β-lactam of known mechanism of action. Firstly, we demonstrated the purity of tested honeys from potential β-lactam contaminations using quantitative LC-ESI-MS. Exposure of log-phase E. coli to honey or ampicillin resulted in time- and concentration-dependent changes in bacterial cell shape with the appearance of filamentous phenotypes at sub-inhibitory concentrations and spheroplasts at the MBC. Cell wall destruction by both agents, clearly visible on microscopic micrographs, was accompanied by increased permeability of the lipopolysaccharide outer membrane as indicated by fluorescence-activated cell sorting (FACS). More than 90% E. coli exposed to honey or ampicillin became permeable to propidium iodide. Consistently with the FACS results, both honey-treated and ampicillin-treated E. coli cells released lipopolysaccharide endotoxins at comparable levels, which were significantly higher than controls (p<0.0001). E. coli cells transformed with the ampicillin-resistance gene (β–lactamase) remained sensitive to honey, displayed the same level of cytotoxicity, cell shape changes and endotoxin release as ampicillin-sensitive cells. As expected, β–lactamase protected the host cell from antibacterial action of ampicillin. Thus, both honey and ampicillin induced similar structural changes to the cell wall and LPS and that this ability underlies antibacterial activities of both agents. Since the cell wall is critical for cell growth and survival, honey

  11. Effects of histamine on monocyte complement production. I. Inhibition of C2 production mediated by its action on H2 receptors.

    PubMed

    Lappin, D; Whaley, K

    1980-09-01

    Histamine produced dose-dependent inhibition of the production of the second complement component (C2) by monocytes in tissue culture. The effect was not associated with either cell death, as ascertained by trypan blue exclusion, or loss of cells from the monolayer, as determined by measuring their DNA content. The specificity of the response was shown by the failure of histidine or histamine metabolites to inhibit C2 production. Preincubation of histamine with histaminase also abrogated the histamine effect. The kinetics of the effect were extremely rapid and irreversible, most of the reduction being achieved during a 5-min exposure to histamine. The H2 receptor antagonist cimetidine was able to prevent the histamine response, whereas chlorpheniramine, the H1 receptor antagonist, had no effect. Dimaprit and 4-methyl histamine, H2 receptor agonists, simulated the effect of histamine whereas the H1 receptor agonist 2-(2-aminoethylthiazole) was ineffective, confirming that the effect of histamine on C2 production by monocytes is mediated by the H2 receptors. Thus histamine, released from basophils or mast cells by the C3 and C5 cleavage products C3a and C5a respectively, may exert a negative feedback on further C3 and C5 cleavage by limiting the formation of the C3 (C42) and C5 (C423b) convertases.

  12. Octopamine--a single modulator with double action on the heart of two insect species (Apis mellifera macedonica and Bactrocera oleae): Acceleration vs. inhibition.

    PubMed

    Papaefthimiou, Chrisovalantis; Theophilidis, George

    2011-02-01

    The effects of octopamine, the main cardioacceleratory transmitter in insects, were investigated, in the isolated hearts of the honeybee, Apis mellifera macedonica, and the olive fruit fly, Bactrocera oleae. Octopamine induced a biphasic effect on the frequency and force of cardiac contractions acting as an agonist, with a strong acceleratory effect, at concentrations higher than 10(-12)M for the honeybee and higher than 50×10(-9)M for the olive fruit fly. The heart of the honeybee is far more sensitive than the heart of olive fruit fly. This unusual sensitivity is extended to the blockers of octopaminergic receptors, where phentolamine at 10(-5)M stopped the spontaneous contractions of the honeybee heart completely and permanently, while the same blocker at the same concentration caused only 50% inhibition in the heart of the olive fruit fly. Phentolamine and mianserin at low concentrations of 10(-7)M also blocked the heart octopaminergic receptors, but for a short period of time, of less than 15.0 min, while a partial recovery in heart contraction started in spite of the presence of the antagonist. The unusual response of the honeybee heart in the presence of phentolamine and/or mianserin suggests excitatory effects of octopamine via two different receptor subtypes. At lower concentrations, 10(-14)M, the agonist octopamine was converted to an antagonist, inducing a hyperpolarization in the membrane potential of the honeybee cardiac pacemaker cells and inhibiting the firing rate of the heart. The inhibitory effects of octopamine on certain parameters of the rhythmic bursts of the heart of the honeybee, were similar to those of mianserin and phentolamine, typical blockers of octopaminergic receptors. The heart of the olive fruit fly was 10(5) times less sensitive to octopamine, since a persistent inhibition of heart contractions occurred at 10(-9)M. In conclusion, the acceleration of the insect heart is achieved by increasing the levels of octopamine, while there

  13. Cyanamide mode of action during inhibition of onion (Allium cepa L.) root growth involves disturbances in cell division and cytoskeleton formation.

    PubMed

    Soltys, Dorota; Rudzińska-Langwald, Anna; Kurek, Wojciech; Gniazdowska, Agnieszka; Sliwinska, Elwira; Bogatek, Renata

    2011-09-01

    Cyanamide is an allelochemical produced by hairy vetch (Vicia villosa Roth.). Its phyotoxic effect on plant growth was examined on roots of onion (Allium cepa L.) bulbs. Water solution of cyanamide (2-10 mM) restricted growth of onion roots in a dose-dependent manner. Treatment of onion roots with cyanamide resulted in a decrease in root growth rate accompanied by a decrease in accumulation of fresh and dry weight. The inhibitory effect of cyanamide was reversed by its removal from the environment, but full recovery was observed only for tissue treated with this chemical at low concentration (2-6 mM). Cytological observations of root tip cells suggest that disturbances in cell division may explain the strong cyanamide allelopathic activity. Moreover, in cyanamide-treated onion the following changes were detected: reduction of mitotic cells, inhibition of proliferation of meristematic cells and cell cycle, and modifications of cytoskeleton arrangement.

  14. Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators.

    PubMed

    Pustylnikov, Sergey; Dave, Rajnish S; Khan, Zafar K; Porkolab, Vanessa; Rashad, Adel A; Hutchinson, Matthew; Fieschi, Frank; Chaiken, Irwin; Jain, Pooja

    2016-01-01

    The DC-SIGN receptor on human dendritic cells interacts with HIV gp120 to promote both infection of antigen-presenting cells and transinfection of T cells. We hypothesized that in DC-SIGN-expressing cells, both DC-SIGN ligands such as dextrans and gp120 antagonists such as peptide triazoles would inhibit HIV infection with potential complementary antagonist effects. To test this hypothesis, we evaluated the effects of dextran (D66), isomaltooligosaccharides (D06), and several peptide triazoles (HNG156, K13, and UM15) on HIV infection of B-THP-1/DC-SIGN cells. In surface plasmon resonance competition assays, D66 (IC50 = 35.4 μM) and D06 (IC50 = 3.4 mM) prevented binding of soluble DC-SIGN to immobilized mannosylated bovine serum albumin (BSA). An efficacious dose-dependent inhibition of DC-SIGN-mediated HIV infection in both pretreatment and posttreatment settings was observed, as indicated by inhibitory potentials (EC50) [D66 (8 μM), D06 (48 mM), HNG156 (40 μM), UM15 (100 nM), and K13 (25 nM)]. Importantly, both dextrans and peptide triazoles significantly decreased HIV gag RNA levels [D66 (7-fold), D06 (13-fold), HNG156 (7-fold), K-13 (3-fold), and UM15 (6-fold)]. Interestingly, D06 at the highest effective concentration showed a 14-fold decrease of infection, while its combination with 50 μM HNG156 showed a 26-fold decrease. Hence, these compounds can combine to inactivate the viruses and suppress DC-SIGN-mediated virus-cell interaction that as shown earlier leads to dendritic cell HIV infection and transinfection dependent on the DC-SIGN receptor.

  15. An Unprecedented alteration in mode of action of IsCT resulting its translocation into bacterial cytoplasm and inhibition of macromolecular syntheses

    PubMed Central

    Tripathi, Jitendra K.; Kathuria, Manoj; Kumar, Amit; Mitra, Kalyan; Ghosh, Jimut K.

    2015-01-01

    IsCT, a 13-residue, non-cell-selective antimicrobial peptide is comprised of mostly hydrophobic residues and lesser cationic residues. Assuming that placement of an additional positive charge in the non-polar face of IsCT could reduce its hydrophobic interaction, resulting in its reduction of cytotoxicity, an analog, I9K-IsCT was designed. Two more analogs, namely, E7K-IsCT and E7K,I9K-IsCT, were designed to investigate the impact of positive charges in the polar face as well as polar and non-polar faces at a time. These amino acid substitutions resulted in a significant enhancement of therapeutic potential of IsCT. IsCT and E7K-IsCT seem to target bacterial membrane for their anti-bacterial activity. However, I9K-IsCT and E7K,I9K-IsCT inhibited nucleic acid and protein syntheses in tested E. coli without perturbing its membrane. This was further supported by the observation that NBD-IsCT localized onto bacterial membrane while NBD-labeled I9K-IsCT and E7K,I9K-IsCT translocated into bacterial cytoplasm. Interestingly, IsCT and E7K-IsCT were significantly helical while I9K-IsCT and E7K,I9K-IsCT were mostly unstructured with no helix content in presence of mammalian and bacterial membrane-mimetic lipid vesicles. Altogether, the results identify two novel cell-selective analogs of IsCT with new prototype amino acid sequences that can translocate into bacterial cytoplasm without any helical structure and inhibit macromolecular syntheses. PMID:25773522

  16. Inhibition of DNA and Histone Methylation by 5-Aza-2′-Deoxycytidine (Decitabine) and 3-Deazaneplanocin-A on Antineoplastic Action and Gene Expression in Myeloid Leukemic Cells

    PubMed Central

    Momparler, Richard L.; Côté, Sylvie; Momparler, Louise F.; Idaghdour, Youssef

    2017-01-01

    Epigenetic alterations play an important role in the development of acute myeloid leukemia (AML) by silencing of genes that suppress leukemogenesis and differentiation. One of the key epigenetic changes in AML is gene silencing by DNA methylation. The importance of this alteration is illustrated by the induction of remissions in AML by 5-aza-2′-deoxycytidine (5-AZA-CdR, decitabine), a potent inhibitor of DNA methylation. However, most patients induced into remission by 5-AZA-CdR will relapse, suggesting that a second agent should be sought to increase the efficacy of this epigenetic therapy. An interesting candidate for this purpose is 3-deazaneplanocin A (DZNep). This analog inhibits EZH2, a histone methyltransferase that trimethylates lysine 27 histone H3 (H3K27me3), a marker for gene silencing. This second epigenetic silencing mechanism also plays an important role in leukemogenesis as shown in preclinical studies where DZNep exhibits potent inhibition of colony formation by AML cells. We reported previously that 5-AZA-CdR in combination with DZNep exhibits a synergistic antineoplastic action against human HL-60 AML cells and the synergistic activation of several tumor suppressor genes. In this report, we showed that this combination also induced a synergistic activation of apoptosis in HL-60 cells. The synergistic antineoplastic action of 5-AZA-CdR plus DZNep was also observed on a second human myeloid leukemia cell line, AML-3. In addition, 5-AZA-CdR in combination with the specific inhibitors of EZH2, GSK-126, or GSK-343, also exhibited a synergistic antineoplastic action on both HL-60 and AML-3. The combined action of 5-AZA-CdR and DZNep on global gene expression in HL-60 cells was investigated in greater depth using RNA sequencing analysis. We observed that this combination of epigenetic agents exhibited a synergistic activation of hundreds of genes. The synergistic activation of so many genes that suppress malignancy by 5-AZA-CdR plus DZNep suggests that

  17. Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases—Not Glycolipid Processing Enzymes

    PubMed Central

    Sayce, Andrew C.; Alonzi, Dominic S.; Killingbeck, Sarah S.; Tyrrell, Beatrice E.; Hill, Michelle L.; Caputo, Alessandro T.; Iwaki, Ren; Kinami, Kyoko; Ide, Daisuke; Kiappes, J. L.; Beatty, P. Robert; Kato, Atsushi; Harris, Eva; Dwek, Raymond A.; Miller, Joanna L.; Zitzmann, Nicole

    2016-01-01

    It has long been thought that iminosugar antiviral activity is a function of inhibition of endoplasmic reticulum-resident α-glucosidases, and on this basis, many iminosugars have been investigated as therapeutic agents for treatment of infection by a diverse spectrum of viruses, including dengue virus (DENV). However, iminosugars are glycomimetics possessing a nitrogen atom in place of the endocyclic oxygen atom, and the ubiquity of glycans in host metabolism suggests that multiple pathways can be targeted via iminosugar treatment. Successful treatment of patients with glycolipid processing defects using iminosugars highlights the clinical exploitation of iminosugar inhibition of enzymes other than ER α-glucosidases. Evidence correlating antiviral activity with successful inhibition of ER glucosidases together with the exclusion of alternative mechanisms of action of iminosugars in the context of DENV infection is limited. Celgosivir, a bicyclic iminosugar evaluated in phase Ib clinical trials as a therapeutic for the treatment of DENV infection, was confirmed to be antiviral in a lethal mouse model of antibody-enhanced DENV infection. In this study we provide the first evidence of the antiviral activity of celgosivir in primary human macrophages in vitro, in which it inhibits DENV secretion with an EC50 of 5 μM. We further demonstrate that monocyclic glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. By comparison to bicyclic glucose-mimicking iminosugars which inhibit glycoprotein processing but do not inhibit glycolipid processing and galactose-mimicking iminosugars which do not inhibit glycoprotein processing but do inhibit glycolipid processing, we demonstrate that inhibition of endoplasmic reticulum-resident α-glucosidases, not glycolipid processing, is responsible for iminosugar antiviral activity against DENV. Our data suggest that

  18. Action in Development

    ERIC Educational Resources Information Center

    von Hofsten, Claes

    2007-01-01

    It is argued that cognitive development has to be understood in the functional perspective provided by actions. Actions reflect all aspects of cognitive development including the motives of the child, the problems to be solved, and the constraints and possibilities of the child's body and sensorimotor system. Actions are directed into the future…

  19. Action Learning at Work.

    ERIC Educational Resources Information Center

    Mumford, Alan, Ed.

    This book contains 34 papers examining the theory, process, and outcomes of action learning at work. The following papers are included: "An Introduction to the Text" (Alan Mumford); "The Learning Equation" (Reg Revans); "Action Learning as a Vehicle for Learning" (Alan Mumford); "Placing Action Learning and…

  20. [Antimicrobial mechanisms of action].

    PubMed

    Calvo, Jorge; Martínez-Martínez, Luis

    2009-01-01

    A large number of families and groups of antimicrobial agents are of clinical interest. The mechanisms by which compounds with antibacterial activity inhibit growth or cause bacterial death are varied and depend on the affected targets. The bacterial cell wall-a unique structure in most bacteria that is absent in eukaryotic cells-can be affected in several ways: at different stages of synthesis (fosfomycin, cycloserine) or transport (bacitracin, mureidomycins) of its metabolic precursors, or by a direct action on its structural organization (beta-lactams, glycopeptides). The main drugs affecting the cytoplasmic membrane are polymyxins and daptomycin. Protein synthesis can be blocked by a large variety of compounds that affect any of the phases of this process, including activation (mupirocin), initiation (oxazolidinones, aminoglycosides), binding of the tRNA amino acid complex to ribosomes (tetracyclines, glycylcyclines) and elongation (amphenicols, lincosamides, macrolides, ketolides, streptogramins, fusidic acid). The metabolism of nucleic acids can be altered at the DNA-dependent RNA polymerase or in the process of DNA coiling (quinolones); some compounds affect DNA directly (nitroimidazoles, nitrofurans). Trimethoprim and sulfamides (often used in combination) are examples of antimicrobial agents that block bacterial metabolic pathways. Some compounds are unable to inhibit or kill bacteria in themselves, but can block bacterial mechanisms of resistance, enhancing the activity of other antimicrobials administered in combination. Among this group of agents, only certain beta-lactamase inhibitors are currently in clinical use.

  1. Plan for early action: Recommendations

    SciTech Connect

    1998-12-31

    This report contains recommendations on the implementation of an action plan to reduce or recapture greenhouse gas (GHG) emissions in British Columbia. The report includes the consensus recommendations of the BC Greenhouse Gas Forum, as well as those items on which Forum participants have agreed to disagree, plus the reasons for those differences. The recommendations include: Umbrella actions which may affect several or all sectors of the economy, or support the success of other actions; actions to reduce vehicle kilometers travelled; actions to increase vehicle efficiency or increase the use of alternative fuels or technologies; actions to decrease GHG emissions from energy production; actions to increase end-use energy efficiency; and actions to reduce non-energy-related emissions. Appendices include work sheets on each action, with a description of the action and information on the action`s rationale, experience elsewhere, related policy initiatives, and key issues regarding feasibility and implementation.

  2. Concerted actions of ameliorated colitis, aberrant crypt foci inhibition and 15-hydroxyprostaglandin dehydrogenase induction by sonic hedgehog inhibitor led to prevention of colitis-associated cancer.

    PubMed

    Kangwan, Napapan; Kim, Yoon-Jae; Han, Young-Min; Jeong, Migyeong; Park, Jong-Min; Hahm, Ki-Baik

    2016-03-15

    The sonic hedgehog (Shh) signaling has been known to contribute to carcinogenesis in organ, where hedgehog exerted organogenesis and in cancers, which are developed based on mutagenic inflammation. Therefore, colitis-associated cancer (CAC) can be a good model to prove whether Shh inhibitors can be applied to prevent, as the efforts to discover potent anti-inflammatory agent are active to prevent CAC. Here, under the hypothesis that Shh inhibitors can prevent CAC, mouse model was generated to develop CAC by azoxymethane (AOM)-initiated, dextran sodium sulfate-promoted carcinogenesis. Shh inhibitors, cerulenin and itraconazole were treated by oral gavage and the mice were sacrificed at early phase of 3 weeks and late phase of 16 weeks. Compared to control group, the number of aberrant crypt foci at 3 weeks and tumor incidence at 16 weeks were all significantly decreased with Shh inhibitor. Significant attenuations of macrophage infiltration accompanied with significant decreases of IL-6, COX-2, STAT3 and NF-κB as well as significant ameliorations of β-catenin nuclear translocation, cyclin D1 and CDK4 were imposed with Shh inhibitors. Especially, CAC was accompanied with significant cancellation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), but their levels were significantly preserved with Shh inhibitors. Among inflammatory mediators, significantly decreased levels of IL-6 and TNF-α, regulated with repressed NF-κb and STAT3, were prominent with Shh inhibitor, whereas significant inductions of apoptosis were noted with Shh inhibitors. In conclusion, Shh inhibitors significantly prevented CAC covering either ameliorating oncogenic inflammation or suppressing tumor proliferation, especially supported with significant inhibition of IL-6 and STAT3 signaling, 15-PGDH preservation and apoptosis induction.

  3. PDE5 inhibitors enhance the lethality of pemetrexed through inhibition of multiple chaperone proteins and via the actions of cyclic GMP and nitric oxide

    PubMed Central

    Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew; Gordon, Sarah; Dent, Paul

    2017-01-01

    Phosphodiesterase 5 (PDE5) inhibitors prevent the breakdown of cGMP that results in prolonged protein kinase G activation and the generation of nitric oxide. PDE5 inhibitors enhanced the anti-NSCLC cell effects of the NSCLC therapeutic pemetrexed. [Pemetrexed + sildenafil] activated an eIF2α – ATF4 – CHOP – Beclin1 pathway causing formation of toxic autophagosomes; activated a protective IRE1 – XBP-1 – chaperone induction pathway; and activated a toxic eIF2α – CHOP – DR4 / DR5 / CD95 induction pathway. [Pemetrexed + sildenafil] reduced the expression of c-FLIP-s, MCL-1 and BCL-XL that was blocked in a cell-type -dependent fashion by either over-expression of HSP90 / GRP78 / HSP70 / HSP27 or by blockade of eIF2α-CHOP signaling. Knock down of PKGI/II abolished the ability of sildenafil to enhance pemetrexed toxicity whereas pan-inhibition of NOS using L-NAME or knock down of [iNOS + eNOS] only partially reduced the lethal drug interaction. Pemetrexed reduced the ATPase activities of HSP90 and HSP70 in an ATM-AMPK-dependent fashion that was enhanced by sildenafil signaling via PKGI/II. The drug combination activated an ATM-AMPK-TSC2 pathway that was associated with reduced mTOR S2448 and ULK-1 S757 phosphorylation and increased ULK-1 S317 and ATG13 S318 phosphorylation. These effects were prevented by chaperone over-expression or by expression of an activated form of mTOR that prevented autophagosome formation and reduced cell killing. In two models of NSCLC, sildenafil enhanced the ability of pemetrexed to suppress tumor growth. Collectively we argue that the combination of [pemetrexed + PDE5 inhibitor] should be explored in a new NSCLC phase I trial. PMID:27903966

  4. A survey of surface hemorheological experiments on the inhibition of fibrinogenin formation employing surface layers of fibrinogen systems with heparins and other substances. A contribution on antithrombogenic action.

    PubMed

    Copley, A L; King, R G

    1984-08-01

    In earlier studies using a modified Weissenberg Rheogoniometer, we found decreased rigidity or torque values (tau) in surface layers of heparin plasma, when compared to tau of oxalate plasma from the same blood withdrawal (Thrombosis Res. 1, 1-17, 1972). In subsequent studies of the viscoelasticity of surface layers of highly purified fibrinogen (97-100% clottability) of human and bovine origin, we found, with some heparins, marked lowering of surface viscous moduli (eta's) and of surface elastic moduli (Gs). With some heparins no changes in tau, eta's and Gs occurred. Certain low molecular weight (LMW) preparations of heparins showed decreases, but some did not. This is also the case with heparins of low and high affinity for antithrombin. Calcium heparin and Ca2+ alone always increased eta's and Gs, when added to the fibrinogen system. N-desulfated heparin both decreased or did not change eta's and Gs. Preparations of fibrinogen in dog plasma, to which sodium heparin was added, resulted in a decrease of tau values. These results appear to emphasize that plasma proteins other than fibrinogen, and other plasma constituents, may affect surface hemorheological values. These findings suggest needed interface studies of fibrinogen systems to which plasma or plasma constituents are added. We found also that other substances, i.e., dextran MW 20,000; dextran sulfate MW 17,000; sodium hyaluronate and depolymerized hyaluronate decreased tau, eta's and Gs markedly. Recent findings in the literature are discussed in relation to thrombogenesis in which fibrinogenin gelation is considered as the initial phase of blood clotting. Fibrinogenin is the new term for initial fibrinogen aggregation and subsequent fibrinogen gelation without thrombin participation. The inhibition of fibrinogenin formation extra vivum is considered to be a valid indicator of antithrombogenic activity of substances which play a significant role in investigations on the therapy and prevention of

  5. Glycogen synthase kinase-3β inhibition in the medial prefrontal cortex mediates paradoxical amphetamine action in a mouse model of ADHD.

    PubMed

    Yen, Yi-Chun; Gassen, Nils C; Zellner, Andreas; Rein, Theo; Landgraf, Rainer; Wotjak, Carsten T; Anderzhanova, Elmira

    2015-01-01

    Psychostimulants show therapeutic efficacy in the treatment of attention-deficit hyperactivity disorder (ADHD). It is generally assumed that they ameliorate ADHD symptoms via interfering with monoaminergic signaling. We combined behavioral pharmacology, neurochemistry and molecular analyses to identify mechanisms underlying the paradoxical calming effect of amphetamine in low trait anxiety behavior (LAB) mice, a novel multigenetic animal model of ADHD. Amphetamine (1 mg/kg) and methylphenidate (10 mg/kg) elicited similar dopamine and norepinephrine release in the medial prefrontal cortex (mPFC) and in the striatum of LAB mice. In contrast, amphetamine decreased, while methylphenidate increased locomotor activity. This argues against changes in dopamine and/or norepinephrine release as mediators of amphetamine paradoxical effects. Instead, the calming activity of amphetamine corresponded to the inhibition of glycogen synthase kinase 3β (GSK3β) activity, specifically in the mPFC. Accordingly, not only systemic administration of the GSK3β inhibitor TDZD-8 (20 mg/kg), but also local microinjections of TDZD-8 and amphetamine into the mPFC, but not into the striatum, decreased locomotor activity in LAB mice. Amphetamine effects seem to depend on NMDA receptor signaling, since pre- or co-treatment with MK-801 (0.3 mg/kg) abolished the effects of amphetamine (1 mg/kg) on the locomotion and on the phosphorylation of GSK3β at the level of the mPFC. Taken together, the paradoxical calming effect of amphetamine in hyperactive LAB mice concurs with a decreased GSK3β activity in the mPFC. This effect appears to be independent of dopamine or norepinephrine release, but contingent on NMDA receptor signaling.

  6. Berberine Antifungal Activity in Fluconazole-Resistant Pathogenic Yeasts: Action Mechanism Evaluated by Flow Cytometry and Biofilm Growth Inhibition in Candida spp.

    PubMed Central

    da Silva, Anderson Ramos; de Andrade Neto, João Batista; da Silva, Cecília Rocha; Campos, Rosana de Sousa; Costa Silva, Rose Anny; Freitas, Daniel Domingues; do Nascimento, Francisca Bruna Stefany Aires; de Andrade, Larissa Nara Dantas; Sampaio, Letícia Serpa; Grangeiro, Thalles Barbosa; Magalhães, Hemerson Iury Ferreira; Cavalcanti, Bruno Coêlho; de Moraes, Manoel Odorico

    2016-01-01

    The incidence of fungal infections and, in particular, the incidence of fungal antibiotic resistance, which is associated with biofilm formation, have significantly increased, contributing to morbidity and mortality. Thus, new therapeutic strategies need to be developed. In this context, natural products have emerged as a major source of possible antifungal agents. Berberine is a protoberberine-type isoquinoline alkaloid isolated from the roots, rhizomes, and stem bark of natural herbs, such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, and Hydrastis canadensis, and of Phellodendron amurense. Berberine has been proven to have broad antibacterial and antifungal activity. In the present study, the potential antifungal effect of berberine against fluconazole-resistant Candida and Cryptococcus neoformans strains, as well as against the biofilm form of Candida spp., was assessed. The antifungal effect of berberine was determined by a broth microdilution method (the M27-A3 method of the Clinical and Laboratory Standards Institute) and flow cytometry techniques, in which the probable mechanism of action of the compound was also assessed. For biofilm assessment, a colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine the susceptibility of sessile cells. The isolates used in the study belonged to the Laboratory of Bioprospection and Experiments in Yeast (LABEL) of the Federal University of Ceará. After 24 and 72 h, fluconazole-resistant Candida and Cryptococcus neoformans strains showed berberine MICs equal to 8 μg/ml and 16 μg/ml, respectively. Cytometric analysis showed that treatment with berberine caused alterations to the integrity of the plasma and mitochondrial membranes and DNA damage, which led to cell death, probably by apoptosis. Assessment of biofilm-forming isolates after treatment showed statistically significant reductions in biofilm cell activity (P < 0.001). PMID:27021328

  7. The generalized anomeric effect in the 1,3-thiazolidines: Evidence for both sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin action

    NASA Astrophysics Data System (ADS)

    Chandrasekhar, Sosale; Chopra, Deepak; Gopalaiah, Kovuru; Guru Row, Tayur N.

    2007-06-01

    Evidence for the generalized anomeric effect (GAE) in the N-acyl-1,3-thiazolidines, an important structural motif in the penicillins, was sought in the crystal structures of N-(4-nitrobenzoyl)-1,3-thiazolidine and its (2:1) complex with mercuric chloride, N-acetyl-2-phenyl-1,3-thiazolidine, and the (2:1) complex of N-benzoyl-1,3-thiazolidine with mercuric bromide. An inverse relationship was generally observed between the C2- N and C2- S bond lengths of the thiazolidine ring, supporting the existence of the GAE. (Maximal bond length changes were ˜0.04 Å for C2- N3, S1- C2, and ˜0.08 Å for N3- C6.) Comparison with N-acylpyrrolidines and tetrahydrothiophenes indicates that both the nitrogen-to-sulphur and sulphur-to-nitrogen GAE's operate simultaneously in the 1,3-thiazolidines, the former being dominant. (This is analogous to the normal and exo-anomeric effects in pyranoses, and also leads to an interesting application of Baldwin's rules.) The nitrogen-to-sulphur GAE is generally enhanced in the mercury(II) complexes (presumably via coordination at the sulphur); a 'competition' between the GAE and the amide resonance of the N-acyl moiety is apparent. There is evidence for a 'push-pull' charge transfer between the thiazolidine moieties in the mercury(II) complexes, and for a 'back-donation' of charge from the bromine atoms to the thiazolidine moieties in the HgBr 2 complex. (The sulphur atom appears to be sp 2 hybridised in the mercury(II) complexes, possibly for stereoelectronic reasons.) These results are apparently relevant to the mode of action of the penicillins.

  8. Piperine, a dietary phytochemical, inhibits angiogenesis

    PubMed Central

    Doucette, Carolyn D.; Hilchie, Ashley L.; Liwski, Robert; Hoskin, David W.

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induced angiogenic activity by rat aorta explants and breast cancer cell-induced angiogenesis in chick embryos. Although piperine binds to and activates the cation channel transient receptor potential vanilloid 1 (TRPV1), its effects on endothelial cells did not involve TRPV1 since the antiproliferative effect of piperine was not affected by TRPV1-selective antagonists, nor did HUVECs express detectable TRPV1 mRNA. Importantly, piperine inhibited phosphorylation of Ser 473 and Thr 308 residues of Akt (protein kinase B), which is a key regulator of endothelial cell function and angiogenesis. Consistent with Akt inhibition as the basis of piperine’s action on HUVECs, inhibition of the phosphoinositide-3 kinase/Akt signaling pathway with LY-294002 also inhibited HUVEC proliferation and collagen-induced angiogenesis. Taken together, these data support the further investigation of piperine as an angiogenesis inhibitor for use in cancer treatment. PMID:22902327

  9. Choosing Actions

    PubMed Central

    Rosenbaum, David A.; Chapman, Kate M.; Coelho, Chase J.; Gong, Lanyun; Studenka, Breanna E.

    2013-01-01

    Actions that are chosen have properties that distinguish them from actions that are not. Of the nearly infinite possible actions that can achieve any given task, many of the unchosen actions are irrelevant, incorrect, or inappropriate. Others are relevant, correct, or appropriate but are disfavored for other reasons. Our research focuses on the question of what distinguishes actions that are chosen from actions that are possible but are not. We review studies that use simple preference methods to identify factors that contribute to action choices, especially for object-manipulation tasks. We can determine which factors are especially important through simple behavioral experiments. PMID:23761769

  10. Action semantics modulate action prediction.

    PubMed

    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.

  11. Action physics

    NASA Astrophysics Data System (ADS)

    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.

  12. Complementary actions.

    PubMed

    Sartori, Luisa; Betti, Sonia

    2015-01-01

    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.

  13. Complementary actions

    PubMed Central

    Sartori, Luisa; Betti, Sonia

    2015-01-01

    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. PMID:25983717

  14. 25 Action Learning Schools.

    ERIC Educational Resources Information Center

    National Association of Secondary School Principals, Reston, VA.

    This booklet on action-learning reflects an interest in preparing youth for the world of real experiences. Arranged in two major parts, the first offers information on the background and development of action-learning. Included in this section are the conclusions of the Panel on Youth of the President's Science Advisory Committee, the National…

  15. ACTION. 1977 Annual Report.

    ERIC Educational Resources Information Center

    ACTION, Washington, DC.

    In this report are described projects and activities undertaken by ACTION's volunteer programs in 1977. The first section concentrates on reviews conducted, including a major review of ACTION's domestic volunteer programs and the management systems supporting them and an assessment of its programs using the Zero-Base Budget approach called for by…

  16. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings.

    PubMed

    Graham, Garry G; Davies, Michael J; Day, Richard O; Mohamudally, Anthoulla; Scott, Kieran F

    2013-06-01

    Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and

  17. Environmental inhibition of 11beta-hydroxysteroid dehydrogenase.

    PubMed

    Reidenberg, M M

    2000-04-03

    Gossypol, a polyphenolic compound from cotton seed, caused hypokalemia in some men receiving it in a trial of its contraceptive activity. Searching for the mechanism for its hypokalemic action led to the observation that it inhibited 11beta-hydroxysteroid dehydrogenase. This would enhance mineralocorticoid effect in the kidney. Many other polyphenols also inhibit this enzyme including those in grapefruit juice. Ingesting 1-2 l of grapefruit juice inhibited this enzyme in two men in a clinical experiment. Tea polyphenols inhibit this enzyme and add to the inhibition caused by gossypol. Men in China have lower serum potassium values than men elsewhere and this is due to the environment, presumably the diet, in China. The importance of dietary and other exogenous inhibitors of this enzyme in electrolyte metabolism remains to be determined.

  18. Action Learning.

    ERIC Educational Resources Information Center

    1996

    These four papers were presented at a symposium on action learning moderated by Lex Dilworth at the 1996 conference of the Academy of Human Resource Development. "Developing an Infrastructure for Individual and Organizational Change: Transfer of Learning from an Action Reflection Learning (ARL) Program" (ARL Inquiry) reports findings…

  19. Common and unique neural networks for proactive and reactive response inhibition revealed by independent component analysis of functional MRI data.

    PubMed

    van Belle, Janna; Vink, Matthijs; Durston, Sarah; Zandbelt, Bram B

    2014-12-01

    Response inhibition involves proactive and reactive modes. Proactive inhibition is goal-directed, triggered by warning cues, and serves to restrain actions. Reactive inhibition is stimulus-driven, triggered by salient stop-signals, and used to stop actions completely. Functional MRI studies have identified brain regions that activate during proactive and reactive inhibition. It remains unclear how these brain regions operate in functional networks, and whether proactive and reactive inhibition depend on common networks, unique networks, or a combination. To address this we analyzed a large fMRI dataset (N=65) of a stop-signal task designed to measure proactive and reactive inhibition, using independent component analysis (ICA). We found 1) three frontal networks that were associated with both proactive and reactive inhibition, 2) one network in the superior parietal lobe, which also included dorsal premotor cortex and left putamen, that was specifically associated with proactive inhibition, and 3) two right-lateralized frontal and fronto-parietal networks, including the right inferior frontal gyrus and temporoparietal junction as well as a bilateral fronto-temporal network that were uniquely associated with reactive inhibition. Overlap between networks was observed in dorsolateral prefrontal and parietal cortices. Taken together, we offer a new perspective on the neural underpinnings of inhibitory control, by showing that proactive inhibition and reactive inhibition are supported by a group of common and unique networks that appear to integrate and interact in frontoparietal areas.

  20. Action Research in Music Education.

    ERIC Educational Resources Information Center

    Conway, Colleen M.; Borst, James

    2001-01-01

    Provides background information on using action research in music education. Offers guidelines for teachers to help them do action research. Includes an example of how a music teacher conducted action research in which the teacher asked, "Why did [the students] continue vocal music from middle school to high school?" (CMK)

  1. Action perception predicts action performance

    PubMed Central

    Bailey, Heather R.; Kurby, Christopher A.; Giovannetti, Tania; Zacks, Jeffrey M.

    2013-01-01

    Everyday action impairments often are observed in demented older adults, and they are common potential barriers to functional independence. We evaluated whether the ability to segment and efficiently encode activities is related to the ability to execute activities. Further, we evaluated whether brain regions important for segmentation also were important for action performance. Cognitively healthy older adults and those with very mild or mild dementia of the Alzheimer's type watched and segmented movies of everyday activities and then completed the Naturalistic Action Test. Structural MRI was used to measure volume in the dorsolateral prefrontal cortex (DLPFC), medial temporal lobes (MTL), posterior cortex, and anterior cingulate cortex (ACC). Dementia status and the ability to segment everyday activities strongly predicted naturalistic action performance, and MTL volume largely accounted for this relationship. In addition, the current results supported the Omission-Commission Model: Different cognitive and neurological mechanisms predicted different types of action error. Segmentation, dementia severity, and MTL volume predicted everyday omission errors, DLPFC volume predicted commission errors, and ACC volume predicted action additions. These findings suggest that event segmentation may be critical for effective action production, and that the segmentation and production of activities may recruit the same event representation system. PMID:23851113

  2. Action perception predicts action performance.

    PubMed

    Bailey, Heather R; Kurby, Christopher A; Giovannetti, Tania; Zacks, Jeffrey M

    2013-09-01

    Everyday action impairments often are observed in demented older adults, and they are common potential barriers to functional independence. We evaluated whether the ability to segment and efficiently encode activities is related to the ability to execute activities. Further, we evaluated whether brain regions important for segmentation also were important for action performance. Cognitively healthy older adults and those with very mild or mild dementia of the Alzheimer's type watched and segmented movies of everyday activities and then completed the Naturalistic Action Test. Structural MRI was used to measure volume in the dorsolateral prefrontal cortex (DLPFC), medial temporal lobes (MTL), posterior cortex, and anterior cingulate cortex (ACC). Dementia status and the ability to segment everyday activities strongly predicted naturalistic action performance, and MTL volume largely accounted for this relationship. In addition, the current results supported the Omission-Commission Model: Different cognitive and neurological mechanisms predicted different types of action error. Segmentation, dementia severity, and MTL volume predicted everyday omission errors, DLPFC volume predicted commission errors, and ACC volume predicted action additions. These findings suggest that event segmentation may be critical for effective action production, and that the segmentation and production of activities may recruit the same event representation system.

  3. [Mechanism of action of antiepileptic drugs].

    PubMed

    Saidón, Patricia

    2003-01-01

    Antiepileptic drugs (DAEs) act through different mechanisms of action: increase in central inhibition, inhibition of excitatorios mechanisms and modification of the excitability through their action on the ionic channels. Epilepsy is characterized by an abnormal and hypersynchronic unloading of a neuronal population. The activity of numerous drugs is associated to increase in gabaergic activity. Another group of drugs decreases excitatory mechanisms, through the inhibition of ionic channels, or through a decrease in the activity of the excitatory neurotransmitters. There are some of antiepileptic drugs, especially within the group of drugs of recent appearance, for wich the mechanism of action remains unknown.

  4. Spacelike brane actions.

    PubMed

    Hashimoto, Koji; Ho, Pei-Ming; Wang, John E

    2003-04-11

    We derive effective actions for "spacelike branes" (S-branes) and find a solution describing the formation of fundamental strings in the rolling tachyon background. The S-brane action is a Dirac-Born-Infeld action for Euclidean world volumes defined in the context of time-dependent tachyon condensation of non-BPS (Bogomol'nyi-Prasad-Sommerfield) branes. It includes gauge fields and, in particular, a scalar field associated with translation along the time direction. We show that the BIon spike solutions constructed in this system correspond to the production of a confined electric flux tube (a fundamental string) at late time of the rolling tachyon.

  5. Pump apparatus including deconsolidator

    DOEpatents

    Sonwane, Chandrashekhar; Saunders, Timothy; Fitzsimmons, Mark Andrew

    2014-10-07

    A pump apparatus includes a particulate pump that defines a passage that extends from an inlet to an outlet. A duct is in flow communication with the outlet. The duct includes a deconsolidator configured to fragment particle agglomerates received from the passage.

  6. Developing an action concept inventory

    NASA Astrophysics Data System (ADS)

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

    2016-06-01

    We report on progress towards the development of an Action Concept Inventory (ACI), a test that measures student understanding of action principles in introductory mechanics and optics. The ACI also covers key concepts of many-paths quantum mechanics, from which classical action physics arises. We used a multistage iterative development cycle for incorporating expert and student feedback into successive revisions of the ACI. The student feedback, including think-aloud interviews, enabled us to identify their misconceptions about action physics.

  7. Optical modulator including grapene

    DOEpatents

    Liu, Ming; Yin, Xiaobo; Zhang, Xiang

    2016-06-07

    The present invention provides for a one or more layer graphene optical modulator. In a first exemplary embodiment the optical modulator includes an optical waveguide, a nanoscale oxide spacer adjacent to a working region of the waveguide, and a monolayer graphene sheet adjacent to the spacer. In a second exemplary embodiment, the optical modulator includes at least one pair of active media, where the pair includes an oxide spacer, a first monolayer graphene sheet adjacent to a first side of the spacer, and a second monolayer graphene sheet adjacent to a second side of the spacer, and at least one optical waveguide adjacent to the pair.

  8. Phosphatidic acid inhibits ceramide 1-phosphate-stimulated macrophage migration.

    PubMed

    Ouro, Alberto; Arana, Lide; Rivera, Io-Guané; Ordoñez, Marta; Gomez-Larrauri, Ana; Presa, Natalia; Simón, Jorge; Trueba, Miguel; Gangoiti, Patricia; Bittman, Robert; Gomez-Muñoz, Antonio

    2014-12-15

    Ceramide 1-phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis.

  9. Economics Action Pack.

    ERIC Educational Resources Information Center

    McDonald's Corp., Oak Brook, IL.

    One of five McDonald's Action Packs, this learning package introduces intermediate grade students to basic economic concepts. The fourteen activities include the topics of consumption (4 activities), production (5), the market system (3), a pretest, and a posttest. Specific titles under consumption include The Wonderful Treasure Tree (introduction…

  10. Large-scale integration of small molecule-induced genome-wide transcriptional responses, Kinome-wide binding affinities and cell-growth inhibition profiles reveal global trends characterizing systems-level drug action.

    PubMed

    Vidović, Dušica; Koleti, Amar; Schürer, Stephan C

    2014-01-01

    The Library of Integrated Network-based Cellular Signatures (LINCS) project is a large-scale coordinated effort to build a comprehensive systems biology reference resource. The goals of the program include the generation of a very large multidimensional data matrix and informatics and computational tools to integrate, analyze, and make the data readily accessible. LINCS data include genome-wide transcriptional signatures, biochemical protein binding profiles, cellular phenotypic response profiles and various other datasets for a wide range of cell model systems and molecular and genetic perturbations. Here we present a partial survey of this data facilitated by data standards and in particular a robust compound standardization workflow; we integrated several types of LINCS signatures and analyzed the results with a focus on mechanism of action (MoA) and chemical compounds. We illustrate how kinase targets can be related to disease models and relevant drugs. We identified some fundamental trends that appear to link Kinome binding profiles and transcriptional signatures to chemical information and biochemical binding profiles to transcriptional responses independent of chemical similarity. To fill gaps in the datasets we developed and applied predictive models. The results can be interpreted at the systems level as demonstrated based on a large number of signaling pathways. We can identify clear global relationships, suggesting robustness of cellular responses to chemical perturbation. Overall, the results suggest that chemical similarity is a useful measure at the systems level, which would support phenotypic drug optimization efforts. With this study we demonstrate the potential of such integrated analysis approaches and suggest prioritizing further experiments to fill the gaps in the current data.

  11. Skeletal and extraskeletal actions of denosumab.

    PubMed

    Sinningen, Kathrin; Tsourdi, Elena; Rauner, Martina; Rachner, Tilman D; Hamann, Christine; Hofbauer, Lorenz C

    2012-08-01

    Osteoclasts and osteoblasts define skeletal mass, structure and strength through their respective actions in resorbing and forming bone. This remodeling process is orchestrated by the actions of hormones and growth factors, which regulate a cytokine system comprising the receptor activator of nuclear factor κB ligand (RANKL), its receptor RANK and the soluble decoy receptor osteoprotegerin (OPG). Bone resorption depends on RANKL, which determines osteoclast formation, activity and survival. Importantly, cells of the osteoblastic lineage mainly provide RANKL and therefore, are central in the regulation of osteoclast functions. Catabolic effects of RANKL are inhibited by OPG, a TNF receptor family member that binds RANKL, thereby preventing the activation of its receptor RANK, which is expressed by osteoclast precursors. Because this cytokine network is pivotal for the regulation of bone mass in health and diseases, including osteoporosis, rheumatoid arthritis and malignant bone conditions, it has been successfully used for the generation of a targeted therapy to block osteoclast actions. The clinical approval of denosumab, a fully monoclonal antibody against RANKL, provides a novel option to treat bone diseases with a potent, targeted and reversible inhibitor of bone resorption. Although RANKL is also expressed by endothelial cells, T lymphocytes, synovial fibroblasts and various tumor cells, no meaningful clinical extraskeletal effects have been reported after administration of denosumab. This article summarizes the molecular and cellular basis of the RANKL/RANK/OPG system and presents preclinical and clinical studies on the skeletal actions of denosumab.

  12. Mechanism of action of purpuromycin.

    PubMed Central

    Landini, P; Corti, E; Goldstein, B P; Denaro, M

    1992-01-01

    Purpuromycin, an antibiotic active against both fungi and bacteria, shows different modes of action against these two kinds of micro-organisms; in Candida albicans it inhibits RNA synthesis, whereas in Bacillus subtilis protein synthesis is primarily affected, with DNA and RNA synthesis blocked at higher concentrations of the drug. In bacterial cell-free protein-synthesis systems, purpuromycin did not inhibit synthesis from endogenous mRNA (elongation of peptides initiated within the intact cell) but inhibited MS2-phase RNA-dependent protein synthesis (which requires initiation) by 50% at 0.1 mg/l. Poly(U)-directed polyphenylalanine synthesis was 50% inhibited by 20 mg of purpuromycin/l when added to a complete system; however, when purpuromycin was preincubated with ribosomes dissociated into 30 S and 50 S subunits, the concentration for 50% inhibition fell to 0.1 mg/l. By contrast, in a C. albicans cell-free system poly(U)-directed polyphenylalanine synthesis was partially inhibited only at 200 mg/l. Purpuromycin also inhibited polynucleotide synthesis in vitro in reactions using Escherichia coli or wheat-germ RNA polymerases or E. coli DNA polymerase I. We suggest that in bacteria the primary target of purpuromycin is on ribosomes and that its action precedes the elongation step of protein synthesis. The effect on nucleic acid synthesis in both fungi and bacteria may be due to interaction of purpuromycin with DNA. PMID:1599409

  13. Convulsant actions of calycanthine.

    PubMed

    Chebib, Mary; Duke, Rujee K; Duke, Colin C; Connor, Mark; Mewett, Kenneth N; Johnston, Graham A R

    2003-07-01

    The principal alkaloid of the family Calycanthaceae, calycanthine has long been recognized as a central convulsant. The alkaloid inhibited the potassium-stimulated release of [(3)H]GABA from slices of rat hippocampus with an ED(50) of approximately 21 microM. This effect appeared to be moderately selective since calycanthine at 100 microM had only a weak effect on the potassium-stimulated release of [(3)H]acetylcholine (15%) and no significant effects on the release of [(3)H]D-aspartate from hippocampal and cerebellar slices or the release of [(3)H]glycine from spinal cord slices. Calycanthine blocked the L-type calcium currents with an IC(50) of approximately 42 microM and also weakly inhibited the N-type calcium currents (IC(50) > 100 microM) from neuroblastoma X glioma cells, suggesting voltage-dependent calcium channel blockade as a possible mechanism for its inhibition of GABA and ACh release. Calycanthine was also found to directly inhibit GABA-mediated currents (K(B) approximately 135 microM) from human alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes but had no effect at 100 microM on human rho(1) GABA(c) receptors. The results indicated that calycanthine may mediate its convulsant action predominantly by inhibiting the release of the inhibitory neurotransmitter GABA as a result of interactions with L-type Ca(2+) channels and by inhibiting GABA-mediated chloride currents at GABA(A) receptors.

  14. Including Jews in Multiculturalism.

    ERIC Educational Resources Information Center

    Langman, Peter F.

    1995-01-01

    Discusses reasons for the lack of attention to Jews as an ethnic minority within multiculturalism both by Jews and non-Jews; why Jews and Jewish issues need to be included; and addresses some of the issues involved in the ethical treatment of Jewish clients. (Author)

  15. Neurobiological actions of cysteamine

    SciTech Connect

    Brown, M.; Fisher, L.; Mason, R.T.; Rivier, J.; Vale, W.

    1985-06-01

    Somatostatin (SS)-related peptides act within discrete brain regions to inhibit adrenal epinephrine (E) secretion, to prevent hypothermia, and to produce hyperthermia. Depletion of brain concentrations of these SS-related peptides using cysteamine (CSH) or central administration of an SS receptor antagonist increases adrenal E secretion and impairs thermoregulation. These actions of CSH and the SS receptor antagonist are reversed by administration of SS into the central nervous system. These results support the hypothesis that endogenous brain SS-related peptides are involved in the regulation of adrenal E secretion and thermoregulation.

  16. Citizen's actions

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The role played by individual citizens as consumers of energy was examined, with emphasis on studying ways in which their action could result in energy conservation. It was shown that there are ways that energy can be conserved in this way, with citizens acting either individually or in groups. The potential savings are significant, but the actual savings may be quite small. The citizens need to be motivated to save and to believe in a conservation ethic; developing such an ethic is difficult, and perhaps not responsive to the shotgun approach now being attempted. The true course of action may be to synthesize new societal structures that provide the maximum evolution of culture within the limitation of scarce energy resources.

  17. Nutritional therapies (including fosteum).

    PubMed

    Nieves, Jeri W

    2009-03-01

    Nutrition is important in promoting bone health and in managing an individual with low bone mass or osteoporosis. In adult women and men, known losses of bone mass and microarchitecture occur, and nutrition can help minimize these losses. In every patient, a healthy diet with adequate protein, fruits, vegetables, calcium, and vitamin D is required to maintain bone health. Recent reports on nutritional remedies for osteoporosis have highlighted the importance of calcium in youth and continued importance in conjunction with vitamin D as the population ages. It is likely that a calcium intake of 1200 mg/d is ideal, and there are some concerns about excessive calcium intakes. However, vitamin D intake needs to be increased in most populations. The ability of soy products, particularly genistein aglycone, to provide skeletal benefit has been recently studied, including some data that support a new medical food marketed as Fosteum (Primus Pharmaceuticals, Scottsdale, AZ).

  18. Mu Opioid Receptor Actions in the Lateral Habenula

    PubMed Central

    Margolis, Elyssa B.; Fields, Howard L.

    2016-01-01

    Increased activity of lateral habenula (LHb) neurons is correlated with aversive states including pain, opioid abstinence, rodent models of depression, and failure to receive a predicted reward. Agonists at the mu opioid receptor (MOR) are among the most powerful rewarding and pain relieving drugs. Injection of the MOR agonist morphine directly into the habenula produces analgesia, raising the possibility that MOR acts locally within the LHb. Consequently, we examined the synaptic actions of MOR agonists in the LHb using whole cell patch clamp recording. We found that the MOR selective agonist DAMGO inhibits a subset of LHb neurons both directly and by inhibiting glutamate release onto these cells. Paradoxically, DAMGO also presynaptically inhibited GABA release onto most LHb neurons. The behavioral effect of MOR activation will thus depend upon both the level of intrinsic neuronal activity in the LHb and the balance of activity in glutamate and GABA inputs to different LHb neuronal populations. PMID:27427945

  19. Recent insights into the actions of IGFBP-6.

    PubMed

    Bach, Leon A

    2015-06-01

    IGFBP-6 is an O-linked glycoprotein that preferentially binds IGF-II over IGF-I. It is a relatively selective inhibitor of IGF-II actions including proliferation, survival and differentiation of a wide range of cells. IGFBP-6 has recently been shown to have a number of IGF-independent actions, including promotion of apoptosis in some cells and inhibition of angiogenesis. IGFBP-6 also induces migration of tumour cells including rhabdomyosarcomas by an IGF-independent mechanism. This chemotactic effect is mediated by MAP kinases. IGFBP-6 binds to prohibitin-2 on the cell surface and the latter is required for IGFBP-6-induced migration by a mechanism that is independent of MAP kinases. IGFBP-6 may enter the nucleus and modulate cell survival and differentiation. IGFBP-6 expression is decreased in a number of cancer cells and it has been postulated to act as a tumour suppressor. IGFBP-6 expression is increased in a smaller number of cancers, which may reflect a compensatory mechanism to control IGF-II actions or IGF-independent actions. The relative balance of IGF-dependent and IGF-independent actions of IGFBP-6 in vivo together with the related question regarding the roles of IGFBP-6 binding to IGF and non-IGF ligands are keys to understanding the physiological role of this protein.

  20. The Cost of Action Miscues: Hemispheric Asymmetries

    ERIC Educational Resources Information Center

    Shenal, Brian V.; Hinze, Stephan; Heilman, Kenneth M.

    2012-01-01

    Adaptive behaviors require preparation and when necessary inhibition or alteration of actions. The right hemisphere has been posited to be dominant for preparatory motor activation. This experiment was designed to learn if there are hemispheric asymmetries in the control of altered plans of actions. Cues, both valid and invalid, which indicate the…

  1. Conscious Action/Zombie Action

    PubMed Central

    Shepherd, Joshua

    2015-01-01

    Abstract I argue that the neural realizers of experiences of trying (that is, experiences of directing effort towards the satisfaction of an intention) are not distinct from the neural realizers of actual trying (that is, actual effort directed towards the satisfaction of an intention). I then ask how experiences of trying might relate to the perceptual experiences one has while acting. First, I assess recent zombie action arguments regarding conscious visual experience, and I argue that contrary to what some have claimed, conscious visual experience plays a causal role for action control in some circumstances. Second, I propose a multimodal account of the experience of acting. According to this account, the experience of acting is (at the very least) a temporally extended, co‐conscious collection of agentive and perceptual experiences, functionally integrated and structured both by multimodal perceptual processing as well as by what an agent is, at the time, trying to do. PMID:27667859

  2. Conscious Action/Zombie Action.

    PubMed

    Shepherd, Joshua

    2016-06-01

    I argue that the neural realizers of experiences of trying (that is, experiences of directing effort towards the satisfaction of an intention) are not distinct from the neural realizers of actual trying (that is, actual effort directed towards the satisfaction of an intention). I then ask how experiences of trying might relate to the perceptual experiences one has while acting. First, I assess recent zombie action arguments regarding conscious visual experience, and I argue that contrary to what some have claimed, conscious visual experience plays a causal role for action control in some circumstances. Second, I propose a multimodal account of the experience of acting. According to this account, the experience of acting is (at the very least) a temporally extended, co-conscious collection of agentive and perceptual experiences, functionally integrated and structured both by multimodal perceptual processing as well as by what an agent is, at the time, trying to do.

  3. Refraction, including prisms.

    PubMed

    Hiatt, R L

    1991-02-01

    The literature in the past year on refraction is replete with several isolated but very important topics that have been of interest to strabismologists and refractionists for many decades. The refractive changes in scleral buckling procedures include an increase in axial length as well as an increase in myopia, as would be expected. Tinted lenses in dyslexia show little positive effect in the nonasthmatic patients in one study. The use of spectacles or bifocals as a way to control increase in myopia is refuted in another report. It has been shown that in accommodative esotropia not all patients will be able to escape the use of bifocals in the teenage years, even though surgery might be performed. The hope that disposable contact lenses would cut down on the instance of giant papillary conjunctivitis and keratitis has been given some credence, and the conventional theory that sclerosis alone is the cause of presbyopia is attacked. Also, gas permeable bifocal contact lenses are reviewed and the difficulties of correcting presbyopia by this method outlined. The practice of giving an aphakic less bifocal addition instead of a nonaphakic, based on the presumption of increased effective power, is challenged. In the review of prisms, the majority of articles concern prism adaption. The most significant report is that of the Prism Adaptation Study Research Group (Arch Ophthalmol 1990, 108:1248-1256), showing that acquired esotropia in particular has an increased incidence of stable and full corrections surgically in the prism adaptation group versus the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Design of dual action antibiotics as an approach to search for new promising drugs

    NASA Astrophysics Data System (ADS)

    Tevyashova, A. N.; Olsufyeva, E. N.; Preobrazhenskaya, M. N.

    2015-01-01

    The review is devoted to the latest achievements in the design of dual action antibiotics — heterodimeric (chimeric) structures based on antibacterial agents of different classes (fluoroquinolones, anthracyclines, oxazolidines, macrolides and so on). Covalent binding can make the pharmacokinetic characteristics of these molecules more predictable and improve the penetration of each component into the cell. Consequently, not only does the drug efficacy increase owing to inhibition of two targets but also the resistance to one or both antibiotics can be overcome. The theoretical grounds of elaboration, design principles and methods for the synthesis of dual action antibiotics are considered. The structures are classified according to the type of covalent spacer (cleavable or not) connecting the moieties of two agents. Dual action antibiotics with a spacer that can be cleaved in a living cell are considered as dual action prodrugs. Data on the biological action of heterodimeric compounds are presented and structure-activity relationships are analyzed. The bibliography includes 225 references.

  5. Action for Children's Television.

    ERIC Educational Resources Information Center

    Ranly, Donald P.

    The origins, development, and effectiveness of Action for Children's Television (ACT) are examined in this pamphlet. The strategies used by ACT to obtain change at the congressional level and within television stations and networks include the following: a "tuneout" day when people are urged to turn off their television sets, a boycott…

  6. Nutrition Action Pack.

    ERIC Educational Resources Information Center

    Sockut, Joanne; Stumpe, Stephanie

    One of five McDonald's Action Packs, these instructional materials integrate elementary school-level nutrition education into other disciplines--biology, sociology, physiology, mathematics, and art. Contents include four units consisting of twelve activities. Unit 1, Why You Need Food, is a self-examination of what is needed for growth, health,…

  7. 24 CFR 91.420 - Action plan.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 1 2013-04-01 2013-04-01 false Action plan. 91.420 Section 91.420... Plan § 91.420 Action plan. (a) Form application. The action plan for the consortium must include a...) Description of resources and activities. The action plan must describe the resources to be used and...

  8. 24 CFR 91.420 - Action plan.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 1 2014-04-01 2014-04-01 false Action plan. 91.420 Section 91.420... Plan § 91.420 Action plan. (a) Form application. The action plan for the consortium must include a...) Description of resources and activities. The action plan must describe the resources to be used and...

  9. Pyrilamine inhibits nicotine-induced catecholamine secretion.

    PubMed

    Kim, Dong-Chan; Yun, So Jeong; Park, Yong-Soo; Jun, Dong-Jae; Kim, Dongjin; Jiten Singh, N; Kim, Sanguk; Kim, Kyong-Tai

    2014-07-01

    Function of nicotine, which induces activation of all parts of the body including our brain, has been receiving much attention for a long period of time and also been actively studied by researchers for its pharmacological actions in the central nervous system. The modulation of nicotine concentration and the inhibition of nicotine binding on target receptors in the brain are the key factors for smoking addiction therapy. In previous studies showed that influx of nicotine at the blood-brain barrier was through the pyrilamine-sensitive organic cation transporters. But the direct interacting mechanism of pyrilamine on the nicotine binding target receptors has not yet been clarified. The aim of the present study is to investigate the direct binding mechanisms of a pyrilamine on the nicotinic acetylcholine receptors (nAChRs). We found that pyrilamine shares the same ligand binding pocket of nicotine (NCT) on nAChRs but interacts with more amino acid residues than NCT does. The extended part of pyrilamine interacts with additional residues in the ligand binding pocket of nAChRs which are located nearby the entrance of the binding pocket. The catecholamine (CA) secretion induced by nAChR agonist (NCT') was significantly inhibited by the pyrilamine pretreatment. Real time carbon-fiber amperometry confirmed the inhibition of the NCT'-induced exocytosis by pyrilamine in a single cell level. We also found that pyrilamine inhibited the NCT'-induced [Ca(2+)]i. In contrast, pyrilamine did not affect the increase in calcium induced by high K(+). Overall, these data suggest that pyrilamine directly docks into the ligand binding site of nAChRs and specifically inhibits the nAChR-mediated effects thereby causing inhibition of CA secretion. Therefore, pyrilamine may play an important role to explore new treatments to aid smoking cessation.

  10. FcR epsilon+ lymphocytes and regulation of the IgE antibody system. IV. Delineation of target cells and mechanisms of action of SFA and EFA in inhibiting in vitro induction of FcR epsilon expression.

    PubMed

    Marcelletti, J F; Katz, D H

    1984-12-01

    SFA and EFA are derived from distinct mouse T cell hybridomas secreting one or the other (but not both) factor, and although both are capable of inhibiting FcR epsilon expression by unfractionated spleen cells induced by monomeric IgE, neither was inhibitory for EIRT-induced FcR epsilon expression by T cells in the same cell population. This suggests that the final target cell for the inhibitory effects of SFA and EFA is the FcR epsilon+ B lymphocyte. T cells are required for both SFA- and EFA-mediated FcR epsilon inhibition, and more precisely, as shown in this study, SFA stimulates Lyt-1+ cells in the presence or absence of IgE to produce a suppressive effector molecule (SEM), and EFA together with IgE stimulates Lyt-2+ cells to produce an enhancing effector molecule (EEM), both of which can directly inhibit FcR epsilon expression by B cells. SFA and SEM can inhibit both IgE- and EIRB-induced FcR epsilon expression by B cells, indicating that SFA may act by blocking the EIRB-mediated expansion of the FcR epsilon+ B cell population. EFA and EEM, in contrast, can inhibit IgE-induced but not EIRB-induced FcR epsilon expression, indicating that EFA may act at some point before the release of EIR, perhaps involving those FcR epsilon+ B cells that respond to IgE and produce EIRB. Finally, although neither SFA and EFA display IgE binding properties, both SEM and EEM, in contrast, are IgE binding factors (IgE-BF) and may be homologous to the suppressive IgE binding factor and potentiating IgE binding factor described by other investigators. The possible interrelationships between these various cells and factors are discussed.

  11. To require the Secretary of the Interior to assemble a team of technical, policy, and financial experts to address the energy needs of the insular areas of the United States and the Freely Associated States through the development of energy action plans aimed at promoting access to affordable, reliable energy, including increasing use of indigenous clean-energy resources, and for other purposes.

    THOMAS, 113th Congress

    Rep. Christensen, Donna M. [D-VI-At Large

    2014-12-08

    12/12/2014 Received in the Senate. (All Actions) Notes: For further action, see H.R.83, which became Public Law 113-235 on 12/16/2014. Tracker: This bill has the status Passed HouseHere are the steps for Status of Legislation:

  12. Action Learning: Avoiding Conflict or Enabling Action

    ERIC Educational Resources Information Center

    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…

  13. Antidromic propagation of action potentials in branched axons: implications for the mechanisms of action of deep brain stimulation.

    PubMed

    Grill, Warren M; Cantrell, Meredith B; Robertson, Matthew S

    2008-02-01

    Electrical stimulation of the central nervous system creates both orthodromically propagating action potentials, by stimulation of local cells and passing axons, and antidromically propagating action potentials, by stimulation of presynaptic axons and terminals. Our aim was to understand how antidromic action potentials navigate through complex arborizations, such as those of thalamic and basal ganglia afferents-sites of electrical activation during deep brain stimulation. We developed computational models to study the propagation of antidromic action potentials past the bifurcation in branched axons. In both unmyelinated and myelinated branched axons, when the diameters of each axon branch remained under a specific threshold (set by the antidromic geometric ratio), antidromic propagation occurred robustly; action potentials traveled both antidromically into the primary segment as well as "re-orthodromically" into the terminal secondary segment. Propagation occurred across a broad range of stimulation frequencies, axon segment geometries, and concentrations of extracellular potassium, but was strongly dependent on the geometry of the node of Ranvier at the axonal bifurcation. Thus, antidromic activation of axon terminals can, through axon collaterals, lead to widespread activation or inhibition of targets remote from the site of stimulation. These effects should be included when interpreting the results of functional imaging or evoked potential studies on the mechanisms of action of DBS.

  14. The mechanism of action of antidepressants revised.

    PubMed

    Ackenheil, M

    1990-01-01

    The discovery of the clinical efficacy of imipramine and of the MAO-inhibitor iproniazid intensively stimulated biochemical-pharmacological research on the mechanism of action of antidepressants. Due to these investigations, until recently an enhanced activity of the central noradrenergic and/or serotonergic transmitter system was considered essential for the clinical antidepressive action. Such enhancement could be achieved either presynaptically by blocking alpha 2-adrenergic receptors, or in the synaptic cleft by inhibiting the transmitter reuptake or the main metabolic enzyme, MAO. The common final result, especially of chronic treatment, was the down-regulation of postsynaptic beta-receptors, modulated by interaction with the serotonergic system, neuropeptides, and hormones. The delay of clinical response corresponded better with such receptor alterations. However, the introduction of new, more selective antidepressants led to new reflections upon the mechanism of action. On the level of transmitters, alpha 1-upregulation, increased activity of the dopaminergic system, an alteration in the balance between the different transmitter systems, are reported and seem to be important. Most promising are recent investigations of the second messenger systems, the adenylate cyclase system and the phosphatidylinositol system. Both systems are modulated by antidepressant drugs including lithium and carbamazepine. These second messengers, in turn, modulate the phosphorylation status of neuronal proteins via protein kinase, which may lead to elevations of the above mentioned receptors and again their transduction systems.

  15. Semantic processing and response inhibition.

    PubMed

    Chiang, Hsueh-Sheng; Motes, Michael A; Mudar, Raksha A; Rao, Neena K; Mansinghani, Sethesh; Brier, Matthew R; Maguire, Mandy J; Kraut, Michael A; Hart, John

    2013-11-13

    The present study examined functional MRI (fMRI) BOLD signal changes in response to object categorization during response selection and inhibition. Young adults (N=16) completed a Go/NoGo task with varying object categorization requirements while fMRI data were recorded. Response inhibition elicited increased signal change in various brain regions, including medial frontal areas, compared with response selection. BOLD signal in an area within the right angular gyrus was increased when higher-order categorization was mandated. In addition, signal change during response inhibition varied with categorization requirements in the left inferior temporal gyrus (lIT). lIT-mediated response inhibition when inhibiting the response only required lower-order categorization, but lIT mediated both response selection and inhibition when selecting and inhibiting the response required higher-order categorization. The findings characterized mechanisms mediating response inhibition associated with semantic object categorization in the 'what' visual object memory system.

  16. Investigation of the inhibiting action of O-, S- and N-dithiocarbamato(1,4,8,11-tetraazacyclotetradecane)cobalt(III) complexes on the corrosion of iron in HClO 4 acid

    NASA Astrophysics Data System (ADS)

    Babić-Samardžija, K.; Khaled, K. F.; Hackerman, N.

    2005-02-01

    The inhibiting properties of four macrocyclic cobalt(III) complexes of the general formula [Co III(Rdtc)cyclam](ClO 4) 2, where cyclam and Rdtc- refer to 1,4,8,11-tetraazacyclotetradecane and morpholine-, thiomorpholine-, piperazine-, N-methylpiperazine-dithiocarbamates, respectively, has been studied on the corrosion of iron in aerated 0.1 M HClO 4 solutions by potentiodynamic polarization (dc) technique and electrochemical impedance spectroscopy (ac). Inhibitor efficiency for the corrosion of iron is found to be better for cobalt complexes then for related amino-ligands. The impedance increases with inhibitor concentration. Polarization curves indicate that the inhibitors are predominantly mixed-type. Better protection by the complex inhibitors was obtained with longer immersion time. The best fit for inhibitors adsorption is obtained using the Langmuir isotherm model. Molecular modeling calculations were used to correlate structural properties of the complex species and their inhibition efficiency.

  17. Classifying Facial Actions

    PubMed Central

    Donato, Gianluca; Bartlett, Marian Stewart; Hager, Joseph C.; Ekman, Paul; Sejnowski, Terrence J.

    2010-01-01

    The Facial Action Coding System (FACS) [23] is an objective method for quantifying facial movement in terms of component actions. This system is widely used in behavioral investigations of emotion, cognitive processes, and social interaction. The coding is presently performed by highly trained human experts. This paper explores and compares techniques for automatically recognizing facial actions in sequences of images. These techniques include analysis of facial motion through estimation of optical flow; holistic spatial analysis, such as principal component analysis, independent component analysis, local feature analysis, and linear discriminant analysis; and methods based on the outputs of local filters, such as Gabor wavelet representations and local principal components. Performance of these systems is compared to naive and expert human subjects. Best performances were obtained using the Gabor wavelet representation and the independent component representation, both of which achieved 96 percent accuracy for classifying 12 facial actions of the upper and lower face. The results provide converging evidence for the importance of using local filters, high spatial frequencies, and statistical independence for classifying facial actions. PMID:21188284

  18. Technology assessment and citizen action

    NASA Technical Reports Server (NTRS)

    Mottur, E. R.

    1975-01-01

    Citizen participation in the nation's total social, political, economic decisionmaking processes was studied. Impediments are discussed which prevent citizens from taking effective assessment action; these include finance, organization and motivation, and information. The proposal for establishing citizens assessment associations is considered along with implications of citizen assessment action.

  19. Action slips during whole-body vibration.

    PubMed

    Ishimatsu, Kazuma; Meland, Anders; Hansen, Tor Are S; Kåsin, Jan Ivar; Wagstaff, Anthony S

    2016-07-01

    Helicopter aircrew members engage in highly demanding cognitive tasks in an environment subject to whole-body vibration (WBV). Sometimes their actions may not be according to plan (e.g. action slips and lapses). This study used a Sustained Attention to Response Task (SART) to examine whether action slips were more frequent during exposure to WBV. Nineteen participants performed the SART in two blocks. In the WBV block participants were exposed to 17 Hz vertical WBV, which is typical of larger helicopter working environments. In the No-WBV block there was no WBV. There were more responses to the rare no-go digit 3 (i.e. action slips) in the WBV block, and participants responded faster in the WBV block. These results suggest that WBV influences response inhibition, and can induce impulsive responding. WBV may increase the likelihood of action slips, mainly due to failure of response inhibition.

  20. 24 CFR 91.320 - Action plan.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 1 2011-04-01 2011-04-01 false Action plan. 91.320 Section 91.320... Consolidated Plan § 91.320 Action plan. The action plan must include the following: (a) Standard Form 424; (b) A concise executive summary that includes the objectives and outcomes identified in the plan as...

  1. 24 CFR 91.220 - Action plan.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 1 2011-04-01 2011-04-01 false Action plan. 91.220 Section 91.220... Consolidated Plan § 91.220 Action plan. The action plan must include the following: (a) Standard Form 424; (b) A concise executive summary that includes the objectives and outcomes identified in the plan as...

  2. Enforcement actions: Significant actions resolved individual actions. Semiannual progress report, January 1996--June 1996

    SciTech Connect

    1996-08-01

    This document summarizes significant enforcement actions that have been resolved during the period of January-June 1996. The report includes copies of Orders and Notices of Violations sent by the Nuclear Regulatory Commission to individuals with respect to the enforcement actions.

  3. European drug market entries 2015 with new mechanisms of action.

    PubMed

    van den Heuvel, Titus W P; Cohen, Adam F; Rissmann, Robert

    2016-10-01

    In this article, we consider the new drugs approved for the European market in 2015. We present a summary of the new mechanisms of action introduced and highlight three new mechanisms of action with a potentially high future impact: PCSK9 inhibition (alirocumab (Praluent®) and evolocumab (Repatha®)) for hypercholesterolaemia, neprilysin inhibition (sacubitril in combination with valsartan (Entresto®)) for heart failure, and interleukin-5 inhibition (mepolizumab (Nucala®)) for asthma.

  4. Inhibition by streptovaricins of Rauscher leukemia virus splenomegaly.

    PubMed

    Borden, E C; Carter, W A; Sensenbrenner, L L; Owens, A H; Lichtenstein, J; Gray, G D; Neil, G L; Nichol, F R; Li, L H

    1974-12-15

    Streptovaricins (Sv), ansa macrolide antibiotics, inhibited Rauscher leukemia virus (RLV) splenomegaly by 25-50%. All streptovaricins tested were effective when administered orally either by diet ad lib or by intubation from infection to time of killing. When delivered by intubation, Sv was measurable in plasma for up to 6 h. SvC, at 300 mg/kg/day, reduced mean spleen weight of infected mice from 478 plus or minus 51 (SE) mg to 300 plus or minus 55 (SE) mg. Rifampicin, at 250 mg/kg/day, had no similar activity. Decrease in caloric intake and in body-weight gain also resulted in an inhibition of RLV splenomegaly; although Sv-treated mice gained weight, the increase was usually slightly less than controls. However, mice treated with a Sv diet for a week prior to infection, after an initial period of weight loss, gained at a rate equivalent to control group, and when killed had a marked reduction in splenomegaly. The selectivity of streptovaricins and specificity for viral events was suggested by several observations: (1) Splenomegaly and mortality, induced by L1210 or a non-infective transplantable tumor of RLV origin, was not inhibited. (2) No inhibition of normal hematopoietic spleen colonies was observed. (3) Host immune responses, including cellular and humoral immunity and interferon production and action, were not inhibited. Thus, although the effect of slightly decreased weight and intake could not be unequivocally established, the findings were most compatible with a selective inhibition of RLV splenomegaly by Sv.

  5. Superfund Removal Guidance for Preparing Action Memoranda

    EPA Pesticide Factsheets

    Dated September 2009, this updates and replaces previous documents. An Action Memo (AM) should substantiate need for removal action based upon criteria in the National Oil and Hazardous Substances Pollution Contingency Plan (NCP). Includes AM template.

  6. Action Theory, Control and Motivation: A Symposium.

    ERIC Educational Resources Information Center

    Eckensberger, L. H.; Meacham, J. A., Eds.

    1984-01-01

    Describes the symposium on action theory presented at the 1983 meeting of the International Society for the Study of Behavioral Development in Munich. The symposium included reactions to action theory from a variety of theoretical perspectives. (Author/RH)

  7. CORROSION INHIBITION

    DOEpatents

    Cartledge, G.H.

    1958-06-01

    The protection of ferrous metsls from the corrosive action of aqueous solutions is accomplished by the incorporation of small amounts of certain additive agents into the aqueous solutions. The method comprises providing a small concentration of technetium, in the form of pertechnetate ion, dissolved in the solution.

  8. Toluene Diisocyanates (TDI) Action Plan

    EPA Pesticide Factsheets

    This Action Plan addresses the use of toluene diisocyanate (TDI) and related compounds in products that may result in consumer and general population exposures, particularly in or around buildings, including homes and schools.

  9. InterAction Database (IADB)

    Cancer.gov

    The InterAction Database includes demographic and prescription information for more than 500,000 patients in the northern and middle Netherlands and has been integrated with other systems to enhance data collection and analysis.

  10. Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action by inhibition of cAMP-phosphodiesterase (PDE).

    PubMed

    Dallas, Constantin; Gerbi, Alain; Tenca, Guillaume; Juchaux, Franck; Bernard, François-Xavier

    2008-10-01

    The present study investigated the lipolytic (break of fat stored) effect of a citrus-based polyphenolic dietary supplement (SINETROL) at human adipocytes (ex vivo), body fat (clinical) and biochemical levels (inhibition of phosphodiesterase). Free fatty acids (FFA) release was used as indicator of human adipocyte lipolysis and SINETROL activity has been compared with known lipolytic products (isoproterenol, theopylline and caffeine). SINETROL stimulated significantly the lipolytic activity in a range of 6 fold greater than the control. Moreover, SINETROL has 2.1 greater activity than guarana 12% caffeine while its content in caffeine is 3 times lower. Clinically, two groups of 10 volunteers with BMI relevant of overweight were compared during 4 and 12 weeks with 1.4 g/day SINETROL and placebo supplementation. In the SINETROL Group the body fat (%) decreased with a significant difference of 5.53% and 15.6% after 4 and 12 weeks, respectively, while the body weight (kg) decreased with a significant difference of 2.2 and 5.2 kg after 4 and 12 weeks, respectively. These observed effects are linked to SINETROL polyphenolic composition and its resulting synergistic activity. SINETROL is a potent inhibitor of cAMP-phosphodiesterase (PDE) (97%) compared to other purified compounds (cyanidin-3 glycoside, narangin, caffeine). These results suggest that SINETROL has a strong lipolytic effect mediated by cAMP-PDE inhibition. SINETROL may serve to prevent obesity by decreasing BMI.

  11. Inhibition of X-ray-induced potentially lethal damage (PLD) repair by cordycepin (3'-deoxyadenosine) and enhancement of its action by 2'-deoxycoformycin in Chinese Hamster hai cells in the stationary phase in Vitro

    SciTech Connect

    Nakatsugawa, S.; Sugahara, T.

    1980-11-01

    The effects of growth phase and chemicals on PLD repair were studied in X-irradiated Chinese hamster hai cells. The change in capacity of cells in different growth phases to repair PLD was investigated. Starting from cells in the log phase, the magnitude of PLD repair during 10 hr of postirradiation incubation in Hanks' balanced salt solution increased for 2.5 to 18 as the cultures approached the stationary phase, which occurred on the 7th or 8th day. The effects of chemicals dissolved in Hanks' BSS on PLD repair were studied using 10th- or 12th-day cultures. Among the chemicals tested, caffeine and cordycepin were effective in inhibiting PLD repair. When 2'-deoxycoformycin, an inhibitor of adenosine deaminase, was combined with cordycepin, the effect of cordycepin was enhanced. Due to this prevention of the deamination of cordycepin by 2'-deoxycoformycin, the inhibition of PLD repair was prolonged, indicating a possible clinical application of cordycepin as a radiosensitizer.

  12. Action-based flood forecasting for triggering humanitarian action

    NASA Astrophysics Data System (ADS)

    Coughlan de Perez, Erin; van den Hurk, Bart; van Aalst, Maarten K.; Amuron, Irene; Bamanya, Deus; Hauser, Tristan; Jongma, Brenden; Lopez, Ana; Mason, Simon; Mendler de Suarez, Janot; Pappenberger, Florian; Rueth, Alexandra; Stephens, Elisabeth; Suarez, Pablo; Wagemaker, Jurjen; Zsoter, Ervin

    2016-09-01

    Too often, credible scientific early warning information of increased disaster risk does not result in humanitarian action. With financial resources tilted heavily towards response after a disaster, disaster managers have limited incentive and ability to process complex scientific data, including uncertainties. These incentives are beginning to change, with the advent of several new forecast-based financing systems that provide funding based on a forecast of an extreme event. Given the changing landscape, here we demonstrate a method to select and use appropriate forecasts for specific humanitarian disaster prevention actions, even in a data-scarce location. This action-based forecasting methodology takes into account the parameters of each action, such as action lifetime, when verifying a forecast. Forecasts are linked with action based on an understanding of (1) the magnitude of previous flooding events and (2) the willingness to act "in vain" for specific actions. This is applied in the context of the Uganda Red Cross Society forecast-based financing pilot project, with forecasts from the Global Flood Awareness System (GloFAS). Using this method, we define the "danger level" of flooding, and we select the probabilistic forecast triggers that are appropriate for specific actions. Results from this methodology can be applied globally across hazards and fed into a financing system that ensures that automatic, pre-funded early action will be triggered by forecasts.

  13. Molecular basis determining inhibition/activation of nociceptive receptor TRPA1 protein: a single amino acid dictates species-specific actions of the most potent mammalian TRPA1 antagonist.

    PubMed

    Banzawa, Nagako; Saito, Shigeru; Imagawa, Toshiaki; Kashio, Makiko; Takahashi, Kenji; Tominaga, Makoto; Ohta, Toshio

    2014-11-14

    The transient receptor potential ankyrin 1 (TRPA1) is a Ca(2+)-permeable, nonselective cation channel mainly expressed in a subset of nociceptive neurons. TRPA1 functions as a cellular sensor detecting mechanical, chemical, and thermal stimuli. Because TRPA1 is considered to be a key player in nociception and inflammatory pain, TRPA1 antagonists have been developed as analgesic agents. Recently, by utilizing species differences, we identified the molecular basis of the antagonistic action of A967079, one of the most potent mammalian TRPA1 antagonists. Here, we show a unique effect of A967079 on TRPA1 from diverse vertebrate species, i.e. it acts as an agonist but not as an antagonist for chicken and frog TRPA1s. By characterizing chimeric channels of human and chicken TRPA1s, as well as point mutants, we found that a single specific amino acid residue located within the putative fifth transmembrane domain was involved in not only the stimulatory but also the inhibitory actions of A967079. AP18, structurally related to A967079, exerted similar pharmacological properties to A967079. Our findings and previous reports on species differences in the sensitivity to TRPA1 antagonists supply useful information in the search for novel analgesic medicines targeting TRPA1.

  14. Genistein promotes insulin action through adenosine monophosphate-activated protein kinase activation and p70 ribosomal protein S6 kinase 1 inhibition in the skeletal muscle of mice fed a high energy diet.

    PubMed

    Arunkumar, Elumalai; Anuradha, Carani Venkatraman

    2012-08-01

    Genistein (GEN), a soy isoflavone, exerts insulin-sensitizing actions in animals; however, the underlying mechanisms have not been determined. Because GEN is a known activator of adenosine monophosphate-activated protein kinase (AMPK), we hypothesize that GEN activates insulin signaling through AMPK activation. To test this hypothesis, a high fat-high fructose diet (HFFD)-fed mice model of insulin resistance was administered GEN, and the insulin signaling pathway proteins in the skeletal muscle were examined. Hyperglycemia and hyperinsulinemia observed in HFFD-fed mice were significantly lowered by GEN. GEN increased insulin-stimulated tyrosine phosphorylation of insulin receptor-β and insulin receptor substrate (IRS) 1 but down-regulated IRS-1 serine phosphorylation in the skeletal muscle of HFFD-fed mice. Furthermore, GEN treatment improved muscle IRS-1-associated phospatidylinositol-3 kinase expression, phosphorylation of Akt at Ser(473), and translocation of glucose transporter subtype 4. Phosphorylation of AMPK at Thr(172) and acetyl coenzyme A carboxylase (ACC) at Ser(79) was augmented, whereas phosphorylation of p70 ribosomal protein S6 kinase 1 at Thr(389) was significantly decreased after GEN treatment in the skeletal muscle of HFFD-fed mice. These results suggest that GEN might improve insulin action in the skeletal muscle by targeting AMPK.

  15. Immunoglobulin: production, mechanisms of action and formulations

    PubMed Central

    Novaretti, Marcia Cristina Zago; Dinardo, Carla Luana

    2011-01-01

    Human immunoglobulin (Ig) began to be applied in the clinical practice with the treatment of primary immunodeficiencies. Quickly, applications of Ig increased, as its anti-inflammatory and immunomodulatory functions were elucidated. Currently, Ig is the most commonly used blood product. Ig is obtained by processing plasma; methods, in particular, techniques to reduce plasma viral loads have been evolving over the years and include: pasteurization, solvent/ detergent treatment, caprylic acid treatment and nanofiltration. These methods contribute to increased safety and quality of blood products. The mechanisms of action of Ig not only involve the blockade of Fc receptors of phagocytes, but also control complement pathways, idiotype-anti-idiotype dimer formation, blockage of superantigen binding to T cells, inhibition of dendritic cells and stimulation of regulatory T cells (Tregs). There are several formulations of Ig available, each one with its own peculiar characteristics. In Brazil, there is stringent legislation regulating the quality of Ig. Only Ig products that completely fulfill the quality control criteria are released for use. These standards involve different tests from visual inspection to determination of anti-complementary activity. This paper will further review the history and current status of Ig, including its production and mechanisms of action. The formulations available in Brazil and also the criteria of quality control currently applied will be presented. PMID:23049343

  16. Inhibition of lung tumorigenesis by tea.

    PubMed

    Yang, Chung S; Liao, Jie; Yang, Guang-yu; Lu, Gary

    2005-01-01

    Tea and tea constituents have been shown by different investigators to inhibit lung tumorigenesis in different animal model systems. This includes lung tumorigenesis in A/J mice induced by 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK), N-nitrosodiethylamine, benzo[a]pyrene, N-nitrosomethylurea, or cisplatin. Inhibition of lung tumorigenesis has also been demonstrated in C3H mice treated with N-nitrosodiethylamine. In most of these experiments, reduction in tumor number and tumor size has been observed in the tea-treated group, and in some experiments, decreased tumor incidence has also been observed. The green tea constituent, epigallocatechin-3-gallate (EGCG), and the black tea constituent, theaflavins, have also been shown to be effective. Black tea preparations have been shown to reduce the incidence and number of spontaneously generated lung adenocarcinomas and rhabdomyosarcoma in A/J mice, as well as inhibit the progression of lung adenoma to adenocarcinoma. The mechanisms for the inhibitory action have not been well elucidated. It may be related to the antiproliferative, proapoptotic, and antiangiogenic activities of tea constituents that have been demonstrated in some experiments. These activities may be a result of the inhibition of key protein kinases involved in signal transduction and cell cycle regulation. Tea catechins, such as EGCG, have been suggested to be the effective components. However, a study suggests that caffeine is the key effective constituent for the inhibitory activity of lung tumorigenesis in Fisher 344 rats by black tea. In many of the experiments, tea consumption resulted in the reduction of body fat and body weight; these factors may also contribute to the inhibition of tumorigenesis.

  17. Infrared inhibition of embryonic hearts

    NASA Astrophysics Data System (ADS)

    Wang, Yves T.; Rollins, Andrew M.; Jenkins, Michael W.

    2016-06-01

    Infrared control is a new technique that uses pulsed infrared lasers to thermally alter electrical activity. Originally developed for nerves, we have applied this technology to embryonic hearts using a quail model, previously demonstrating infrared stimulation and, here, infrared inhibition. Infrared inhibition enables repeatable and reversible block, stopping cardiac contractions for several seconds. Normal beating resumes after the laser is turned off. The block can be spatially specific, affecting propagation on the ventricle or initiation on the atrium. Optical mapping showed that the block affects action potentials and not just calcium or contraction. Increased resting intracellular calcium was observed after a 30-s exposure to the inhibition laser, which likely resulted in reduced mechanical function. Further optimization of the laser illumination should reduce potential damage. Stopping cardiac contractions by disrupting electrical activity with infrared inhibition has the potential to be a powerful tool for studying the developing heart.

  18. Inhibition of aromatase and α-amylase by flavonoids and proanthocyanidins from Sorghum bicolor bran extracts.

    PubMed

    Hargrove, James L; Greenspan, Phillip; Hartle, Diane K; Dowd, Christopher

    2011-01-01

    We compared the ability of simple flavonoids and proanthocyanidins in Sorghum bicolor bran extracts to inhibit enzymes in vitro. In particular, aromatase is a target for breast cancer therapy, and inhibition of α-amylase can reduce the glycemic effect of dietary starches. Proanthocyanidin-rich sumac sorghum bran extract inhibited α-amylase at a lower concentration (50% inhibitory concentration [IC₅₀]=1.4 μg/mL) than did proanthocyanidin-free black sorghum bran extract (IC₅₀=11.4 μg/mL). Sumac sorghum bran extract inhibited aromatase activity more strongly than black sorghum bran extract (IC₅₀=12.1 μg/mL vs. 18.8 μg/mL, respectively). Bovine serum albumin (BSA), which binds proanthocyanidins, reduced inhibition by sumac but not black sorghum bran extract. When separated on Sephadex LH-20, sumac sorghum proanthocyanidins inhibited both enzymes but showed reduced inhibition with BSA. Flavonoids from either cultivar had higher IC₅₀ values than proanthocyanidins, and BSA had little effect on their inhibition. Proanthocyanidins and simple flavonoids in LH-20 fractions both inhibited aromatase with mixed kinetics and affected K(m) and V(max). The results show that potential health benefits of sorghum bran may include actions of monomeric flavanoids as well as proanthocyanidins.

  19. Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3K/AKT/Nrf-2-mediated heme oxygenase-1 expression.

    PubMed

    Seo, Seung-Hee; Jeong, Gil-Saeng

    2015-12-01

    Oxidative skin damage and skin inflammation play key roles in the pathogenesis of skin-related diseases. Fisetin is a naturally occurring flavonoid abundantly found in several vegetables and fruits. Fisetin has been shown to exert various positive biological effects, such as anti-cancer, anti-proliferative, neuroprotective and anti-oxidative effects. In this study, we investigate the skin protective effects and anti-inflammatory properties of fisetin in hydrogen peroxide- and TNF-α-challenged human keratinocyte HaCaT cells. When HaCaT cells were treated with non-cytotoxic concentrations of fisetin (1-20μM), heme oxygenase (HO)-1 mRNA and protein expression increased in a dose-dependent manner. Furthermore, fisetin dose-dependently increased cell viability and reduced ROS production in hydrogen peroxide-treated HaCaT cells. Fisetin also inhibited the production of NO, PGE2 IL-1β, IL-6, expression of iNOS and COX-2, and activation of NF-κB in HaCaT cells treated with TNF-α. Fisetin induced Nrf2 translocation to the nuclei. HO-1 siRNA transient transfection reversed the effects of fisetin on cytoprotection, ROS reduction, NO, PGE2, IL-1β, IL-6, and TNF-α production, and NF-κB DNA-binding activity. Moreover, fisetin increased Akt phosphorylation and a PI3K pathway inhibitor (LY294002) abolished fisetin-induced cytoprotection and NO inhibition. Taken together, these results provide evidence for a beneficial role of fisetin in skin therapy.

  20. Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase Enzyme Inhibition

    PubMed Central

    Hamza, May; Dionne, Raymond A.

    2009-01-01

    Non-opioid analgesics including both selective and non-selective cyclooxygenase (COX) inhibitors and acetaminophen are the most widely used treatments for pain. Inhibition of COX is thought to be largely responsible for both the therapeutic and adverse effects of this class of drugs. Accumulating evidence over the past two decades has demonstrated effects of non-opioids beyond the inhibition of COX and prostaglandin synthesis that might also explain their therapeutic and adverse effects. These include their interaction with endocannabinoids, nitric oxide, monoaminergic, and cholinergic systems. Moreover, the recent development of microarray technology that allows the study of human gene expression suggests multiple pathways that may be related to the analgesic and anti-inflammatory effects of non-opioids. The present review will discuss the multiple actions of non-opioids and their interactions with these systems during inflammation and pain, suggesting that COX inhibition is an incomplete explanation for the actions of non-opioids and proposes the involvement of multiple selective targets for their analgesic, as well as, their adverse effects. PMID:19779578

  1. Action of Patulin on a Yeast

    PubMed Central

    Sumbu, Z. Lezi; Thonart, P.; Bechet, J.

    1983-01-01

    The action of patulin on Saccharomyces cerevisiae was studied. At weak doses, the drug inhibited growth, but inhibition was transient. After 10 min, syntheses of rRNA, tRNA, and probably mRNA were blocked; this was shown by radioactive precursor incorporation assays and gel electrophoresis of RNAs. After recovery of growth, patulin disappeared from the medium. It seemed that this degradation resulted from the activity of an inducible enzymatic system. Induced cells resisted very high patulin concentrations. PMID:6337546

  2. 24 CFR 81.46 - Remedial actions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... jurisdiction. The Secretary shall direct the GSE to take remedial action(s) against a lender charged with.... The Secretary shall direct the GSEs to take one or more remedial actions, including suspension, probation, reprimand or settlement, against lenders found to have engaged in discriminatory...

  3. Mechanism-based inhibition reveals transitions between two conformational states in the action of lysine 5,6-aminomutase: a combination of electron paramagnetic resonance spectroscopy, electron nuclear double resonance spectroscopy, and density functional theory study.

    PubMed

    Chen, Yung-Han; Maity, Amarendra N; Frey, Perry A; Ke, Shyue-Chu

    2013-01-16

    An "open"-state crystal structure of lysine 5,6-aminomutase suggests that transition to a hypothetical "closed"-state is required to bring the cofactors adenosylcobalamin (AdoCbl) and pyridoxal-5'-phosphate (PLP) and the substrate into proximity for the radical-mediated 1,2-amino group migration. This process is achieved by transaldimination of the PLP-Lys144β internal aldimine with the PLP-substrate external aldimine. A closed-state crystal structure is not available. UV-vis and electron paramagnetic resonance studies show that homologues of substrate D-lysine, 2,5-DAPn, 2,4-DAB, and 2,3-DAPr bind to PLP as an external aldimine and elicit the AdoCbl Co-C bond homolysis and the accumulations of cob(II)alamin and analogue-based radicals, demonstrating the existence of a closed state. (2)H- and (31)P-electron nuclear double resonance studies, supported by computations, show that the position for hydrogen atom abstraction from 2,5-DAPn and 2,4-DAB by the 5'-deoxyadenosyl radical occurs at the carbon adjacent to the imine, resulting in overstabilized radicals by spin delocalization through the imine into the pyridine ring of PLP. These radicals block the active site, inhibit the enzyme, and poise the enzyme into two distinct conformations: for even-numbered analogues, the cob(II)alamin remains proximal to and spin-coupled with the analogue-based radical in the closed state while odd-numbered analogues could trigger the transition to the open state of the enzyme. We provide here direct spectroscopic evidence that strongly support the existence of a closed state and its analogue-dependent transition to the open state, which is one step that was proposed to complete the catalytic turnover of the substrate lysine.

  4. Dynamic root exudation of sorgoleone and its in planta mechanism of action

    PubMed Central

    Dayan, Franck E.; Howell, J'Lynn; Weidenhamer, Jeffrey D.

    2009-01-01

    The oily droplets exuded from the root hairs of sorghum are composed of a 1:1 ratio of sorgoleone and its lipid resorcinol analogue. The production of these droplets appears to be suppressed when c. 20 μg of exudate mg−1 root dry weight accumulates at the tip of the root hairs. However, more exudate is produced following gentle washing of the roots with water, suggesting that the biosynthesis of lipid benzoquinones and resorcinols is a dynamic process. Sorgoleone interferes with several molecular target sites, including photosynthetic electron transport, in in vitro assays. However, the in planta mechanism of action of sorgoleone remains controversial because it is not clear whether this lipid benzoquinone exuding from the roots of sorghum is taken up by roots of the receiving plants and translocated to their foliage where it must enter the chloroplast and inhibit PSII in the thylakoid membrane. Experiments designed to test the in planta mode of action of sorgoleone demonstrated that it has no effect on the photosynthesis of older plants, but inhibits photosynthesis in germinating seedlings. Sorgoleone is not translocated acropetally in older plants, but can be absorbed through the hypocotyl and cotyledonary tissues. Therefore, the mode of action of sorgoleone may be the result of inhibition of photosynthesis in young seedlings in concert with inhibition of its other molecular target sites in older plants. PMID:19357432

  5. A possible action mechanism of HALS

    SciTech Connect

    Ohkatsu, Y.; Yamaguchi, K.

    1993-12-31

    The action mechanisms of HALS (hindered amine light stabilizers) proposed so far include several functions of HALS as radical scavenger, hydroperoxide decomposer, metal deactivator, etc., but don`t explain the photo-stabilizing action satisfactorily. The authors found that the action of HALS is demonstrated markably in the presence of phenolic antioxidants, and concluded that HALS work as hydrogen donor (reducing agent) and regenerate phenols from quinones derived from the phenolic antioxidants in which the quinone absorb and are activated by uv light. In this paper, a possible action mechanism of HALS including the photo-stabilizing action without any contradiction with functions reported will be presented on kinetic and spectroscopic studies.

  6. Dioscin inhibits colon tumor growth and tumor angiogenesis through regulating VEGFR2 and AKT/MAPK signaling pathways

    SciTech Connect

    Tong, Qingyi; Qing, Yong; Wu, Yang; Hu, Xiaojuan; Jiang, Lei; Wu, Xiaohua

    2014-12-01

    Dioscin has shown cytotoxicity against cancer cells, but its in vivo effects and the mechanisms have not elucidated yet. The purpose of the current study was to assess the antitumor effects and the molecular mechanisms of dioscin. We showed that dioscin could inhibit tumor growth in vivo and has no toxicity at the test condition. The growth suppression was accompanied by obvious blood vessel decrease within solid tumors. We also found dioscin treatment inhibited the proliferation of cancer and endothelial cell lines, and most sensitive to primary cultured human umbilical vein endothelial cells (HUVECs). What's more, analysis of HUVECs migration, invasion, and tube formation exhibited that dioscin has significantly inhibitive effects to these actions. Further analysis of blood vessel formation in the matrigel plugs indicated that dioscin could inhibit VEGF-induced blood vessel formation in vivo. We also identified that dioscin could suppress the downstream protein kinases of VEGFR2, including Src, FAK, AKT and Erk1/2, accompanied by the increase of phosphorylated P38MAPK. The results potently suggest that dioscin may be a potential anticancer drug, which efficiently inhibits angiogenesis induced by VEGFR2 signaling pathway as well as AKT/MAPK pathways. - Highlights: • Dioscin inhibits tumor growth in vivo and does not exhibit any toxicity. • Dioscin inhibits angiogenesis within solid tumors. • Dioscin inhibits the proliferation, migration, invasion, and tube formation of HUVECs. • Dioscin inhibits VEGF–induced blood vessel formation in vivo. • Dioscin inhibits VEGFR2 signaling pathway as well as AKT/MAPK pathway.

  7. Platform for Action: update.

    PubMed

    1995-01-01

    The Center for Women's Global Leadership (CWGL) has collaborated in the preparation of amendments and strategies designed to withstand the challenges being posed to the Platform for Action of the Fourth World Conference on Women. Specific challenges include the inappropriate use of the word "universal" to modify "human rights." This implies that some human rights are less than universal. The strategy proposed is to accept the use of the word "universal" in this context only when it affirms principles of universality contained in the Vienna Programme of Action and not where its use would restrict the rights to which women are entitled. A second concern is over the use of the word "equity" rather than "equality" when referring to gender relations. The use of these terms will be carefully monitored to insure that "equity" not be used to undermine the principle of gender equality. The third concern is the efforts of some governments to hinder the integration of women's human rights throughout the UN system. Such efforts will be opposed. Fourth, the CWGL will seek the inclusion of language which recognizes the barriers that different groups of women face when trying to secure their rights. Finally, the CWGL will propose inclusion of language recognizing and protecting sexual orientation rights. The CWGL is also going to work to translate the abstract language of the Platform for Action into political organizing potential to insure that governments will follow through on their agreements.

  8. Protective Action Guides (PAGs)

    EPA Pesticide Factsheets

    The Protective Action Guide (PAG) manual contains radiation dose guidelines that would trigger public safety measures. EPA developed Protective Action Guides to help responders plan for radiation emergencies.

  9. Enforcement actions: Significant actions resolved individuals actions. Semiannual progress report, July--December 1996

    SciTech Connect

    1997-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July - December 1996) and includes copies of Orders and Notices of Violation sent by the Nuclear Regulatory Commission to individuals with respect to-these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC. The Commission believes this information may be useful to licensees in making employment decisions.

  10. Enforcement actions: Significant actions resolved individual actions. Semiannual progress report, January 1997--June 1997

    SciTech Connect

    1997-09-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (January - June 1997) and includes copies of Orders and Notices of Violation sent by the Nuclear Regulatory Commission to individuals with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC. The Commission believes this information may be useful to licensees in making employment decisions.

  11. A Model of Motor Inhibition for a Complex Skill: Baseball Batting

    ERIC Educational Resources Information Center

    Gray, Rob

    2009-01-01

    The ability to inhibit an ongoing action in response to a signal from the environment is important for many perceptual-motor actions. This paper examines a particular example of this behavior: attempting to inhibit or "check" a swing in baseball batting. A model of motor inhibition in batting is proposed. In the model there are three different…

  12. Multiple Modes of Ryanodine Receptor 2 Inhibition by Flecainide

    PubMed Central

    Mehra, D.; Imtiaz, M. S.; van Helden, D. F.; Knollmann, B. C.

    2014-01-01

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) causes sudden cardiac death due to mutations in cardiac ryanodine receptors (RyR2), calsequestrin, or calmodulin. Flecainide, a class I antiarrhythmic drug, inhibits Na+ and RyR2 channels and prevents CPVT. The purpose of this study is to identify inhibitory mechanisms of flecainide on RyR2. RyR2 were isolated from sheep heart, incorporated into lipid bilayers, and investigated by single-channel recording under various activating conditions, including the presence of cytoplasmic ATP (2 mM) and a range of cytoplasmic [Ca2+], [Mg2+], pH, and [caffeine]. Flecainide applied to either the cytoplasmic or luminal sides of the membrane inhibited RyR2 by two distinct modes: 1) a fast block consisting of brief substate and closed events with a mean duration of ∼1 ms, and 2) a slow block consisting of closed events with a mean duration of ∼1 second. Both inhibition modes were alleviated by increasing cytoplasmic pH from 7.4 to 9.5 but were unaffected by luminal pH. The slow block was potentiated in RyR2 channels that had relatively low open probability, whereas the fast block was unaffected by RyR2 activation. These results show that these two modes are independent mechanisms for RyR2 inhibition, both having a cytoplasmic site of action. The slow mode is a closed-channel block, whereas the fast mode blocks RyR2 in the open state. At diastolic cytoplasmic [Ca2+] (100 nM), flecainide possesses an additional inhibitory mechanism that reduces RyR2 burst duration. Hence, multiple modes of action underlie RyR2 inhibition by flecainide. PMID:25274603

  13. Exploitation of pleiotropic actions of statins by using tumour-targeted delivery systems.

    PubMed

    Licarete, Emilia; Sesarman, Alina; Banciu, Manuela

    2015-01-01

    Statins are drugs traditionally used to lower cholesterol levels in blood. At concentrations 100- to 500-fold higher than those needed for reaching cholesterol lowering activity, they have anti-tumour activity. This anti-tumour activity is based on statins pleiotropic effects derived from their ability to inhibit the mevalonate synthesis and include anti-proliferative, pro-apoptotic, anti-angiogenic, anti-inflammatory, anti-metastatic actions and modulatory effects on intra-tumour oxidative stress. Thus, in this review, we summarise the possible pleiotropic actions of statins involved in tumour growth inhibition. Since the administration of these high doses of statins is accompanied by severe side effects, targeted delivery of statins seems to be the appropriate strategy for efficient application of statins in oncology. Therefore, we also present an overview of the current status of targeted delivery systems for statins with possible utilisation in oncology.

  14. The mechanisms of action of nicotinamide and zinc in inflammatory skin disease.

    PubMed

    Fivenson, David P

    2006-01-01

    Nicotinamide (niacinamide), a physiologically active form of niacin (nicotinic acid), in combination with zinc is being assessed in clinical studies for the treatment of inflammatory skin diseases such as acne vulgaris and bullous pemphigoid. The basis for these investigations is the variety of potential mechanisms of action of nicotinamide and zinc, including an anti-inflammatory effect via inhibition of leukocyte chemotaxis, lysosomal enzyme release, lymphocytic transformation, mast cell degranulation, bacteriostatic effect against Propionibacterium acnes, inhibition of vasoactive amines, preservation of intracellular coenzyme homeostasis, and decreased sebum production. Other possible mechanisms involve suppression of vascular permeability and inflammatory cell accumulation, as well as protection against DNA damage. The goal of this paper is to review the pathophysiology of inflammatory skin diseases and discuss the role, mechanisms of action, and safety of nicotinamide and zinc as therapeutic options for these disorders.

  15. Caffeine's Vascular Mechanisms of Action

    PubMed Central

    Echeverri, Darío; Montes, Félix R.; Cabrera, Mariana; Galán, Angélica; Prieto, Angélica

    2010-01-01

    Caffeine is the most widely consumed stimulating substance in the world. It is found in coffee, tea, soft drinks, chocolate, and many medications. Caffeine is a xanthine with various effects and mechanisms of action in vascular tissue. In endothelial cells, it increases intracellular calcium stimulating the production of nitric oxide through the expression of the endothelial nitric oxide synthase enzyme. Nitric oxide is diffused to the vascular smooth muscle cell to produce vasodilation. In vascular smooth muscle cells its effect is predominantly a competitive inhibition of phosphodiesterase, producing an accumulation of cAMP and vasodilation. In addition, it blocks the adenosine receptors present in the vascular tissue to produce vasoconstriction. In this paper the main mechanisms of action of caffeine on the vascular tissue are described, in which it is shown that caffeine has some cardiovascular properties and effects which could be considered beneficial. PMID:21188209

  16. Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake

    PubMed Central

    McNelis, Joanne C.; Manolopoulos, Konstantinos N.; Gathercole, Laura L.; Bujalska, Iwona J.; Stewart, Paul M.; Tomlinson, Jeremy W.

    2013-01-01

    Glucocorticoids increase adipocyte proliferation and differentiation, a process underpinned by the local reactivation of inactive cortisone to active cortisol within adipocytes catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal sex steroid precursor dehydroepiandrosterone (DHEA) has been shown to inhibit 11β-HSD1 in murine adipocytes; however, rodent adrenals do not produce DHEA physiologically. Here, we aimed to determine the effects and underlying mechanisms of the potential antiglucocorticoid action of DHEA and its sulfate ester DHEAS in human preadipocytes. Utilizing a human subcutaneous preadipocyte cell line, Chub-S7, we examined the metabolism and effects of DHEA in human adipocytes, including adipocyte proliferation, differentiation, 11β-HSD1 expression, and activity and glucose uptake. DHEA, but not DHEAS, significantly inhibited preadipocyte proliferation via cell cycle arrest in the G1 phase independent of sex steroid and glucocorticoid receptor activation. 11β-HSD1 oxoreductase activity in differentiated adipocytes was inhibited by DHEA. DHEA coincubated with cortisone significantly inhibited preadipocyte differentiation, which was assessed by the expression of markers of early (LPL) and terminal (G3PDH) adipocyte differentiation. Coincubation with cortisol, negating the requirement for 11β-HSD1 oxoreductase activity, diminished the inhibitory effect of DHEA. Further consistent with glucocorticoid-opposing effects of DHEA, insulin-independent glucose uptake was significantly enhanced by DHEA treatment. DHEA increases basal glucose uptake and inhibits human preadipocyte proliferation and differentiation, thereby exerting an antiglucocorticoid action. DHEA inhibition of the amplification of glucocorticoid action mediated by 11β-HSD1 contributes to the inhibitory effect of DHEA on human preadipocyte differentiation. PMID:24022868

  17. Action Research: Rethinking Lewin.

    ERIC Educational Resources Information Center

    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)

  18. ACTION OF SYNTHETIC DETERGENTS ON THE METABOLISM OF BACTERIA.

    PubMed

    Baker, Z; Harrison, R W; Miller, B F

    1941-01-31

    A study of the effects of synthetic detergents and wetting agents on respiration and glycolysis of Gram-positive and Gram-negative microorganisms has led to the following conclusions. 1. All the cationic detergents studied are very effective inhibitors of bacterial metabolism at 1:3000 concentration, and several are equally active at 1:30,000. Few of the anionic detergents inhibit as effectively as the cationic compounds. 2. Gram-positive and Gram-negative microorganisms are equally sensitive to the action of the cationic detergents. On the other hand, all the anionic detergents included in our studies selectively inhibit the metabolism of Gram-positive microorganisms. 3. The inhibitory action of both types of detergents is influenced markedly by hydrogen ion concentration. Cationic detergents exhibit their maximum activity in the alkaline pH range, and the anionic, in the acid range. 4. Studies of homologous series of straight chain alkyl sulfates and sulfoacetates (C(8) to C(18)) demonstrate that maximum inhibition is exerted by the 12, 14, and 16 carbon compounds (lauryl, myristyl, and cetyl). 5. It has been observed that three lauryl esters of amino acids are powerful inhibitors of bacterial metabolism. To our knowledge, the effects on bacterial metabolism of such cationic detergents (without the quaternary ammonium structure) have not been studied previously. Our results demonstrate that other cationic detergents can exhibit an inhibitory activity comparable to quaternary ammonium compounds. 6. Certain detergents stimulate bacterial metabolism at concentrations lower than the inhibiting values. This effect has been found more frequently among the anionic detergents.

  19. Cholesterol Inhibits M-type K+ Channels via Protein Kinase C-dependent Phosphorylation in Sympathetic Neurons*

    PubMed Central

    Lee, Seul-Yi; Choi, Hyun-Kyung; Kim, Seong-Tae; Chung, Sungkwon; Park, Myoung Kyu; Cho, Jung-Hwa; Ho, Won-Kyung; Cho, Hana

    2010-01-01

    M-type (KCNQ) potassium channels play an important role in regulating the action potential firing in neurons. Here, we investigated the effect of cholesterol on M current in superior cervical ganglion (SCG) sympathetic neurons, using the patch clamp technique. M current was inhibited in a dose-dependent manner by cholesterol loading with a methyl-β-cyclodextrin-cholesterol complex. This effect was prevented when membrane cholesterol level was restored by including empty methyl-β-cyclodextrin in the pipette solution. Dialysis of cells with AMP-PNP instead of ATP prevented cholesterol action on M currents. Protein kinase C (PKC) inhibitor, calphostin C, abolished cholesterol-induced inhibition whereas the PKC activator, PDBu, mimicked the inhibition of M currents by cholesterol. The in vitro kinase assay showed that KCNQ2 subunits of M channel can be phosphorylated by PKC. A KCNQ2 mutant that is defective in phosphorylation by PKC failed to show current inhibition not only by PDBu but also by cholesterol. These results indicate that cholesterol-induced inhibition of M currents is mediated by PKC phosphorylation. The inhibition of M currents by PDBu and cholesterol was completely blocked by PIP2 loading, indicating that the decrease in PIP2-channel interaction underlies M channel inhibition by PKC-mediated phosphorylation. We conclude that cholesterol specifically regulates M currents in SCG neurons via PKC activation. PMID:20123983

  20. Effect of chlorpromazine on the smg GDS action.

    PubMed

    Kim, Y S; Kikuchi, A; Takai, Y

    1992-02-14

    A stimulatory GDP/GTP exchange protein for smg p21 (smg GDS) stimulated the binding of guanosine 5'-(3-0-thio) triphosphate (GTP gamma S) to smg p21B. Chlorpromazine (CPZ) inhibited the smg GDS action in a manner competitive with smg GDS and in a manner noncompetitive with smg p21B. In spite of the inhibitory effect of CPZ on the smg GDS action, it counteracted the inhibition of the smg GDS action by acidic phospholipids. These results suggest that CPZ interacts with smg p21B, smg GDS, or both, and thereby inhibits the smg GDS action, and that CPZ also interacts with the acidic phospholipids and thereby counteracts their inhibitory effect on the smg GDS action.

  1. Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

    NASA Astrophysics Data System (ADS)

    Brem, Jürgen; Cain, Ricky; Cahill, Samuel; McDonough, Michael A.; Clifton, Ian J.; Jiménez-Castellanos, Juan-Carlos; Avison, Matthew B.; Spencer, James; Fishwick, Colin W. G.; Schofield, Christopher J.

    2016-08-01

    β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as `transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs.

  2. Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

    PubMed Central

    Brem, Jürgen; Cain, Ricky; Cahill, Samuel; McDonough, Michael A.; Clifton, Ian J.; Jiménez-Castellanos, Juan-Carlos; Avison, Matthew B.; Spencer, James; Fishwick, Colin W. G.; Schofield, Christopher J.

    2016-01-01

    β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as ‘transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs. PMID:27499424

  3. Treatment for pulmonary hypertension including lung transplantation.

    PubMed

    Kusano, Kengo F

    2011-08-01

    Pulmonary hypertension (PH) is a progressive disease characterized by sustained elevation in pulmonary arterial pressure and increased pulmonary vascular resistance, leading to right-sided ventricular failure. The untreated median survival period is 2-3 years from the time of diagnosis, with the cause of death usually being right-sided ventricular failure. However, outcomes have dramatically changed in recent years because of great advances in medical management of PH, including early diagnosis and new drugs such as prostaglandins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Long-term continuous intravenous prostacyclin therapy has shown excellent results in patients with PH. More recently, a molecular-targeted agent, imatinib mesylate, that acts by specifically inhibiting a certain enzyme that is characteristic of a particular cancer cell, rather than nonspecifically inhibiting and killing all rapidly dividing cells, has also been shown to have a potential role in the treatment of PH. This drug has been shown to reduce both pulmonary arterial smooth muscle cell hypertrophy and hyperplasia in a variety of disease processes. We summarize here recent topics regarding PH and advances in treatments for PH, particularly pulmonary arterial hypertension, including lung transplantation.

  4. The Legendre transform of the Holst action

    NASA Astrophysics Data System (ADS)

    Gao, Caixia

    I start with a short introduction on 3+1 ADM form and the tetrad form of General Relativity, then I review the Legendre transform of the Einstein-Hilbert action and the Palatini action. The Holst action is a generalization of the Palatini action by including a topological term. I derive Ashtekar's connection form directly from this action by doing the Legendre transformation rather than by a canonical transformation in the usual phase space. This is done in both Remmanian signature with half-flat connection and Lorentz signature with general Barbero-Immirzi parameter.

  5. Numerical Tests of the Improved Fermilab Action

    SciTech Connect

    Detar, C.; Kronfeld, A.S.; Oktay, M.B.

    2010-11-01

    Recently, the Fermilab heavy-quark action was extended to include dimension-six and -seven operators in order to reduce the discretization errors. In this talk, we present results of the first numerical simulations with this action (the OK action), where we study the masses of the quarkonium and heavy-light systems. We calculate combinations of masses designed to test improvement and compare results obtained with the OK action to their counterparts obtained with the clover action. Our preliminary results show a clear improvement.

  6. Inferences about Action Engage Action Systems

    ERIC Educational Resources Information Center

    Taylor, Lawrence J.; Lev-Ari, Shiri; Zwaan, Rolf A.

    2008-01-01

    Verbal descriptions of actions activate compatible motor responses [Glenberg, A. M., & Kaschak, M. P. (2002). Grounding language in action. "Psychonomic Bulletin & Review, 9", 558-565]. Previous studies have found that the motor processes for manual rotation are engaged in a direction-specific manner when a verb disambiguates the direction of…

  7. Modulation of motor inhibition by subthalamic stimulation in obsessive-compulsive disorder

    PubMed Central

    Kibleur, A; Gras-Combe, G; Benis, D; Bastin, J; Bougerol, T; Chabardès, S; Polosan, M; David, O

    2016-01-01

    High-frequency deep brain stimulation of the subthalamic nucleus can be used to treat severe obsessive-compulsive disorders that are refractory to conventional treatments. The mechanisms of action of this approach possibly rely on the modulation of associative-limbic subcortical–cortical loops, but remain to be fully elucidated. Here in 12 patients, we report the effects of high-frequency stimulation of the subthalamic nucleus on behavior, and on electroencephalographic responses and inferred effective connectivity during motor inhibition processes involved in the stop signal task. First, we found that patients were faster to respond and had slower motor inhibition processes when stimulated. Second, the subthalamic stimulation modulated the amplitude and delayed inhibition-related electroencephalographic responses. The power of reconstructed cortical current densities decreased in the stimulation condition in a parietal–frontal network including cortical regions of the inhibition network such as the superior parts of the inferior frontal gyri and the dorsolateral prefrontal cortex. Finally, dynamic causal modeling revealed that the subthalamic stimulation was more likely to modulate efferent connections from the basal ganglia, modeled as a hidden source, to the cortex. The connection from the basal ganglia to the right inferior frontal gyrus was significantly decreased by subthalamic stimulation. Beyond motor inhibition, our study thus strongly suggests that the mechanisms of action of high-frequency subthalamic stimulation are not restricted to the subthalamic nucleus, but also involve the modulation of distributed subcortical–cortical networks. PMID:27754484

  8. Inhibition of rat platelet aggregation by Urtica dioica leaves extracts.

    PubMed

    El Haouari, Mohammed; Bnouham, Mohamed; Bendahou, Mourad; Aziz, Mohammed; Ziyyat, Abderrahim; Legssyer, Abdelkhaleq; Mekhfi, Hassane

    2006-07-01

    Platelet hyperactivity plays an important role in arterial thrombosis and atherosclerosis. The present study was undertaken to investigate the effects of different extracts of Urtica dioica leaves on platelet aggregation. Rat platelets were prepared and incubated in vitro with different concentrations of the tested extracts and aggregation was induced by different agonists including thrombin (0.5 U/mL), ADP (10 microm), epinephrine (100 microm) and collagen (5 mg/mL). The crude aqueous extract inhibited thrombin-induced platelet aggregation in a dose-dependent manner. At 1 mg/mL, the percent inhibition was 17.1 +/- 4.2%. Soxhlet extraction of the plant leaves with different successive solvents showed that the ethyl acetate extract exhibited the most antiaggregant effect with an inhibition of 76.8 +/- 6.1% at 1 mg/mL. Flavonoids isolated from the plant leaves, produced a strong inhibitory effect on thrombin-induced platelet aggregation with an IC(50) of 0.25 +/- 0.05 and 0.40 +/- 0.04 mg/mL for genins and heterosidic flavonoids, respectively. Flavonoids also markedly inhibited platelet aggregation induced by ADP, collagen and epinephrine. It is concluded that Urtica dioica has an antiplatelet action in which flavonoids are mainly implicated. These results support the traditional use of Urtica dioica in the treatment and/or prevention of cardiovascular disease.

  9. Presynaptic inhibition in the vertebrate spinal cord revisited.

    PubMed

    Rudomin, P; Schmidt, R F

    1999-11-01

    The present review examines the experimental evidence supporting the existence of central mechanisms able to modulate the synaptic effectiveness of sensory fibers ending in the spinal cord of vertebrates. The first section covers work on the mode of operation and the synaptic mechanisms of presynaptic inhibition, in particular of the presynaptic control involving axo-axonic synapses made by GABAergic interneurons with the terminal arborizations of the afferent fibers. This includes reviewing of the ionic mechanisms involved in the generation of primary afferent depolarization (PAD) by GABAergic synapses, the ultrastructural basis underlying the generation of PAD, the relationship between PAD and presynaptic inhibition, the conduction of action potentials in the terminal arborizations of the afferent fibers, and the modeling of the presynaptic inhibitory synapse. The second section of the review deals with the functional organization of presynaptic inhibition. This includes the segmental and descending presynaptic control of the synaptic effectiveness of group-I and group-II muscle afferents, the evidence dealing with the local character of PAD as well as the differential inhibition of PAD in selected collaterals of individual muscle-spindle afferents by cutaneous and descending inputs. This section also examines observations on the presynaptic modulation of large cutaneous afferents, including the modulation of the synaptic effectiveness of thin myelinated and unmyelinated cutaneous fibers and of visceral afferents, as well as the presynaptic control of the synaptic actions of interneurons and descending tract neurons. The third section deals with the changes in PAD occurring during sleep and fictive locomotion in higher vertebrates and with the changes of presynaptic inhibition in humans during the execution of a variety of voluntary movements. In the final section, we examine the non-synaptic presynaptic modulation of transmitter release, including the

  10. Competing mechanisms for mapping action-related categorical knowledge and observed actions.

    PubMed

    Candidi, Matteo; Vicario, Carmelo Mario; Abreu, Ana Maria; Aglioti, Salvatore Maria

    2010-12-01

    Responses to pictures of famous tennis and soccer athletes are slower when the responding effector is a hand or foot, respectively, indicating that visual recognition of individuals characterized by skilled motor behavior interferes with the motor reactivity of nonproficient observers. By contrast, directly viewing actions induces motor facilitation, suggesting that actions are mapped in the observers' motor system. Here, we used single-pulse Transcranial Magnetic Stimulation to determine 1) whether observing and recognizing the identity of famous tennis and soccer athletes selectively reduce the corticospinal excitability of arm and leg representations (categorization), 2) whether any athlete-related inhibition effect contrasts the facilitation associated with direct action observation (categorization + action), and 3) whether the classic action observation-related facilitation effect is found when viewing "in action" nonathlete models (action). In 3 experiments, we found that amplitude of motor evoked potentials (MEPs) recorded from leg and arm muscles gradually shifted from reduction to facilitation, moving from the categorization to the action observation tasks. Thus, semantic derivation of motor skills is reflected in limb-specific reduction of MEP amplitude, indicating that even abstract action knowledge is embodied in the motor system and that mapping others' actions on the basis of categorization or of their direct observation relies on competing functional mechanisms.

  11. The grapevine polygalacturonase-inhibiting protein (VvPGIP1) reduces Botrytis cinerea susceptibility in transgenic tobacco and differentially inhibits fungal polygalacturonases.

    PubMed

    Joubert, Dirk A; Slaughter, Ana R; Kemp, Gabré; Becker, John V W; Krooshof, Geja H; Bergmann, Carl; Benen, Jacques; Pretorius, Isak S; Vivier, Melané A

    2006-12-01

    Polygalacturonase-inhibiting proteins (PGIPs) selectively inhibit polygalacturonases (PGs) secreted by invading plant pathogenic fungi. PGIPs display differential inhibition towards PGs from different fungi, also towards different isoforms of PGs originating from a specific pathogen. Recently, a PGIP-encoding gene from Vitis vinifera (Vvpgip1) was isolated and characterised. PGIP purified from grapevine was shown to inhibit crude polygalacturonase extracts from Botrytis cinerea, but this inhibitory activity has not yet been linked conclusively to the activity of the Vvpgip1 gene product. Here we use a transgenic over-expression approach to show that the PGIP encoded by the Vvpgip1 gene is active against PGs of B. cinerea and that over-expression of this gene in transgenic tobacco confers a reduced susceptibility to infection by this pathogen. A calculated reduction in disease susceptibility of 47-69% was observed for a homogeneous group of transgenic lines that was statistically clearly separated from untransformed control plants following infection with Botrytis over a 15-day-period. VvPGIP1 was subsequently purified from transgenic tobacco and used to study the specific inhibition profile of individual PGs from Botrytis and Aspergillus. The heterologously expressed and purified VvPGIP1 selectively inhibited PGs from both A. niger and B. cinerea, including BcPG1, a PG from B. cinerea that has previously been shown to be essential for virulence and symptom development. Altogether our data confirm the antifungal nature of the VvPGIP1, and the in vitro inhibition data suggest at least in part, that the VvPGIP1 contributed to the observed reduction in disease symptoms by inhibiting the macerating action of certain Botrytis PGs in planta. The ability to correlate inhibition profiles to individual PGs provides a more comprehensive analysis of PGIPs as antifungal genes with biotechnological potential, and adds to our understanding of the importance of PGIP

  12. TAS-102, a novel antitumor agent: a review of the mechanism of action.

    PubMed

    Lenz, Heinz-Josef; Stintzing, Sebastian; Loupakis, Fotios

    2015-11-01

    Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5-FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.

  13. Ecology and Energy Action Pack.

    ERIC Educational Resources Information Center

    McDonald's Corp., Oak Brook, IL.

    One of five McDonald's Action Packs, these elementary school-level instructional materials are for use as an introduction to existing units of study, supplements to a textbook, or a source of special projects for environmental education. Contents include these six units: Make Your Own Ecology Mini-spinner, Let's Look at a Food Chain, Drip the…

  14. State Governance Action Report, 2007

    ERIC Educational Resources Information Center

    Association of Governing Boards of Universities and Colleges, 2007

    2007-01-01

    This paper presents the State Governance Action Report for 2007. Compiled in this report are state policy developments, including legislation, commissions, and studies, affecting the structure, responsibilities, and operations of public higher education governing boards and institutionally related foundations. Governance and governance-related…

  15. Set Goals & Select Actions

    EPA Pesticide Factsheets

    This phase of the Local Climate Action Framework will help users articulate the goals for their climate, energy, and sustainability programs, as well as to identify the actions that are most appropriate to help meet those goals.

  16. American Lead Action Memorandum

    EPA Pesticide Factsheets

    ACTION MEMORANDUM— Request for a Time-Critical Removal Action andExemption from the $2 Million and 12-Month Statutory Limits at the AmericanLead Site, Indianapolis, Marion County, Indiana (Site ID #B56J)

  17. 40 CFR 1508.18 - Major Federal action.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Major Federal action. 1508.18 Section 1508.18 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY TERMINOLOGY AND INDEX § 1508.18 Major Federal action. Major Federal action includes actions with effects that may be major and which...

  18. Action Research: An Approach for the Teachers in Higher Education

    ERIC Educational Resources Information Center

    Yasmeen, G.

    2008-01-01

    Introduction: Action Research is a formative study of progress commonly practiced by teachers in schools. Basically an action research is a spiral process that includes problem investigation, taking action & fact-finding about the result of action. It enables a teacher to adopt/craft most appropriate strategy within its own teaching…

  19. Action Research: An Approach for the Teachers in Higher Education

    ERIC Educational Resources Information Center

    Yasmeen, Ghazala

    2008-01-01

    Introduction: Action Research is a formative study of progress commonly practiced by teachers in schools. Basically an action research is a spiral process that includes problem investigation, taking action & fact-finding about the result of action. It enables a teacher to adopt/craft most appropriate strategy within its own teaching environment.…

  20. THE BACTERICIDAL ACTION OF SYNTHETIC DETERGENTS.

    PubMed

    Baker, Z; Harrison, R W; Miller, B F

    1941-11-30

    1. The bactericidal action of a number of anionic and cationic synthetic detergents on four Gram-positive and three Gram-negative bacteria has been investigated. 2. Cationic detergents, as a group, were found to exhibit marked bactericidal effects on Gram-positive microorganisms and somewhat less pronounced action on Gram-negative organisms. 3. The anionic detergents were germicidal only against the Gram-positive organisms, and they were considerably less effective than the cationic compounds. Of the anionic detergents, the most active one was an alkyl sulfate derived from a branched-chain, secondary alcohol. 4. Correlations between bactericidal action and inhibition of bacterial metabolism, and also between bactericidal action and chemical structure of the detergents are discussed.

  1. Testing fractional action cosmology

    NASA Astrophysics Data System (ADS)

    Shchigolev, V. K.

    2016-08-01

    The present work deals with a combined test of the so-called Fractional Action Cosmology (FAC) on the example of a specific model obtained by the author earlier. In this model, the effective cosmological term is proportional to the Hubble parameter squared through the so-called kinematic induction. The reason of studying this cosmological model could be explained by its ability to describe two periods of accelerated expansion, that is in agreement with the recent observations and the cosmological inflation paradigm. First of all, we put our model through the theoretical tests, which gives a general conception of the influence of the model parameters on its behavior. Then, we obtain some restrictions on the principal parameters of the model, including the fractional index, by means of the observational data. Finally, the cosmography parameters and the observational data compared to the theoretical predictions are presented both analytically and graphically.

  2. Taking action against violence.

    PubMed

    Kunz, K

    1996-05-01

    Significant increase in violent crimes in recent years forced Icelandic men to take action against violence. Television was seen as a major contributory factor in increasing violence. Surveys indicate that 10-15 years after television broadcasting commences in a particular society, the incidence of crime can be expected to double. While the majority of the individuals arrested for violent crimes are men, being male does not necessarily mean being violent. The Men's Committee of the Icelandic Equal Rights Council initiated a week-long information and education campaign under the theme "Men Against Violence". This campaign involved several events including an art exhibit, speeches on violence in families, treatment sought by those who are likely to resort to violence, booklet distribution among students in secondary schools, and a mass media campaign to raise public awareness on this pressing problem.

  3. Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities

    PubMed Central

    Tilakaratne, Aruni; Soory, Mena

    2014-01-01

    The non-antimicrobial properties of tetracyclines such as anti-inflammatory, proanabolic and anti-catabolic actions make them effective pharmaceuticals for the adjunctive management of chronic inflammatory diseases. An over-exuberant inflammatory response to an antigenic trigger in periodontitis and other chronic inflammatory diseases could contribute to an autoimmune element in disease progression. Their adjunctive use in managing periodontitis could have beneficial effects in curbing excessive inflammatory loading from commonly associated comorbidities such as CHD, DM and arthritis. Actions of tetracyclines and their derivatives include interactions with MMPs, tissue inhibitors of MMPs, growth factors and cytokines. They affect the sequence of inflammation with implications on immunomodulation, cell proliferation and angiogenesis; these actions enhance their scope, in treating a range of disease entities. Non-antimicrobial chemically modified tetracyclines (CMTs) sustain their diverse actions in organ systems which include anti-inflammatory, anti-apoptotic, anti-proteolytic actions, inhibition of angiogenesis and tumor metastasis. A spectrum of biological actions in dermatitis, periodontitis, atherosclerosis, diabetes, arthritis, inflammatory bowel disease, malignancy and prevention of bone resorption is particularly relevant to minocycline. Experimental models of ischemia indicate their specific beneficial effects. Parallel molecules with similar functions, improved Zn binding and solubility have been developed for reducing excessive MMP activity. Curbing excessive MMP activity is particularly relevant to periodontitis, and comorbidities addressed here, where specificity is paramount. Unique actions of tetracyclines in a milieu of excessive inflammatory stimuli make them effective therapeutic adjuncts in the management of chronic inflammatory disorders. These beneficial actions of tetracyclines are relevant to the adjunctive management of periodontitis subjects

  4. Putting Action in Perspective

    ERIC Educational Resources Information Center

    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…

  5. Conservation Action Handbook.

    ERIC Educational Resources Information Center

    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…

  6. Planning as Action Research

    ERIC Educational Resources Information Center

    de Gonzalez, Carmen Beatriz; Hernandez, Teresa; Kusch, Jim; Ryan, Charly

    2004-01-01

    Planning contains so much more than the written plan. Early in 2000, an invitation came from the Collaborative Action Research Network (CARN), to people experienced in action research who might want to help plan and present an action research event for elementary school science teachers in Venezuela, South America, in Autumn 2000. This article…

  7. Participatory Action Research.

    ERIC Educational Resources Information Center

    Walker, Martha Lentz

    1993-01-01

    Describes aspects of participatory action research and considers advantages of using participatory action research in research by disabilities and rehabilitation researchers. Notes that participatory action research can be built into any rehabilitation research design but that it rests upon the recognition of persons with disabilities as integral…

  8. Inhibition of Selenium Metabolism in the Oral Pathogen Treponema denticola▿

    PubMed Central

    Jackson-Rosario, Sarah; Self, William T.

    2009-01-01

    In this report we provide evidence that the antimicrobial action of stannous salts and a gold drug, auranofin, against Treponema denticola is mediated through inhibition of the metabolism of selenium for synthesis of selenoproteins. PMID:19363113

  9. Anti-Cancer Effect of Lambertianic Acid by Inhibiting the AR in LNCaP Cells

    PubMed Central

    Lee, Myoung-Sun; Lee, Seon-Ok; Kim, Sung-Hoon; Lee, Eun-Ok; Lee, Hyo-Jeong

    2016-01-01

    Lambertianic acid (LA) is known to have anti-allergic and antibacterial effects. However, the anticancer activities and mechanism of action of LA have not been investigated. Therefore, the anticancer effects and mechanism of LA are investigated in this study. LA decreased not only AR protein levels, but also cellular and secretory levels of PSA. Furthermore, LA inhibited nuclear translocation of the AR induced by mibolerone. LA suppressed cell proliferation by inducing G1 arrest, downregulating CDK4/6 and cyclin D1 and activating p53 and its downstream molecules, p21 and p27. LA induced apoptosis and the expression of related proteins, including cleaved caspase-9 and -3, c-PARP and BAX, and inhibited BCl-2. The role of AR in LA-induced apoptosis was assessed by using siRNA. Collectively, these findings suggest that LA exerts the anticancer effect by inhibiting AR and is a valuable therapeutic agent in prostate cancer treatment. PMID:27399684

  10. Botanical modulation of menopausal symptoms: Mechanisms of action?

    PubMed Central

    Hajirahimkhan, Atieh; Dietz, Birgit M.; Bolton, Judy L.

    2013-01-01

    Menopausal women suffer from a variety of symptoms, including hot flashes and night sweats which can affect quality of life. Although hormone therapy (HT) has been the treatment of choice for relieving these symptoms, HT has been associated with increased breast cancer risk leading many women to search for natural, efficacious, and safe alternatives such as botanical supplements. Data from clinical trials suggesting that botanicals have efficacy for menopausal symptom relief, have been controversial and several mechanisms of action have been proposed including estrogenic, progestogenic, and serotonergic pathways. Plant extracts with potential estrogenic activities include soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chasteberry. Botanicals with reported progestogenic activities are red clover, hops, yam, and chasteberry. Serotonergic mechanisms have also been proposed since women taking antidepressants often report reduction in hot flashes and night sweats. Black cohosh, kudzu, kava, licorice, and dong quai all either have reported 5-HT7 ligands or inhibit serotonin re-uptake, therefore have potential serotonergic activities. Understanding the mechanisms of action of these natural remedies used for women’s health, could lead to more efficacious formulations and to the isolation of active components which have the potential of becoming effective medications in the future. PMID:23408273

  11. The functional neuroanatomy of actions.

    PubMed

    Watson, Christine E; Chatterjee, Anjan

    2011-04-19

    Our current understanding of the neural basis of semantic memory is informed primarily by studies of concrete objects. However, conceptual knowledge encompasses many other, albeit less concrete, domains. This article reviews evidence from neuroimaging and patient studies that speaks to the neural basis of action concepts and the words that refer to them. These data highlight 2 important principles governing the neural instantiation of semantic knowledge. First, the organization of conceptual representations in the brain parallels perception and action. Action concepts are at least partially represented within modality-specific areas responsible for the perception and execution of dynamic actions. Second, unimodal sensory and motor cortices act as "points of entry" for more abstract action knowledge. Increasingly abstract conceptual knowledge derived from these modalities is represented in brain areas located anterior and centripetal to modality-specific regions. Extending research on the neural basis of semantics to include dynamic and relational aspects of the world gives us a more complete appreciation of the range of cognitive and communication impairments that may be experienced by patients with neurologic disease.

  12. Terbinafine inhibits gap junctional intercellular communication.

    PubMed

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca(2+) concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action.

  13. Classification of Drugs Based on Properties of Sodium Channel Inhibition: A Comparative Automated Patch-Clamp Study

    PubMed Central

    Lenkey, Nora; Karoly, Robert; Lukacs, Peter; Vizi, E. Sylvester; Sunesen, Morten; Fodor, Laszlo; Mike, Arpad

    2010-01-01

    Background There is only one established drug binding site on sodium channels. However, drug binding of sodium channels shows extreme promiscuity: ∼25% of investigated drugs have been found to potently inhibit sodium channels. The structural diversity of these molecules suggests that they may not share the binding site, and/or the mode of action. Our goal was to attempt classification of sodium channel inhibitors by measuring multiple properties of inhibition in electrophysiology experiments. We also aimed to investigate if different properties of inhibition correlate with specific chemical properties of the compounds. Methodology/Principal Findings A comparative electrophysiological study of 35 compounds, including classic sodium channel inhibitors (anticonvulsants, antiarrhythmics and local anesthetics), as well as antidepressants, antipsychotics and neuroprotective agents, was carried out using rNav1.2 expressing HEK-293 cells and the QPatch automatic patch-clamp instrument. In the multi-dimensional space defined by the eight properties of inhibition (resting and inactivated affinity, potency, reversibility, time constants of onset and offset, use-dependence and state-dependence), at least three distinct types of inhibition could be identified; these probably reflect distinct modes of action. The compounds were clustered similarly in the multi-dimensional space defined by relevant chemical properties, including measures of lipophilicity, aromaticity, molecular size, polarity and electric charge. Drugs of the same therapeutic indication typically belonged to the same type. We identified chemical properties, which were important in determining specific properties of inhibition. State-dependence correlated with lipophilicity, the ratio of the neutral form of molecules, and aromaticity: We noticed that the highly state dependent inhibitors had at least two aromatic rings, logP>4.0, and pKa<8.0. Conclusions/Significance The correlations of inhibition properties

  14. Gathering Strength: Canada's Aboriginal Action Plan.

    ERIC Educational Resources Information Center

    Department of Indian Affairs and Northern Development, Ottawa (Ontario).

    Designed to renew the relationship between the Canadian government and the Aboriginal peoples of Canada, this action plan contains a statement of reconciliation, a statement of renewal, and four key objectives for action. First, renewing partnerships includes community-based healing to address the negative effects of the residential schools…

  15. 33 CFR 326.5 - Legal action.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... recommend criminal or civil actions to obtain penalties for violations, compliance with the orders and... for criminal or civil action include, but are not limited to, violations which, in the district... directly to the U.S. Attorney. Because of the unique legal system in the Trust Territories, all cases...

  16. 33 CFR 326.5 - Legal action.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... recommend criminal or civil actions to obtain penalties for violations, compliance with the orders and... for criminal or civil action include, but are not limited to, violations which, in the district... directly to the U.S. Attorney. Because of the unique legal system in the Trust Territories, all cases...

  17. Sympathetic actions on the skeletal muscle.

    PubMed

    Roatta, Silvestro; Farina, Dario

    2010-01-01

    The sympathetic nervous system (SNS) modulates several functions in skeletal muscle fibers, including metabolism, ionic transport across the membrane, and contractility. These actions, together with the sympathetic control of other organ systems, support intense motor activity. However, some SNS actions on skeletal muscles may not always be functionally advantageous. Implications for motor control and sport performance are discussed.

  18. 76 FR 80846 - Definition of Enforcement Action

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-27

    ... National Indian Gaming Commission 25 CFR Part 502 RIN 3141-AA43 Definition of Enforcement Action AGENCY... proposes to amend NIGC regulations to include definitions for ``enforcement action''. The Indian Gaming... regulations, and tribal gaming ordinances. However, current NIGC regulations do not provide a definition...

  19. 24 CFR 91.420 - Action plan.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... CONSOLIDATED SUBMISSIONS FOR COMMUNITY PLANNING AND DEVELOPMENT PROGRAMS Consortia; Contents of Consolidated Plan § 91.420 Action plan. (a) Form application. The action plan for the consortium must include a Standard Form 424 for the consortium for the HOME program. Each entitlement jurisdiction also must submit...

  20. 10 CFR 2.1331 - Commission action.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Commission action. 2.1331 Section 2.1331 Energy NUCLEAR... for Hearings on License Transfer Applications § 2.1331 Commission action. (a) Upon completion of a hearing, the Commission will issue a written opinion including its decision on the license...

  1. 33 CFR 326.5 - Legal action.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... recommend criminal or civil actions to obtain penalties for violations, compliance with the orders and... for criminal or civil action include, but are not limited to, violations which, in the district... contains an analysis of the information obtained during his investigation of the violation or during...

  2. Antiviral Actions of Interferons

    PubMed Central

    Samuel, Charles E.

    2001-01-01

    Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2′,5′-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2′-5′-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-α, IFN-β, and IFN-γ, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2′,5′-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system

  3. Antianginal Actions of Beta-Adrenoceptor Antagonists

    PubMed Central

    2007-01-01

    Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of β-adrenoceptor antagonists as it relates to the treatment of angina. The β-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the binding of endogenous catecholamines to β1-adrenoceptors in the heart. Their anti-ischemic effects are due primarily to a reduction in myocardial oxygen demand. By decreasing heart rate, myocardial contractility and afterload, β-adrenoceptor antagonists reduce myocardial workload and oxygen consumption at rest as well as during periods of exertion or stress. Predictable adverse effects include bradycardia and cardiac depression, both of which are a direct result of the blockade of cardiac β1-adrenoceptors, but adverse effects related to the central nervous system (eg, lethargy, sleep disturbances, and depression) may also be bothersome to some patients. Beta-adrenoceptor antagonists must be used cautiously in patients with diabetes mellitus, peripheral vascular disease, heart failure, and asthma or other obstructive airway diseases. Beta-adrenoceptor antagonists may be used in combination with nitrates or calcium channel blockers, which takes advantage of the diverse mechanisms of action of drugs from each pharmacologic category. Moreover, concurrent use of β-adrenoceptor antagonists may alleviate the reflex tachycardia that sometimes occurs with other antianginal agents. PMID:17998992

  4. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  5. Actions and mode of actions of FGF19 subfamily members.

    PubMed

    Fukumoto, Seiji

    2008-03-01

    Fibroblast growth factors (FGFs) are humoral factors with diverse biological functions. While most FGFs were shown to work as local factors regulating cell growth and differentiation, recent investigations indicated that FGF19 subfamily members, FGF15/19, FGF21 and FGF23 work as systemic factors. FGF15/19 produced by intestine inhibits bile acid synthesis and FGF21from liver is involved in carbohydrate and lipid metabolism. In addition, FGF23 was shown to be produced by bone and regulate phosphate and vitamin D metabolism. Furthermore, these FGFs require klotho or betaklotho for their actions in addition to canonical FGF receptors. It is possible that these FGFs together with their receptor systems might be targets for novel therapeutic measures in the future.

  6. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes

    PubMed Central

    Nagaishi, Kanna; Mizue, Yuka; Chikenji, Takako; Otani, Miho; Nakano, Masako; Konari, Naoto; Fujimiya, Mineko

    2016-01-01

    Bone marrow-derived mesenchymal stem cells (MSCs) have contributed to the improvement of diabetic nephropathy (DN); however, the actual mediator of this effect and its role has not been characterized thoroughly. We investigated the effects of MSC therapy on DN, focusing on the paracrine effect of renal trophic factors, including exosomes secreted by MSCs. MSCs and MSC-conditioned medium (MSC-CM) as renal trophic factors were administered in parallel to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. Both therapies showed approximately equivalent curative effects, as each inhibited the exacerbation of albuminuria. They also suppressed the excessive infiltration of BMDCs into the kidney by regulating the expression of the adhesion molecule ICAM-1. Proinflammatory cytokine expression (e.g., TNF-α) and fibrosis in tubular interstitium were inhibited. TGF-β1 expression was down-regulated and tight junction protein expression (e.g., ZO-1) was maintained, which sequentially suppressed the epithelial-to-mesenchymal transition of tubular epithelial cells (TECs). Exosomes purified from MSC-CM exerted an anti-apoptotic effect and protected tight junction structure in TECs. The increase of glomerular mesangium substrate was inhibited in HFD-diabetic mice. MSC therapy is a promising tool to prevent DN via the paracrine effect of renal trophic factors including exosomes due to its multifactorial action. PMID:27721418

  7. Synaptic transmission: inhibition of neurotransmitter release by botulinum toxins.

    PubMed

    Dolly, Oliver

    2003-01-01

    Botulinum toxin type A, a protein long used in the successful treatment of various dystonias, has a complex mechanism of action that results in muscle relaxation. At the neuromuscular junction, the presynaptic nerve ending is packed with synaptic vesicles filled with acetylcholine, and clustered at the tip of the folds of the postsynaptic muscle membrane are the acetylcholine receptors. Synaptic vesicles fuse with the membrane in response to an elevation of intraneuronal calcium concentration and undergo release of their transmitter by exocytosis. Intracellular proteins that contribute to the fusion of the vesicles with the plasma membrane during exocytosis include synaptosomal protein with a molecular weight of 25 kDa (SNAP-25); vesicle-associated membrane protein (VAMP), also known as synaptobrevin; and syntaxin. Through their proteolytic action on these proteins, botulinum toxins prevent exocytosis, thereby inhibiting the release of acetylcholine. There are 7 serotypes of this toxin-A, B, C1, D, E, F, and G-and each cleaves a different intracellular protein or the same target at distinct bonds. The separate cleavage sites in SNAP-25 for botulinum toxin types A and E contribute to their dissimilar durations of muscle relaxation. This report describes the molecular basis for the inhibition by botulinum toxins of neuroexocytosis and subsequent functional recovery at the neuromuscular junction.

  8. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance.

    PubMed

    Ghannoum, M A; Rice, L B

    1999-10-01

    The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

  9. The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein.

    PubMed

    Balasubramanian, Sujata; Fan, Meiyun; Messmer-Blust, Angela F; Yang, Chuan H; Trendel, Jill A; Jeyaratnam, Jonathan A; Pfeffer, Lawrence M; Vestal, Deborah J

    2011-06-03

    Matrix metalloproteinase-9 (MMP-9) is important in numerous normal and pathological processes, including the angiogenic switch during tumor development and tumor metastasis. Whereas TNF-α and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-γ treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-α-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription. The NF-κB transcription factor is required for full induction of MMP-9 by TNF-α. Both IFN-γ and mGBP-2 inhibit the transcription of a NF-κB-dependent reporter construct, suggesting that mGBP-2 inhibits MMP-9 induction via inhibition of NF-κB-mediated transcription. Interestingly, mGBP-2 does not inhibit TNF-α-induced degradation of IκBα or p65/RelA translocation into the nucleus. However, mGBP-2 inhibits p65 binding to a κB oligonucleotide probe in gel shift assays and to the MMP-9 promoter in chromatin immunoprecipitation assays. In addition, TNF-α activation of NF-κB in NIH 3T3 cells is dependent on Rac activation, as evidenced by the inhibition of TNF-α induction of NF-κB-mediated transcription by a dominant inhibitory form of Rac1. A role for Rac in the inhibitory action of mGBP-2 on NF-κB is further shown by the findings that mGBP-2 inhibits TNF-α activation of endogenous Rac and constitutively activate Rac can restore NF-κB transcription in the presence of mGBP-2. This is a novel mechanism by which IFNs can inhibit the cytokine induction of MMP-9 expression.

  10. National Biofuels Action Plan

    DTIC Science & Technology

    2008-10-01

    Leading the Federal Interagency Biomass Research and Development Initiative October 2008 National Biofuels Action Plan Biomass Research and...REPORT DATE OCT 2008 2. REPORT TYPE 3. DATES COVERED 00-00-2008 to 00-00-2008 4. TITLE AND SUBTITLE National Biofuels Action Plan 5a. CONTRACT...goal of the National Biofuels Action Plan is to maximize the environmental and economic benefi ts of biofuels use by advancing sustainable practices

  11. Stereoscopically Observing Manipulative Actions

    PubMed Central

    Ferri, S.; Pauwels, K.; Rizzolatti, G.; Orban, G. A.

    2016-01-01

    The purpose of this study was to investigate the contribution of stereopsis to the processing of observed manipulative actions. To this end, we first combined the factors “stimulus type” (action, static control, and dynamic control), “stereopsis” (present, absent) and “viewpoint” (frontal, lateral) into a single design. Four sites in premotor, retro-insular (2) and parietal cortex operated specifically when actions were viewed stereoscopically and frontally. A second experiment clarified that the stereo-action-specific regions were driven by actions moving out of the frontoparallel plane, an effect amplified by frontal viewing in premotor cortex. Analysis of single voxels and their discriminatory power showed that the representation of action in the stereo-action-specific areas was more accurate when stereopsis was active. Further analyses showed that the 4 stereo-action-specific sites form a closed network converging onto the premotor node, which connects to parietal and occipitotemporal regions outside the network. Several of the specific sites are known to process vestibular signals, suggesting that the network combines observed actions in peripersonal space with gravitational signals. These findings have wider implications for the function of premotor cortex and the role of stereopsis in human behavior. PMID:27252350

  12. Action principles in nature

    NASA Astrophysics Data System (ADS)

    Barrow, John D.; Tipler, Frank J.

    1988-01-01

    Physical theories have their most fundamental expression as action integrals. This suggests that the total action of the universe is the most fundamental physical quantity, and hence finite. In this article it is argued that finite universal action implies that the universe is spatially closed. Further, the possible spatial topologies, the types of matter that can dominate the early universe dynamics, and the form of any quadratic additions to the lagrangian of general relativity are constrained. Initial and final cosmological curvature singularities are required to avoid a universal action singularity.

  13. Autophagy contributes to gefitinib-induced glioma cell growth inhibition

    SciTech Connect

    Chang, Cheng-Yi; Kuan, Yu-Hsiang; Ou, Yen-Chuan; Li, Jian-Ri; Wu, Chih-Cheng; Pan, Pin-Ho; Chen, Wen-Ying; Huang, Hsuan-Yi; Chen, Chun-Jung

    2014-09-10

    Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.

  14. Deriving motor primitives through action segmentation.

    PubMed

    Hemeren, Paul E; Thill, Serge

    2010-01-01

    The purpose of the present experiment is to further understand the effect of levels of processing (top-down vs. bottom-up) on the perception of movement kinematics and primitives for grasping actions in order to gain insight into possible primitives used by the mirror system. In the present study, we investigated the potential of identifying such primitives using an action segmentation task. Specifically, we investigated whether or not segmentation was driven primarily by the kinematics of the action, as opposed to high-level top-down information about the action and the object used in the action. Participants in the experiment were shown 12 point-light movies of object-centered hand/arm actions that were either presented in their canonical orientation together with the object in question (top-down condition) or upside down (inverted) without information about the object (bottom-up condition). The results show that (1) despite impaired high-level action recognition for the inverted actions participants were able to reliably segment the actions according to lower-level kinematic variables, (2) segmentation behavior in both groups was significantly related to the kinematic variables of change in direction, velocity, and acceleration of the wrist (thumb and finger tips) for most of the included actions. This indicates that top-down activation of an action representation leads to similar segmentation behavior for hand/arm actions compared to bottom-up, or local, visual processing when performing a fairly unconstrained segmentation task. Motor primitives as parts of more complex actions may therefore be reliably derived through visual segmentation based on movement kinematics.

  15. [The mechanism of action of cannabis and cannabinoids].

    PubMed

    Scholten, W K

    2006-01-21

    The effect ofcannabis can be explained on the basis of the function of the cannabinoid receptor system, which consists of CB receptors (CB1, CB2), endoligands to activate these receptors and an enzyme--fatty acid amidohydrolase--to metabolize the endoligands. The endoligands of the cannabinoid receptor system are arachidonic acid-like substances, and are called endocannabinoids. Indications exist that the body also contains arachidonic acid-like substances that inhibit fatty acid amido hydrolase. Various cannabinoids have diverse effects on the receptors, functioning as agonists, antagonists or partial antagonists, as well as affecting the vanilloid receptor. Many known effects ofcannabis can be explained on the basis of this mechanism of action as can the use ofcannabis in various conditions including multiple sclerosis, Parkinson's disease, glaucoma, nausea, vomiting and rheumatoid arthritis.

  16. Symbolic Action in India: Gandhi's Nonverbal Persuasion

    ERIC Educational Resources Information Center

    Merriam, Allen H.

    1975-01-01

    Examines symbolic action as a method of exerting public influence nonverbally through nonviolent behavior. Discusses Gandhi's persuasive tactics including fasting, propaganda tours, silence, clothing and adoption of symbols. (MH)

  17. 34 CFR 200.42 - Corrective action.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... action; and (ii) Any underlying staffing, curriculum, or other problems in the school; (2) Is designed to... curriculum, including the provision of appropriate professional development for all relevant staff, that—...

  18. National Action Plan for Energy Efficiency Report

    EPA Pesticide Factsheets

    This seminal report includes the Action Plan recommendations, identifies key barriers, and summarizes methods for energy efficiency in utility ratemaking and revenue requirements, energy resource planning processes, rate design, and other best practices.

  19. Inhibition of Hageman factor activation

    PubMed Central

    Nossel, H. L.; Rubin, H.; Drillings, M.; Hsieh, R.

    1968-01-01

    A method for studying inhibitors of the contact stages of blood coagulation is described. A number of positively charged substances were shown to inhibit the contact stages. The inhibitory substances include spermine, cytochrome c, ribonuclease, and lysozyme. The inhibitory effect of these substances was neutralized by the addition of an activated plasma thromboplastin antecedent, factor XI, (PTA) fraction. Other positively charged substances including protamine, hexadimethrine, polylysine, polyornithine, methylene blue, and ortho-toluidine blue also inhibited the contact stages of coagulation, but the inhibitory effect on coagulation was not neutralized by the activated PTA fraction. Negatively charged substances such as heparin and insulin did not inhibit the contact stages of coagulation. Cytochrome c inhibited Celite adsorption of a partially purified Hageman factor fraction, and cytochrome, ribonuclease, spermine, and lysozome inhibited the adsorption of Hageman factor from PTA-deficient plasma. Very much smaller quantities of Celite completely adsorbed Hageman factor from the fraction rather than from whole plasma, which suggested the possibility that plasma contains an inhibitor or inhibitors of Hageman factor adsorption. Furthermore cytochrome c, spermine, ribonuclease, and lysozyme inhibited the coagulant activity of the following activators of the Hageman and PTA factors: Celite, kaolin, sodium stearate, ellagic acid, and skin. It is suggested that negatively charged sites on these activators are critical for adsorption and activation and that inhibition results from neutralization of the negatively charged sites by the adsorbed inhibtor. Tests with polylysine polymers indicate that inhibitory activity is directly related to molecular size over the molecular weight range of 4000 to 100,000. PMID:5645860

  20. Mechanism of action of niacin.

    PubMed

    Kamanna, Vaijinath S; Kashyap, Moti L

    2008-04-17

    Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines

  1. Luteolin, a flavonoid, inhibits AP-1 activation by basophils

    SciTech Connect

    Hirano, Toru; Higa, Shinji; Arimitsu, Junsuke; Naka, Tetsuji; Ogata, Atsushi; Shima, Yoshihito; Fujimoto, Minoru; Yamadori, Tomoki; Ohkawara, Tomoharu; Kuwabara, Yusuke; Kawai, Mari; Matsuda, Hisashi; Yoshikawa, Masayuki; Maezaki, Naoyoshi; Tanaka, Tetsuaki; Kawase, Ichiro; Tanaka, Toshio . E-mail: ttanak@imed3.med.osaka-u.ac.jp

    2006-02-03

    Flavonoids including luteolin, apigenin, and fisetin are inhibitors of IL-4 synthesis and CD40 ligand expression by basophils. This study was done to search for compounds with greater inhibitory activity of IL-4 expression and to clarify the molecular mechanisms through which flavonoids inhibit their expression. Of the 37 flavonoids and related compounds examined, ayanin, luteolin, and apigenin were the strongest inhibitors of IL-4 production by purified basophils in response to anti-IgE antibody plus IL-3. Luteolin did not suppress Syk or Lyn phosphorylation in basophils, nor did suppress p54/46 SAPK/JNK, p38 MAPK, and p44/42 MAPK activation by a basophilic cell line, KU812 cells, stimulated with A23187 and PMA. However, luteolin did inhibit phosphorylation of c-Jun and DNA binding activity of AP-1 in nuclear lysates from stimulated KU812 cells. These results provide a fundamental structure of flavonoids for IL-4 inhibition and demonstrate a novel action of flavonoids that suppresses the activation of AP-1.

  2. Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition.

    PubMed

    Dean, Afshan; Nilsen, Margaret; Loughlin, Lynn; Salt, Ian P; MacLean, Margaret R

    2016-08-01

    Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1 Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase.

  3. Action Learning in China

    ERIC Educational Resources Information Center

    Marquardt, Michael J.

    2015-01-01

    Action learning was introduced into China less than 20 years ago, but has rapidly become a valuable tool for organizations seeking to solve problems, develop their leaders, and become learning organizations. This article provides an historical overview of action learning in China, its cultural underpinnings, and five case studies. It concludes…

  4. Who Needs Affirmative Action.

    ERIC Educational Resources Information Center

    Ginger, Ann Fagan

    1979-01-01

    Affirmative action and reverse discrimination are discussed. Facts that were omitted from the court record on the Bakke case are examined. The need for encouraging minority students and women to continue to press for school admission and for lawyers to continue to press affirmative action suits is stressed. (MC)

  5. Renormalized action improvements

    SciTech Connect

    Zachos, C.

    1984-01-01

    Finite lattice spacing artifacts are suppressed on the renormalized actions. The renormalized action trajectories of SU(N) lattice gauge theories are considered from the standpoint of the Migdal-Kadanoff approximation. The minor renormalized trajectories which involve representations invariant under the center are discussed and quantified. 17 references.

  6. Training for Nonviolent Action.

    ERIC Educational Resources Information Center

    Olson, Theodore W.; Shivers, Lynne

    The theory and practice of nonviolent action training as it exists to date are reviewed in this pamphlet. A response to a renewal of interest in alternative forms of social action, the pamphlet results specifically from an international seminar of experienced organizers and trainers held at Preston Patrick, Westmorland, England, June 27 - July 2,…

  7. Affirmative Action Program Manual.

    ERIC Educational Resources Information Center

    Ventura County Community Coll. District, CA.

    Guidelines relating to the affirmative action program of the Ventura County Community College District are provided in this manual. Affirmative action is defined as, "A set of specific and result-oriented procedures to which a contractor commits himself/herself to apply every good faith effort. The objective of those procedures, plus such efforts,…

  8. Action Learning and Leadership.

    ERIC Educational Resources Information Center

    Marquardt, Michael J.

    2000-01-01

    Today's leaders perform the following roles: systems thinker, change agent, innovator, servant, polychronic coordinator, teacher-mentor, and visionary. The elements of action learning (real problems, teams, reflective inquiry, commitment to action, focus on learning) contribute to the development of these critical skills. (Author/SK)

  9. Handbook for Ecology Action.

    ERIC Educational Resources Information Center

    Eber, Ronald

    This handbook has been compiled to aid concerned individuals and ecology groups more adequately define their goals, initiate good programs, and take effective action. It examines the ways a group of working individuals can become involved in action programs for ecological change. Part 1 deals with organization, preliminary organizing, structuring,…

  10. Conscious Vision in Action.

    PubMed

    Briscoe, Robert; Schwenkler, John

    2015-09-01

    It is natural to assume that the fine-grained and highly accurate spatial information present in visual experience is often used to guide our bodily actions. Yet this assumption has been challenged by proponents of the Two Visual Systems Hypothesis (TVSH), according to which visuomotor programming is the responsibility of a "zombie" processing stream whose sources of bottom-up spatial information are entirely non-conscious (Clark, 2007, 2009; Goodale & Milner, 1992, 2004a; Milner & Goodale, 1995/2006, 2008). In many formulations of TVSH, the role of conscious vision in action is limited to "recognizing objects, selecting targets for action, and determining what kinds of action, broadly speaking, to perform" (Clark, 2007, p. 570). Our aim in this study is to show that the available evidence not only fails to support this dichotomous view but actually reveals a significant role for conscious vision in motor programming, especially for actions that require deliberate attention.

  11. Documents Pertaining to Resource Conservation and Recovery Act Corrective Action Event Codes

    EPA Pesticide Factsheets

    Document containing RCRA Corrective Action event codes and definitions, including national requirements, initiating sources, dates, and guidance, from the first facility assessment until the Corrective Action is terminated.

  12. Gravitational action with null boundaries

    NASA Astrophysics Data System (ADS)

    Lehner, Luis; Myers, Robert C.; Poisson, Eric; Sorkin, Rafael D.

    2016-10-01

    We present a complete discussion of the boundary term in the action functional of general relativity when the boundary includes null segments in addition to the more usual timelike and spacelike segments. We confirm that ambiguities appear in the contribution from a null segment, because it depends on an arbitrary choice of parametrization for the generators. We also show that similar ambiguities appear in the contribution from a codimension-two surface at which a null segment is joined to another (spacelike, timelike, or null) segment. The parametrization ambiguity can be tamed by insisting that the null generators be affinely parametrized; this forces each null contribution to the boundary action to vanish, but leaves intact the fredom to rescale the affine parameter by a constant factor on each generator. Once a choice of parametrization is made, the ambiguity in the joint contributions can be eliminated by formulating well-motivated rules that ensure the additivity of the gravitational action. Enforcing these rules, we calculate the time rate of change of the action when it is evaluated for a so-called "Wheeler-DeWitt patch" of a black hole in asymptotically anti de Sitter space. We recover a number of results cited in the literature, obtained with a less complete analysis.

  13. Nuclear facility decommissioning and site remedial actions

    SciTech Connect

    Knox, N.P.; Webb, J.R.; Ferguson, S.D.; Goins, L.F.; Owen, P.T.

    1990-09-01

    The 394 abstracted references on environmental restoration, nuclear facility decommissioning, uranium mill tailings management, and site remedial actions constitute the eleventh in a series of reports prepared annually for the US Department of Energy's Remedial Action Programs. Citations to foreign and domestic literature of all types -- technical reports, progress reports, journal articles, symposia proceedings, theses, books, patents, legislation, and research project descriptions -- have been included. The bibliography contains scientific, technical, economic, regulatory, and legal information pertinent to the US Department of Energy's Remedial Action Programs. Major sections are (1) Surplus Facilities Management Program, (2) Nuclear Facilities Decommissioning, (3) Formerly Utilized Sites Remedial Action Programs, (4) Facilities Contaminated with Naturally Occurring Radionuclides, (5) Uranium Mill Tailings Remedial Action Program, (6) Grand Junction Remedial Action Program, (7) Uranium Mill Tailings Management, (8) Technical Measurements Center, (9) Remedial Action Program, and (10) Environmental Restoration Program. Within these categories, references are arranged alphabetically by first author. Those references having no individual author are listed by corporate affiliation or by publication title. Indexes are provided for author, corporate affiliation, title word, publication description, geographic location, subject category, and keywords. This report is a product of the Remedial Action Program Information Center (RAPIC), which selects and analyzes information on remedial actions and relevant radioactive waste management technologies.

  14. Testosterone and dihydrotestosterone inhibit gallbladder motility through multiple signalling pathways.

    PubMed

    Kline, Loren W; Karpinski, Edward

    2008-10-01

    Testosterone (T) has been shown to cause vasodilation in rabbit coronary arteries through a nongenomic pathway. Part of this T-induced relaxation was shown to be mediated by opening voltage dependent K(+) channels. T infusion also reduces peripheral resistance in human males with heart failure. The effects of T or its active metabolite 5-alpha dihydrotestosterone (DHT) are not well studied. This study investigates the effect of T and DHT on contraction in guinea pig gallbladder strips. T or DHT induced a concentration-dependent relaxation of cholecystokinin octapeptide (CCK)-induced tension. Pretreatment of the strips with PKA inhibitor 14-22 amide myristolated had no significant effect on the relaxation induced by either T or DHT. Pretreatment of strips with 2-APB, an inhibitor of IP(3) induced Ca(2+) release, produced a significant (p<0.001) reduction in the T- or DHT-induced relaxation. Bisindolymaleimide IV and chelerythrine Cl(-) when used in combination had no significant effect on the amount of CCK-induced tension, but significantly (p<0.01) decreased the amount of T- or DHT-induced relaxation. The flavone chrysin, an aromatase inhibitor, and genistein, an isoflavone, each produced a significant (p<0.01) reduction in CCK-induced tension. Chrysin significantly (p<0.05) increased T-induced relaxation; however, genistein had no effect on T-induced relaxation. It is concluded that T and DHT inhibits gallbladder motility rapidly by nongenomic actions of the hormones. Multiple pathways that include inhibition of intracellular Ca(2+) release, inhibition of extracellular Ca(2+) entry, and the actions of PKC may mediate this effect.

  15. Structure-activity relationships and action mechanisms of collagen-like antimicrobial peptides.

    PubMed

    Masuda, Ryo; Dazai, Yui; Mima, Takehiko; Koide, Takaki

    2017-01-01

    An antimicrobial triple-helical peptide, R3, was previously obtained from a collagen-like combinatorial peptide library. In this research, based on structure-activity relationship studies of R3, a more potent peptide, RR4, with increased positive net charge and charge density relative to R3, was developed. RR4 exhibited antimicrobial activity against both Gram-negative and Gram-positive bacterial strains, including multidrug-resistant strains. Its action could be attributed to entry into cells and interactions with intercellular molecules such as DNA/RNA that inhibited cell division rather than increasing bacterial membrane permeability. Furthermore, RR4 exhibited remarkable stability in serum and low cytotoxicity.

  16. Topoisomerase I and II inhibitors: chemical structure, mechanisms of action and role in cancer chemotherapy

    NASA Astrophysics Data System (ADS)

    Dezhenkova, L. G.; Tsvetkov, V. B.; Shtil, A. A.

    2014-01-01

    The review summarizes and analyzes recent published data on topoisomerase I and II inhibitors as potential antitumour agents. Functions and the mechanism of action of topoisomerases are considered. The molecular mechanism of interactions between low-molecular-weight compounds and these proteins is discussed. Topoisomerase inhibitors belonging to different classes of chemical compounds are systematically covered. Assays for the inhibition of topoisomerases and the possibilities of using the computer-aided modelling for the rational design of novel drugs for cancer chemotherapy are presented. The bibliography includes 127 references.

  17. Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism.

    PubMed

    Shim, Joong Sup; Li, Ruo-Jing; Lv, Junfang; Head, Sarah A; Yang, Eun Ju; Liu, Jun O

    2015-06-28

    Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment.

  18. Perception-action in children with ASD

    PubMed Central

    von Hofsten, Claes; Rosander, Kerstin

    2012-01-01

    How do disturbances to perception and action relate to the deficiencies expressed by children with autism? The ability to predict what is going to happen next is crucial for the construction of all actions and children develop these predictive abilities early in development. Children with autism, however, are deficient in the ability to foresee future events and to plan movements and movement sequences. They are also deficient in the understanding of other people's actions. This includes communicative actions as they are ultimately based on movements. Today there are two promising neurobiological interpretation of Autism Spectrum Disorder (ASD). First, there is strong evidence that the Mirror Neuron System (MNS) is impaired. As stated by this hypothesis, action production and action understanding are intimately related. Both these functions rely on predictive models of the sensory consequences of actions and depend on connectivity between the parietal and premotor areas. Secondly, action prediction is accomplished through a system that includes a loop from the posterior parietal cortex (PPC) through the cerebellum and back to the premotor and motor areas of the brain. Impairment of this loop is probably also part of the explanation of the prediction problems in children with ASD. Both the cortico-cerebellar loop and the MNS rely on distant neural connections. There are multiple evidence that such connections are weak in children with autism. PMID:23248590

  19. Disorders of androgen action.

    PubMed

    Sultan, Charles; Lumbroso, Serge; Paris, Françoise; Jeandel, Claire; Terouanne, B; Belon, Charles; Audran, F; Poujol, N; Georget, V; Gobinet, J; Jalaguier, S; Auzou, G; Nicolas, J C

    2002-08-01

    Disorders of androgen action are the main cause of male pseudohermaphroditism and include 5alphaR deficiency and androgen receptor defects. 5alphaR deficiency is characterized by female genitalia with some degree of masculinization, clitoromegaly, and severely bifid scrotum corresponding to the so-called pseudovaginal perineoscrotal hypospadias. At the onset of puberty, increased muscle mass, development of pubic hair, and phallic growth are associated with the acquisition of male gender identity. Normal or increased levels of testosterone and an elevated testosterone-to-dihydrotestosterone ratio after human chorionic gonadotropin stimulation testing suggest 5alphareductase deficiency, and the diagnosis can be ascertained by identifying the mutation in the 5alphaR-2 gene. Whatever the patient's age at diagnosis, psychological evaluation with 5alphaRD is vital. Androgen receptor defects encompass two clinical expressions: the complete and partial androgen insensitivity syndromes. Complete androgen insensitivity syndrome should be suspected at birth in the presence of inguinal hernia in a girl without genital ambiguity. At puberty, the sign of alert is primary amenorrhea with normal female phenotype and harmonious mammary development but no pubic hair growth. Partial androgen insensitivity syndrome covers a wide spectrum of undervirilized phenotypes ranging from clitoromegaly at birth to infertile men. In all cases, complementary investigations should include plasma testosterone and luteinizing hormone as well as androgen-binding capacity in cultured genital skin fibroblasts. Diagnosis is confirmed by identification of the androgen receptor gene mutation. Although patients with complete androgen insensitivity syndrome are raised as females, patients with partial androgen insensitivity syndrome should be managed according to age at diagnosis, response to treatment with exogenous androgens, and the presence of an androgen gene mutation. Gonadectomy in complete androgen

  20. Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

    PubMed Central

    Lee, Tae-Sun; Lee, Joo-Young; Kyung, Jae Won; Yang, Yoosoo; Park, Seung Ju; Lee, Seulgi; Pavlovic, Igor; Kong, Byoungjae; Jho, Yong Seok; Jessen, Henning J.; Kweon, Dae-Hyuk; Shin, Yeon-Kyun; Kim, Sung Hyun; Yoon, Tae-Young; Kim, Seyun

    2016-01-01

    Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6. Synaptotagmin 1 (Syt1), a Ca2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7. Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6. In addition, 5-IP7–dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca2+ levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca2+. These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates. PMID:27364007

  1. Rimonabant: endocannabinoid inhibition for the metabolic syndrome.

    PubMed

    Wierzbicki, A S

    2006-12-01

    Rimonabant is the first drug to target the endocannabinoid (CB) pathway by inhibiting the actions of anandamide and 2-archidonyl-glycerol on CB1 receptors. This review gives an overview of rimonabant and the CB system and how this system relates to obesity. Rimonabant blocks the central effects of this neurotransmitter pathway involved in obesity and weight control and also blocks the direct effects of CBs on adipocyte and hepatocyte metabolism. Blockade of CB1 receptors leads to a decrease in appetite and also has direct actions in adipose tissue and the liver to improve glucose, fat and cholesterol metabolism so improving insulin resistance, triglycerides and high-density lipoprotein cholesterol (HDL-C) and in some patients, blood pressure. The Rimonabant in Obesity (RIO) trials have shown that rimonabant induces weight loss > 5% in 30-40% of patients and > 10% in 10-20% above both a dietary run-in and long-term hypocaloric management over a 2 year period with a low level of drug-related side effects. Rimonabant therapy is associated with an extra 8-10% increase in HDL-C and a 10-30% reduction in triglycerides and improvements in insulin resistance, glycaemic control in patients with diabetes and also adipokines and cytokines including C-reactive protein over hypocaloric diet therapy. In addition rimonabant abolishes the weight gain associated with smoking cessation and improves the chances of quitting smoking. Thus rimonabant has major effects on both the metabolic syndrome and cardiovascular risk factors thus has the potential to reduce the risks of type 2 diabetes and cardiovascular disease associated with the cardiometabolic phenotype.

  2. Enforcement actions: Significant actions resolved material licensees. Semiannual progress report, July--December 1996

    SciTech Connect

    1997-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to material licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication.

  3. Enforcement actions: Significant actions resolved; Quarterly progress report, October--December 1993: Volume 12, No. 4

    SciTech Connect

    1994-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October - December 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication.

  4. Inhibition of the renin-angiotensin system for lowering coronary artery disease risk.

    PubMed

    Sheppard, Richard J; Schiffrin, Ernesto L

    2013-04-01

    The renin-angiotensin system when activated exerts proliferative and pro-inflammatory actions and thereby contributes to progression of atherosclerosis, including that occurring in the coronary arteries. It thus contributes as well to coronary artery disease (CAD). Several clinical trials have examined effects of renin-angiotensin system inhibition for primary and secondary prevention of coronary heart disease. These include important trials such as HOPE, EUROPA and PEACE using angiotensin converting enzyme inhibitors, VALIANT, OPTIMAAL and TRANSCEND using angiotensin receptor blockers, and the ongoing TOPCAT study in patients with preserved ejection fraction heart failure, many of who also have coronary artery disease. Data are unavailable as yet of effects of either direct renin inhibitors or the new angiotensin receptor/neprilysin inhibitor agents. Today, inhibition of the renin-angiotensin system is standard-of-care therapy for lowering cardiovascular risk in secondary prevention in high cardiovascular risk subjects.

  5. Amiodarone Inhibits Apamin-Sensitive Potassium Currents

    PubMed Central

    Turker, Isik; Yu, Chih-Chieh; Chang, Po-Cheng; Chen, Zhenhui; Sohma, Yoshiro; Lin, Shien-Fong; Chen, Peng-Sheng; Ai, Tomohiko

    2013-01-01

    Background Apamin sensitive potassium current (IKAS), carried by the type 2 small conductance Ca2+-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. Objective To test the hypothesis that amiodarone inhibits IKAS in human embryonic kidney 293 (HEK-293) cells. Methods We used the patch-clamp technique to study IKAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. Results Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca2+). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca2+ (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of IKAS induced with 1 µM Ca2+ (n = 4), and 16.4±4.9% with 250 nM Ca2+ (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca2+ dependent inhibition of IKAS. Conclusion Both amiodarone and desethylamiodarone inhibit IKAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles. PMID:23922993

  6. Topological lattice actions

    NASA Astrophysics Data System (ADS)

    Bietenholz, W.; Gerber, U.; Pepe, M.; Wiese, U.-J.

    2010-12-01

    We consider lattice field theories with topological actions, which are invariant against small deformations of the fields. Some of these actions have infinite barriers separating different topological sectors. Topological actions do not have the correct classical continuum limit and they cannot be treated using perturbation theory, but they still yield the correct quantum continuum limit. To show this, we present analytic studies of the 1-d O(2) and O(3) model, as well as Monte Carlo simulations of the 2-d O(3) model using topological lattice actions. Some topological actions obey and others violate a lattice Schwarz inequality between the action and the topological charge Q. Irrespective of this, in the 2-d O(3) model the topological susceptibility {χ_t} = {{{left< {{Q^2}} rightrangle }} left/ {V} right.} is logarithmically divergent in the continuum limit. Still, at non-zero distance the correlator of the topological charge density has a finite continuum limit which is consistent with analytic predictions. Our study shows explicitly that some classically important features of an action are irrelevant for reaching the correct quantum continuum limit.

  7. 24 CFR 968.315 - Comprehensive Plan (including five-year action plan).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... development and management/operations needs PHA-wide and a specific description of the PHA's process for... and PHA-wide physical and management needs; and (ii) A specific description of the PHA's process for...): (1) The management, financial, and accounting control systems of the PHA; (2) The adequacy...

  8. 24 CFR 968.315 - Comprehensive Plan (including five-year action plan).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... providing resident programs and services; and (iii) The PHA's proposed drug elimination activities are coordinated with, and supportive of, local drug elimination strategies and neighborhood improvement programs..., DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT PUBLIC HOUSING MODERNIZATION Comprehensive Grant Program...

  9. 30 CFR 250.526 - What must I include in my notification of corrective action?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Well-Completion Operations Casing Pressure Management § 250.526 What must I... notification of corrective (a) Lessee or Operator name; (b) Area name and OCS block number; (c) Well name...

  10. 30 CFR 250.526 - What must I include in my notification of corrective action?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Well... Operator name; (b) Area name and OCS block number; (c) Well name and API number; and (d) Casing...

  11. Molecular mechanism of action of fluoride on bone cells.

    PubMed

    Lau, K H; Baylink, D J

    1998-11-01

    Fluoride is an effective anabolic agent to increase spinal bone density by increasing bone formation, and at therapeutically relevant (i.e., micromolar) concentrations, it stimulates bone cell proliferation and activities in vitro and in vivo. However, the fluoride therapy of osteoporosis has been controversial, in large part because of a lack of consistent antifracture efficacy. However, information regarding the molecular mechanism of action of fluoride may improve its optimum and correct usage and may disclose potential targets for the development of new second generation drugs that might have a better efficacy and safety profile. Accordingly, this review will address the molecular mechanisms of the osteogenic action of fluoride. In this regard, we and other workers have proposed two competing models, both of which involve the mitogen activated protein kinase (MAPK) mitogenic signal transduction pathway. Our model involves a fluoride inhibition of a unique fluoride-sensitive phosphotyrosine phosphatase (PTP) in osteoblasts, which results in a sustained increase in the tyrosine phosphorylation level of the key signaling proteins of the MAPK mitogenic transduction pathway, leading to the potentiation of the bone cell proliferation initiated by growth factors. The competing model proposes that fluoride acts in coordination with aluminum to form fluoroaluminate, which activates a pertussis toxin-sensitive Gi/o protein on bone cell membrane, leading to an activation of cellular protein tyrosine kinases (PTKs), which in turn leads to increases in the tyrosine phosphorylation of signaling proteins of the MAPK mitogenic signal transduction pathway, ultimately leading to a stimulation of cell proliferation. A benefit of our model, but not the other model, is that it accounts for all the unique properties of the osteogenic action of fluoride. These include the low effective fluoride dose, the skeletal tissue specificity, the requirement of PTK-activating growth factors

  12. Conscious Control over Action.

    PubMed

    Shepherd, Joshua

    2015-06-01

    The extensive involvement of nonconscious processes in human behaviour has led some to suggest that consciousness is much less important for the control of action than we might think. In this article I push against this trend, developing an understanding of conscious control that is sensitive to our best models of overt (that is, bodily) action control. Further, I assess the cogency of various zombie challenges-challenges that seek to demote the importance of conscious control for human agency. I argue that though nonconscious contributions to action control are evidently robust, these challenges are overblown.

  13. Conscious Control over Action

    PubMed Central

    Shepherd, Joshua

    2015-01-01

    The extensive involvement of nonconscious processes in human behaviour has led some to suggest that consciousness is much less important for the control of action than we might think. In this article I push against this trend, developing an understanding of conscious control that is sensitive to our best models of overt (that is, bodily) action control. Further, I assess the cogency of various zombie challenges—challenges that seek to demote the importance of conscious control for human agency. I argue that though nonconscious contributions to action control are evidently robust, these challenges are overblown. PMID:26113753

  14. Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

    PubMed Central

    Lorente, M; Torres, S; Salazar, M; Carracedo, A; Hernández-Tiedra, S; Rodríguez-Fornés, F; García-Taboada, E; Meléndez, B; Mollejo, M; Campos-Martín, Y; Lakatosh, S A; Barcia, J; Guzmán, M; Velasco, G

    2011-01-01

    Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas. PMID:21233844

  15. Simulation of Accident Sequences Including Emergency Operating Procedures

    SciTech Connect

    Queral, Cesar; Exposito, Antonio; Hortal, Javier

    2004-07-01

    Operator actions play an important role in accident sequences. However, design analysis (Safety Analysis Report, SAR) seldom includes consideration of operator actions, although they are required by compulsory Emergency Operating Procedures (EOP) to perform some checks and actions from the very beginning of the accident. The basic aim of the project is to develop a procedure validation system which consists of the combination of three elements: a plant transient simulation code TRETA (a C based modular program) developed by the CSN, a computerized procedure system COPMA-III (Java technology based program) developed by the OECD-Halden Reactor Project and adapted for simulation with the contribution of our group and a software interface that provides the communication between COPMA-III and TRETA. The new combined system is going to be applied in a pilot study in order to analyze sequences initiated by secondary side breaks in a Pressurized Water Reactors (PWR) plant. (authors)

  16. Rho kinase inhibition in diabetic kidney disease.

    PubMed

    Komers, Radko

    2013-10-01

    Small GTPases of the Rho family and their down-stream effectors Rho associated kinases (ROCKs) are the molecules that converge a spectrum of pathophysiological signals triggered by the diabetic milieu and represent promising molecular targets for nephroprotective treatment in diabetes. The review discusses recent studies exploring the consequences of diabetes-induced Rho-ROCK activation in the kidney and the effects of ROCK inhibition (ROCKi) in experimental diabetic kidney disease (DKD). Studies in models of type 1 and type 2 diabetes have indicated blood pressure-independent nephroprotective actions of ROCKi in DKD. The underlying mechanisms include attenuation of diabetes-induced increases in renal expression of prosclerotic cytokines and extracellular matrix, anti-oxidant effects and protection of mitochondrial function, resulting in slower development of glomerulosclerosis and interstitial fibrosis. The studies have also shown antiproteinuric effects of ROCKi that could be related to reductions in permeability of the glomerular barrier and beneficial effects on podocytes. Glomerular haemodynamic mechanisms might also be involved. Despite remaining questions in this field, such as the effects in podocytes later in the course of DKD, specificity of currently available ROCKi, or the roles of individual ROCK isoforms, recent evidence in experimental diabetes suggests that ROCKi might in future broaden the spectrum of treatments available for patients with DKD. This is supported by the evidence generated in models of non-diabetic kidney disease and in clinical studies in patients with various cardiovascular disorders.

  17. Decision Making in Action

    NASA Technical Reports Server (NTRS)

    Orasanu, Judith; Statler, Irving C. (Technical Monitor)

    1994-01-01

    The importance of decision-making to safety in complex, dynamic environments like mission control centers and offshore installations has been well established. NASA-ARC has a program of research dedicated to fostering safe and effective decision-making in the manned spaceflight environment. Because access to spaceflight is limited, environments with similar characteristics, including aviation and nuclear power plants, serve as analogs from which space-relevant data can be gathered and theories developed. Analyses of aviation accidents cite crew judgement and decision making as causes or contributing factors in over half of all accidents. A similar observation has been made in nuclear power plants. Yet laboratory research on decision making has not proven especially helpful in improving the quality of decisions in these kinds of environments. One reason is that the traditional, analytic decision models are inappropriate to multidimensional, high-risk environments, and do not accurately describe what expert human decision makers do when they make decisions that have consequences. A new model of dynamic, naturalistic decision making is offered that may prove useful for improving decision making in complex, isolated, confined and high-risk environments. Based on analyses of crew performance in full-mission simulators and accident reports, features that define effective decision strategies in abnormal or emergency situations have been identified. These include accurate situation assessment (including time and risk assessment), appreciation of the complexity of the problem, sensitivity to constraints on the decision, timeliness of the response, and use of adequate information. More effective crews also manage their workload to provide themselves with time and resources to make good decisions. In brief, good decisions are appropriate to the demands of the situation. Effective crew decision making and overall performance are mediated by crew communication. Communication

  18. Comparison of beneficial actions of non-steroidal anti-inflammatory drugs to flavonoids.

    PubMed

    Conti, P; Varvara, G; Murmura, G; Tete, S; Sabatino, G; Saggini, A; Rosati, M; Toniato, E; Caraffa, A; Antinolfi, P; Pandolfi, F; Potalivo, G; Galzio, R; Theoharides, T C

    2013-01-01

    Inflammation is involved in increasing number of diseases necessitating the development of new, effective and safe treatments. Non steroidal anti-inflammatory drugs (NSAIDs) have been helpful in many instances, but they only inhibit cyclooxygenase (COX), but not the generation or actions of cytokines. Instead, some natural flavonoids have multiple anti-inflammatory effects, including COX inhibition, and a much safer profile. Increasing evidence indicates that inflammation plays a critical role in the pathogenesis of many diseases that also involve mast cells. Consequently, the need for new, effective and safe anti-inflammatory drugs is all the more urgent. Corticosteroids are quite potent, but have many adverse effects such as increased risk of infections, osteoporosis, glaucoma and depression. Biological agents such anti-TNF are useful in certain conditions, such as rheumatoid arthritis and psoriasis, but has been associated with increased risk of infection and leukemia.

  19. Stabilizing bottomless action theories

    NASA Astrophysics Data System (ADS)

    Greensite, J.; Halpern, M. B.

    1984-08-01

    We show how to construct the euclidean quantum theory corresponding to classical actions which are unbounded from below. Our method preserves the classical limit, the large- N limit, and the perturbative expansion of the unstabilized theories.

  20. Benzidine Dyes Action Plan

    EPA Pesticide Factsheets

    This Action Plan addresses the use of benzidine-based dyes and benzidine congener-based dyes, both metalized and non-metalized, in products that would result in consumer exposure, such as for use to color textiles.

  1. Oak Canyon Action Memo

    EPA Pesticide Factsheets

    This memorandum requests approval for a time-critical removal action at the 27 residential properties that compose the Oak Canyon Site located in the Village of Paguate, Pueblo of Laguna, near Cibola County, New Mexico.

  2. Unexpected events induce motor slowing via a brain mechanism for action-stopping with global suppressive effects.

    PubMed

    Wessel, Jan R; Aron, Adam R

    2013-11-20

    When an unexpected event occurs in everyday life (e.g., a car honking), one experiences a slowing down of ongoing action (e.g., of walking into the street). Motor slowing following unexpected events is a ubiquitous phenomenon, both in laboratory experiments as well as such everyday situations, yet the underlying mechanism is unknown. We hypothesized that unexpected events recruit the same inhibition network in the brain as does complete cancellation of an action (i.e., action-stopping). Using electroencephalography and independent component analysis in humans, we show that a brain signature of successful outright action-stopping also exhibits activity following unexpected events, and more so in blocks with greater motor slowing. Further, using transcranial magnetic stimulation to measure corticospinal excitability, we show that an unexpected event has a global motor suppressive effect, just like outright action-stopping. Thus, unexpected events recruit a common mechanism with outright action-stopping, moreover with global suppressive effects. These findings imply that we can now leverage the considerable extant knowledge of the neural architecture and functional properties of the stopping system to better understand the processing of unexpected events, including perhaps how they induce distraction via global suppression.

  3. Cardiac action potential imaging

    NASA Astrophysics Data System (ADS)

    Tian, Qinghai; Lipp, Peter; Kaestner, Lars

    2013-06-01

    Action potentials in cardiac myocytes have durations in the order of magnitude of 100 milliseconds. In biomedical investigations the documentation of the occurrence of action potentials is often not sufficient, but a recording of the shape of an action potential allows a functional estimation of several molecular players. Therefore a temporal resolution of around 500 images per second is compulsory. In the past such measurements have been performed with photometric approaches limiting the measurement to one cell at a time. In contrast, imaging allows reading out several cells at a time with additional spatial information. Recent developments in camera technologies allow the acquisition with the required speed and sensitivity. We performed action potential imaging on isolated adult cardiomyocytes of guinea pigs utilizing the fluorescent membrane potential sensor di-8-ANEPPS and latest electron-multiplication CCD as well as scientific CMOS cameras of several manufacturers. Furthermore, we characterized the signal to noise ratio of action potential signals of varying sets of cameras, dye concentrations and objective lenses. We ensured that di-8-ANEPPS itself did not alter action potentials by avoiding concentrations above 5 μM. Based on these results we can conclude that imaging is a reliable method to read out action potentials. Compared to conventional current-clamp experiments, this optical approach allows a much higher throughput and due to its contact free concept leaving the cell to a much higher degree undisturbed. Action potential imaging based on isolated adult cardiomyocytes can be utilized in pharmacological cardiac safety screens bearing numerous advantages over approaches based on heterologous expression of hERG channels in cell lines.

  4. Catechol and aldehyde moieties of 3,4-dihydroxyphenylacetaldehyde contribute to tyrosine hydroxylase inhibition and neurotoxicity.

    PubMed

    Vermeer, Lydia M M; Florang, Virginia R; Doorn, Jonathan A

    2012-09-20

    Parkinson's disease (PD) is a progressive neurodegenerative disorder which leads to the selective loss of dopaminergic neurons. This causes a decrease in the important neurotransmitter dopamine (DA), which is essential for coordinated movement. Previous studies have implicated the monoamine oxidase metabolite of DA, 3,4-dihydroxphenylacetaldehyde (DOPAL), in the pathogenesis of PD and have shown it to be a reactive intermediate capable of protein modification. DOPAL also has demonstrated the ability to cause mitochondrial dysfunction and lead to significant inhibition of the rate-limiting enzyme in DA synthesis, tyrosine hydroxylase (TH). The current study was undertaken to investigate four analogs of DOPAL, including a novel nitrile analog, to determine how the structure of DOPAL is related to its toxicity and inhibition of TH. Both mitochondrial function and inhibition of TH in cell lysate were investigated. Furthermore, a novel whole cell assay was designed to determine the consequence to enzyme action when DOPAL levels were elevated. The results presented here demonstrate that changes to DOPAL structure lead to a decrease in toxicity and inhibition of enzyme activity as compared to the parent compound. Furthermore, the production of superoxide anion but not hydrogen peroxide increased in the presence of elevated DOPAL. These results reveal the toxicity of DOPAL and demonstrate that both the catechol and aldehyde are required to potently inhibit TH activity.

  5. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis.

    PubMed

    Xia, Xuan; Yan, Jinhua; Shen, Yunfeng; Tang, Kuanxiao; Yin, Jun; Zhang, Yanhua; Yang, Dongjie; Liang, Hua; Ye, Jianping; Weng, Jianping

    2011-02-03

    Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.

  6. Coextracted dissolved organic carbon has a suppressive effect on the acetylcholinesterase inhibition assay.

    PubMed

    Neale, Peta A; Escher, Beate I

    2013-07-01

    The acetylcholinesterase (AChE) inhibition assay is frequently applied to detect organophosphates and carbamate pesticides in different water types, including dissolved organic carbon (DOC)-rich wastewater and surface water. The aim of the present study was to quantify the effect of coextracted DOC from different water samples on the commonly used enzyme-based AChE inhibition assay. Approximately 40% to 70% of DOC is typically recovered by solid-phase extraction, and this comprises not only organic micropollutants but also natural organic matter. The inhibition of the water extracts in the assay differed greatly from the expected mixture effects based on chemical analysis of organophosphates and carbamates. Binary mixture experiments with the known AChE inhibitor parathion and the water extracts showed reduced toxicity in comparison with predictions using the mixture models of concentration addition and independent action. In addition, the extracts and reference organic matter had a suppressive effect on a constant concentration of parathion. The present study thus indicated that concentrations of DOC as low as 2 mg carbon/L can impair the AChE inhibition assay and, consequently, that only samples with a final DOC concentration of less than 2 mgC /L are suitable for this assay. To check for potential suppression in environmental samples, standard addition experiments using an AChE-inhibiting reference compound are recommended.

  7. Towards a Reflection Repertoire: Using a Thinking Tool to Understand Tensions in an Action Research Project

    ERIC Educational Resources Information Center

    Aas, Marit

    2014-01-01

    Most action researchers agree that action research consists of cycles of planning, acting, reflecting, and taking further action. However, in action research literature, there is something missing. The nature of reflection in the action research process, including its relationship with the tensions that arise while discussing purposes, processes,…

  8. 36 CFR 72.16 - Preliminary Action Program requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Preliminary Action Program... INTERIOR URBAN PARK AND RECREATION RECOVERY ACT OF 1978 Local Recovery Action Programs § 72.16 Preliminary.... Included should be a brief discussion of the relationship of the Preliminary Action Program to...

  9. 36 CFR 72.16 - Preliminary Action Program requirements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Preliminary Action Program... INTERIOR URBAN PARK AND RECREATION RECOVERY ACT OF 1978 Local Recovery Action Programs § 72.16 Preliminary.... Included should be a brief discussion of the relationship of the Preliminary Action Program to...

  10. Why Are We Using Action Learning and in What Contexts?

    ERIC Educational Resources Information Center

    Park, Sunyoung; Kang, Ingu; Valencic, Taryn R.; Cho, Yonjoo

    2013-01-01

    The purpose of this study was to examine the contexts in which action learning has been used and provide implications for the design of action learning programmes. We performed a content analysis of 127 articles (case studies and case reports included) published in "Action Learning: Research and Practice" between 2004 and 2012. In this…

  11. Action Research in EdD Programs in Educational Leadership

    ERIC Educational Resources Information Center

    Osterman, Karen; Furman, Gail; Sernak, Kathleen

    2014-01-01

    This exploratory study gathered information about the use of action research within doctor of education programs in educational leadership and explored faculty understanding of and perspectives on action research. Survey data established that action research is used infrequently to meet dissertation requirements. Contributing factors include lack…

  12. [Addictions and action systems].

    PubMed

    Loonis, E; Apter, M J

    2000-01-01

    Generalizing from some previous analyses of addiction, and introducing the concept of an action system which governs all actions which are focussed on what Brown (1988) calls "hedonic management", we argue that addictions of every kind involve an action system that displays high salience, low variety and low vicariance. Addictions also involve what Apter (1982) calls the "paratelic state". A study was carried out comparing 31 drug addicts with 29 control subjects in terms of action system variables. To measure these variables, we constructed a new instrument, the Activity-System Drawing Test, and also used the Telic Dominance Scale to measure frequency of paratelic states. Dysphoria was measured by means of the BATE (anxiety), IDA-13 (depression), SEI (self-esteem), and TAS-20 (alexithymia) instruments. Strongly significant differences were found between groups for both action system variables and dysphoria, and there were also strong correlations between both groups of variables. This supports the idea that addictions emerge from systemic properties of the action system.

  13. Antisymmetric string actions

    NASA Astrophysics Data System (ADS)

    Aragone, C.

    1986-12-01

    An action is presented for the free bosonic string on external flat space in terms of an antisymmetric second-rank string background tensor which is classically equivalent to the Nambu-Goto action. Both action and field equations are entirely described in terms of 2D world-sheet forms, without any reference to a 2D metric tensor background. The analysis of its canonical formulation shows how the quadratic Virasoro constraints are generated in this case and what their connection with the Bianchi identities are. Since in the orthonormal gauge the reduced action coincides with the standard one, it has the same critical dimension D = 26. The existence of an interaction term of a purely geometric structure stemming in the extrinsic curvature is pointed out. Its action and the new string field equations are then derived. This polynomial antisymmetric string action is uniformly generalized in order to describe d < D-dimensional extended objects in D-dimensional flat space. On leave of absence from Departamento de Física, Universidad Simon Bolívar, Apartado 80659, Caracas 1080A, Venezuela.

  14. Novel intracellular proteins associated with cellular vitamin D action.

    PubMed

    Angelo, Giana; Wood, Richard J; Mayer, Jean

    2002-07-01

    Work with vitamin D-resistant New World primates has revealed novel cellular proteins involved in vitamin D action. An "intracellular vitamin D-binding protein" functions to bind vitamin D metabolites in the cell and enhances vitamin D action. By contrast, a "vitamin D response element-binding protein" inhibits vitamin D receptor binding to the DNA and is responsible for vitamin D resistance in New World primates.

  15. [Biological actions of acetaldehyde].

    PubMed

    Ijiri, I

    1999-11-01

    Acetaldehyde (AcH), the first metabolite of ethanol (EtOH), is a chemically reactive and pharmacologically active compound. The author has been engaged in the study of AcH in cooperation with many researchers for three decades. We have found many biological actions of AcH which cause cardiovascular symptoms after drinking and also inhibited EtOH absorption via the canine and rat intestinal tract. This report covers the following five points. 1. The subjects were classified into a non-flushing group and a flushing group, according to the degree of facial flushing after drinking 200 ml of Sake (Japanese rice wire) at a rate of 100 ml per 5 min. Blood EtOH profile was much the same in both groups, yet peak blood AcH concentration in the flushing group was significantly higher than that in the non-flushing group. All subjects in the flushing group showed marked flushing and an increase in pulse rate after drinking, but these symptoms were not apparent in the non-flushing group. These results suggested that cardiovascular symptoms were caused by AcH itself. 2. Urinary excretions of both norepinephrine and epinephrine increased in the flushing cases after drinking Sake in comparison with those who drank the same volume of water. However, these catecholamines did not change in the non-flushing group. These results suggested that it is catecholamines released from the sympathetic nerve end or the adrenal medulla by AcH which caused an increase in pulse rate. 3. Bradykinin is released from high molecular kininogen by activated kallikrein and acts to dilate distal blood vessels and raise permeability in tissues. On the other hand, kallidin is released from low molecular kininogen by activated glandular kallikrein and its action is weaker than that of bradykinin. Blood low molecular kininogen levels in the flushing group decreased gradually after drinking and were mutually related to the blood AcH concentrations. But levels in the non-flushing group showed no difference

  16. Ozone Inhibits Guard Cell K+ Channels Implicated in Stomatal Opening

    NASA Astrophysics Data System (ADS)

    Torsethaugen, Gro; Pell, Eva J.; Assmann, Sarah M.

    1999-11-01

    Ozone (O3) deleteriously affects organisms ranging from humans to crop plants, yet little is understood regarding the underlying mechanisms. In plants, O3 decreases CO2 assimilation, but whether this could result from direct O3 action on guard cells remained unknown. Potassium flux causes osmotically driven changes in guard cell volume that regulate apertures of associated microscopic pores through which CO2 is supplied to the photosynthetic mesophyll tissue. We show in Vicia faba that O3 inhibits (i) guard cell K+ channels that mediate K+ uptake that drives stomatal opening; (ii) stomatal opening in isolated epidermes; and (iii) stomatal opening in leaves, such that CO2 assimilation is reduced without direct effects of O3 on photosynthetic capacity. Direct O3 effects on guard cells may have ecological and agronomic implications for plant productivity and for response to other environmental stressors including drought.

  17. Pharmacological diversity among drugs that inhibit bone resorption.

    PubMed

    Russell, R Graham G

    2015-06-01

    Drugs that inhibit bone resorption ('anti-resorptives') continue to dominate the therapy of bone diseases characterized by enhanced bone destruction, including Paget's disease, osteoporosis and cancers. The historic use of oestrogens for osteoporosis led on to SERMs (Selective Estrogen Receptor Modulators, e.g. raloxifene and bazedoxifene). Currently the mainstay of treatment worldwide is still with bisphosphonates, as used clinically for over 40 years. The more recently introduced anti-RANK-ligand antibody, denosumab, is also very effective in reducing vertebral, non-vertebral and hip fractures. Odanacatib is the only cathepsin K inhibitor likely to be registered for clinical use. The pharmacological basis for the action of each of these drug classes is different, enabling choices to be made to ensure their optimal use in clinical practice.

  18. Enforcement actions: Significant actions resolved. Volume 14, No. 2, Part 1: Individual actions. Quarterly progress report, April--June 1995

    SciTech Connect

    1995-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1995) and includes copies of Orders sent by the Nuclear Regulatory Commission to individuals with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC. The Commission believes this information may be useful to licensees in making employment decisions.

  19. Enforcement actions: Significant actions resolved -- individual actions. Semiannual progress report, July--December 1997; Volume 16, Number 2, Part 1

    SciTech Connect

    1998-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July--December 1997) and includes copies of Orders and Notices of Violation sent by the Nuclear Regulatory Commission to individuals with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC. The Commission believes this information may be useful to licensees in making employment decisions.

  20. Botulinum toxins: mechanisms of action, antinociception and clinical applications.

    PubMed

    Wheeler, Anthony; Smith, Howard S

    2013-04-05

    Botulinum toxin (BoNT) is a potent neurotoxin that is produced by the gram-positive, spore-forming, anaerobic bacterium, Clostridum botulinum. There are 7 known immunologically distinct serotypes of BoNT: types A, B, C1, D, E, F, and G. Clostridum neurotoxins are produced as a single inactive polypeptide chain of 150kDa, which is cleaved by tissue proteinases into an active di-chain molecule: a heavy chain (H) of ∼100 kDa and a light chain (L) of ∼50 kDa held together by a single disulfide bond. Each serotype demonstrates its own varied mechanisms of action and duration of effect. The heavy chain of each BoNT serotype binds to its specific neuronal ecto-acceptor, whereby, membrane translocation and endocytosis by intracellular synaptic vesicles occurs. The light chain acts to cleave SNAP-25, which inhibits synaptic exocytosis, and therefore, disables neural transmission. The action of BoNT to block the release of acetylcholine botulinum toxin at the neuromuscular junction is best understood, however, most experts acknowledge that this effect alone appears inadequate to explain the entirety of the neurotoxin's apparent analgesic activity. Consequently, scientific and clinical evidence has emerged that suggests multiple antinociceptive mechanisms for botulinum toxins in a variety of painful disorders, including: chronic musculoskeletal, neurological, pelvic, perineal, osteoarticular, and some headache conditions.

  1. Spatiotemporal brain mapping during preparation, perception, and action.

    PubMed

    Di Russo, Francesco; Lucci, Giuliana; Sulpizio, Valentina; Berchicci, Marika; Spinelli, Donatella; Pitzalis, Sabrina; Galati, Gaspare

    2016-02-01

    Deciding whether to act or not to act is a fundamental cognitive function. To avoid incorrect responses, both reactive and proactive modes of control have been postulated. Little is known, however, regarding the brain implementation of proactive mechanisms, which are deployed prior to an actual need to inhibit a response. Via a combination of electrophysiological and neuroimaging measures (recorded in 21 and 16 participants, respectively), we describe the brain localization and timing of neural activity that underlies the anticipatory proactive mechanism. From these results, we conclude that proactive control originates in the inferior Frontal gyrus, is established well before stimulus perception, and is released concomitantly with stimulus appearance. Stimulus perception triggers early activity in the anterior insula and intraparietal cortex contralateral to the responding hand; these areas likely mediate the transition from perception to action. The neural activities leading to the decision to act or not to act are described in the framework of a three-stage model that includes perception, action, and anticipatory functions taking place well before stimulus onset.

  2. Freeze for action: neurobiological mechanisms in animal and human freezing

    PubMed Central

    2017-01-01

    Upon increasing levels of threat, animals activate qualitatively different defensive modes, including freezing and active fight-or-flight reactions. Whereas freezing is a form of behavioural inhibition accompanied by parasympathetically dominated heart rate deceleration, fight-or-flight reactions are associated with sympathetically driven heart rate acceleration. Despite the potential relevance of freezing for human stress-coping, its phenomenology and neurobiological underpinnings remain largely unexplored in humans. Studies in rodents have shown that freezing depends on amygdala projections to the brainstem (periaqueductal grey). Recent neuroimaging studies in humans have indicated that similar brain regions may be involved in human freezing. In addition, flexibly shifting between freezing and active defensive modes is critical for adequate stress-coping and relies on fronto-amygdala connections. This review paper presents a model detailing these neural mechanisms involved in freezing and the shift to fight-or-flight action. Freezing is not a passive state but rather a parasympathetic brake on the motor system, relevant to perception and action preparation. Study of these defensive responses in humans may advance insights into human stress-related psychopathologies characterized by rigidity in behavioural stress reactions. The paper therefore concludes with a research agenda to stimulate translational animal–human research in this emerging field of human defensive stress responses. This article is part of the themed issue ‘Movement suppression: brain mechanisms for stopping and stillness’. PMID:28242739

  3. Beneficial action of resveratrol: How and why?

    PubMed

    Diaz-Gerevini, Gustavo Tomas; Repossi, Gaston; Dain, Alejandro; Tarres, María Cristina; Das, Undurti Narasimha; Eynard, Aldo Renato

    2016-02-01

    Flavonoid resveratrol modulates the transcription factor NF-κB; inhibits the cytochrome P450 isoenzyme CYP1 A1; suppresses the expression and activity of cyclooxygenase enzymes; and modulates Fas/Fas-ligand-mediated apoptosis, p53, mammalian target of rapamycin, and cyclins and various phosphodiesterases. This increases the cytosolic cAMP that activates Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α pathway, which in turn facilitates increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α, interluekin-17 (IL-17), and other proinflammatory molecules, and thus is of benefit in autoimmune diseases. In addition, resveratrol inhibits expression of hypoxia-inducible factor-1α and vascular endothelial growth factor, explaining its effective action against cancer. Brain-derived neurotrophic factor (BDNF) that is involved in the pathogenesis of obesity, type 2 diabetes mellitus, and metabolic syndrome is also altered in depression, schizophrenia, bipolar disorder, and autism. We noted that BDNF protects against cytotoxic actions of alloxan, streptozotocin, and benzo(a)pyrene. Resveratrol prevents bisphenol A-induced autism, type 2 diabetes mellitus, and metabolic syndrome, suggesting that it may augment BDNF synthesis and action. We also observed that BDNF levels are low in type 2 diabetes mellitus and that BDNF enhances production of antiinflammatory lipid, lipoxin A4, whose levels are low in diabetes mellitus. Thus, resveratrol may augment production of lipoxin A4. Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation. These pleiotropic actions of resveratrol may explain the multitude of its actions and benefits.

  4. Salmonella infection inhibits intestinal biotin transport: cellular and molecular mechanisms.

    PubMed

    Ghosal, Abhisek; Jellbauer, Stefan; Kapadia, Rubina; Raffatellu, Manuela; Said, Hamid M

    2015-07-15

    Infection with the nontyphoidal Salmonella is a common cause of food-borne disease that leads to acute gastroenteritis/diarrhea. Severe/prolonged cases of Salmonella infection could also impact host nutritional status, but little is known about its effect on intestinal absorption of vitamins, including biotin. We examined the effect of Salmonella enterica serovar Typhimurium (S. typhimurium) infection on intestinal biotin uptake using in vivo (streptomycin-pretreated mice) and in vitro [mouse (YAMC) and human (NCM460) colonic epithelial cells, and human intestinal epithelial Caco-2 cells] models. The results showed that infecting mice with wild-type S. typhimurium, but not with its nonpathogenic isogenic invA spiB mutant, leads to a significant inhibition in jejunal/colonic biotin uptake and in level of expression of the biotin transporter, sodium-dependent multivitamin transporter. In contrast, infecting YAMC, NCM460, and Caco-2 cells with S. typhimurium did not affect biotin uptake. These findings suggest that the effect of S. typhimurium infection is indirect and is likely mediated by proinflammatory cytokines, the levels of which were markedly induced in the intestine of S. typhimurium-infected mice. Consistent with this hypothesis, exposure of NCM460 cells to the proinflammatory cytokines TNF-α and IFN-γ led to a significant inhibition of biotin uptake, sodium-dependent multivitamin transporter expression, and activity of the SLC5A6 promoter. The latter effects appear to be mediated, at least in part, via the NF-κB signaling pathway. These results demonstrate that S. typhimurium infection inhibits intestinal biotin uptake, and that the inhibition is mediated via the action of proinflammatory cytokines.

  5. Salmonella infection inhibits intestinal biotin transport: cellular and molecular mechanisms

    PubMed Central

    Ghosal, Abhisek; Jellbauer, Stefan; Kapadia, Rubina; Raffatellu, Manuela

    2015-01-01

    Infection with the nontyphoidal Salmonella is a common cause of food-borne disease that leads to acute gastroenteritis/diarrhea. Severe/prolonged cases of Salmonella infection could also impact host nutritional status, but little is known about its effect on intestinal absorption of vitamins, including biotin. We examined the effect of Salmonella enterica serovar Typhimurium (S. typhimurium) infection on intestinal biotin uptake using in vivo (streptomycin-pretreated mice) and in vitro [mouse (YAMC) and human (NCM460) colonic epithelial cells, and human intestinal epithelial Caco-2 cells] models. The results showed that infecting mice with wild-type S. typhimurium, but not with its nonpathogenic isogenic invA spiB mutant, leads to a significant inhibition in jejunal/colonic biotin uptake and in level of expression of the biotin transporter, sodium-dependent multivitamin transporter. In contrast, infecting YAMC, NCM460, and Caco-2 cells with S. typhimurium did not affect biotin uptake. These findings suggest that the effect of S. typhimurium infection is indirect and is likely mediated by proinflammatory cytokines, the levels of which were markedly induced in the intestine of S. typhimurium-infected mice. Consistent with this hypothesis, exposure of NCM460 cells to the proinflammatory cytokines TNF-α and IFN-γ led to a significant inhibition of biotin uptake, sodium-dependent multivitamin transporter expression, and activity of the SLC5A6 promoter. The latter effects appear to be mediated, at least in part, via the NF-κB signaling pathway. These results demonstrate that S. typhimurium infection inhibits intestinal biotin uptake, and that the inhibition is mediated via the action of proinflammatory cytokines. PMID:25999427

  6. National Security Technology Incubator Action Plan

    SciTech Connect

    None, None

    2008-02-28

    This report documents the action plan for developing the National Security Technology Incubator (NSTI) program for southern New Mexico. The NSTI program is being developed as part of the National Security Preparedness Project (NSPP), funded by Department of Energy (DOE)/National Nuclear Security Administration (NNSA). This action plan serves as a tool in measuring progress in the development process and delivery of services for the NSTI program. Continuous review and evaluation of the action plan is necessary in the development process of the NSTI. The action plan includes detailed steps in developing the NSTI program based on recommended best practices in incubator development by the National Business Incubation Association (NBIA). Included are tasks required to implement the NSTI, developed within a work breakdown structure. In addition, a timeline is identified for each task.

  7. Brain-derived neurotrophic factor inhibits calcium channel activation, exocytosis, and endocytosis at a central nerve terminal.

    PubMed

    Baydyuk, Maryna; Wu, Xin-Sheng; He, Liming; Wu, Ling-Gang

    2015-03-18

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic function and plasticity and plays important roles in neuronal development, survival, and brain disorders. Despite such diverse and important roles, how BDNF, or more generally speaking, neurotrophins affect synapses, particularly nerve terminals, remains unclear. By measuring calcium currents and membrane capacitance during depolarization at a large mammalian central nerve terminal, the rat calyx of Held, we report for the first time that BDNF slows down calcium channel activation, including P/Q-type channels, and inhibits exocytosis induced by brief depolarization or single action potentials, inhibits slow and rapid endocytosis, and inhibits vesicle mobilization to the readily releasable pool. These presynaptic mechanisms may contribute to the important roles of BDNF in regulating synapses and neuronal circuits and suggest that regulation of presynaptic calcium channels, exocytosis, and endocytosis are potential mechanisms by which neurotrophins achieve diverse neuronal functions.

  8. What's an Asthma Action Plan?

    MedlinePlus

    ... to 2-Year-Old What's an Asthma Action Plan? KidsHealth > For Parents > What's an Asthma Action Plan? ... normal everyday activities without having asthma symptoms. Action Plans Are Unique Each person's experience with asthma is ...

  9. 22 CFR 161.7 - Categories of actions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... includes routine administrative procurements (e.g., general supplies, negotiating leases for office space... study activities; and (5) Document and information exchanges. Even though an action may be...

  10. 22 CFR 161.7 - Categories of actions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... includes routine administrative procurements (e.g., general supplies, negotiating leases for office space... study activities; and (5) Document and information exchanges. Even though an action may be...

  11. [Mirtazapine--pharmacologic action and clinical advantages].

    PubMed

    Rihmer, Zoltán; Purebl, György

    2009-03-01

    Mirtazapine is an effective antidepressant with unique and special mechanism of action characterized by high response and remission rates, relatively early onest of action and favourable side-effect profile. The present paper reviews some special points of the clinical use of mirtazapine, which is on the market in Hungary for almost 10 years, including its sleep-improving and anxiolytic effets. This review will also touch the management of the most commonly occuring side-effects.

  12. Imaging of axial spondyloarthritis including ankylosing spondylitis.

    PubMed

    Braun, J; Baraliakos, X

    2011-03-01

    New bone formation of the vertebral column is pathognomonic for ankylosing spondylitis (AS), while acute and/or chronic changes in the sacroiliac joints are relevant for diagnosis. The 'gold standard' for assessment of structural changes in AS are conventional radiographs, while MRI is useful to assess inflammation. Recent MRI studies have shown that the lower half of the thoracic spine is most commonly affected in AS. Scoring tools for spinal inflammation such as the ASspiMRI-a have been proposed, successfully used in large clinical trials and compared in a multireader experiment; none was finally preferred by OMERACT. Quantification of structural spinal AS changes is performed by the modified Stokes AS Spine Score (mSASSS), which evaluates lateral cervical and lumbar radiographs. Two years was identified as the shortest possible follow-up time based on the reliability and sensitivity to change of the mSASSS. A potential disadvantage of the mSASSS is that the thoracic spine is not included. Recent data based on the mSASSS have suggested that tumour necrosis factor blockers do not inhibit radiographic progression in AS. Since the mean radiographic change is reported to be less than 1 syndesmophyte over 2 years, the sensitivity to change of the mSASSS has been questioned. However, in one study where continuous non-steroidal anti-inflammatory drugs use was compared with on-demand use, a difference between these two methods of drug intake was reported. The face and construct validity of the mSASSS has been criticised because a score of ´1´ contains a mixture of osteodestructive (erosions) and osteoproliferative changes (squaring and sclerosis). A new scoring system, the RASSS, which concentrates only on bone formation and which includes the lower part of the thoracic spine is currently being evaluated. The relationship between inflammation and new bone formation in AS has recently been investigated. Low sclerostin and DKK-1 serum levels, both inhibitors of bone

  13. ES H action plan

    SciTech Connect

    Not Available

    1991-01-01

    This document contains planned actions to correct the deficiencies identified in the Pre-Tiger Team Self-Assessment (PTTSA), January 1991, of Sandia National Laboratories (SNL -- Albuquerque, New Mexico; Tonopah, Nevada; and Kauai, Hawaii). The Self-Assessment was conducted by a Self-Assessment Working Group consisting of 19 department managers, with support from Environment, Safety, and Health (ES H) professionals, from October through December 1990. Findings from other past audits, dating back to 1985, were reviewed and compared with the PTTSA findings to determine if additional findings, key findings, or root causes were warranted. The resulting ES H Action Plan and individual planned actions were prepared by the ES H Action Plan Project Group with assistance from the Program owners/authors during February and March 1991. The plan was reviewed by SNL Management in April 1991. This document serves as a planning instrument for the Laboratories to aid in the scoping and sizing of activities related to ES H compliance for the coming five years. It will be modified as required to ensure a workload/funding balance and to address the findings resulting from the Tiger Team assessment at SNL, Albuquerque. The process of producing this document has served well to prepare SNL, Albuquerque, for the coming task of producing the required post-Tiger Team action plan document. 8 tabs.

  14. Riverland expedited response action proposal

    SciTech Connect

    Not Available

    1993-04-01

    The US Environmental Protection Agency (EPA) and Washington Department of Ecology (Ecology) recommended that the US Department of Energy (DOE) prepare an expedited response action (ERA) for the Riverland Railroad Car Wash Pit and the 600 Area Army Munitions Burial Site. A non-time-critical ERA proposal includes preparation of an engineering evaluation/cost analysis (EE/CA) section. The EE/CA is a rapid, focused evaluation of available technologies using specific screening factors to assess feasibility, appropriateness, and cost. The ERA proposal will undergo reviews by Westinghouse Hanford Company (WHC), DOE, EPA, Ecology, and the public. Ecology and EPA will issue an Action Agreement Memorandum after resolution of all review comments. The, memorandum will authorize remediation activities. The ERA goal is to reduce the potential for any contaminant migration to the soil column, groundwater, and Columbia River. The ERA may be the final remediation of the 100-IU-1 Operable Unit. A No Action Record of Decision may be issued after cleanup completion.

  15. Formulation of Complex Action Theory

    NASA Astrophysics Data System (ADS)

    Nagao, K.; Nielsen, H. B.

    2011-12-01

    We formulate a complex action theory which includes operators of coordinate and momentum hat{q} and hat{p} being replaced with non-hermitian operators hat{q}_{new} and hat{p}_{new}, and their eigenstates | q >_{new} and | p >_{new} with complex eigenvalues q and p. Introducing a philosophy of keeping the analyticity in path integration variables, we define a modified set of complex conjugate, real and imaginary parts, hermitian conjugates and bras, and explicitly construct hat{q}_{new}, hat{p}_{new}, |q >_{new} and |p >_{new} by formally squeezing coherent states. We also pose a theorem on the relation between functions on the phase space and the corresponding operators. Only in our formalism can we describe a complex action theory or a real action theory with complex saddle points in the tunneling effect etc. in terms of bras and kets in the functional integral. Furthermore, in a system with a non-hermitian diagonalizable bounded Hamiltonian, we show that the mechanism to obtain a hermitian Hamiltonian after a long time development proposed in our paper [Prog. Theor. Phys. 125 (2011), 633] works also in the complex coordinate formalism. If the hermitian Hamiltonian is given in a local form, a conserved probability current density can be constructed with two kinds of wave functions.

  16. Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages

    PubMed Central

    Ma, Tong-Cui; Zhou, Run-Hong; Wang, Xu; Li, Jie-Liang; Sang, Ming; Zhou, Li; Zhuang, Ke; Hou, Wei; Guo, De-Yin; Ho, Wen-Zhe

    2016-01-01

    The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2′,5′-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product. PMID:27734899

  17. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses

    PubMed Central

    Chiappinelli, Katherine B.; Strissel, Pamela L.; Desrichard, Alexis; Li, Huili; Henke, Christine; Akman, Benjamin; Hein, Alexander; Rote, Neal S.; Cope, Leslie M.; Snyder, Alexandra; Makarov, Vladimir; Buhu, Sadna; Slamon, Dennis J.; Wolchok, Jedd D.; Pardoll, Drew M.; Beckmann, Matthias W.; Zahnow, Cynthia A.; Mergoub, Taha; Chan, Timothy A.; Baylin, Stephen B.; Strick, Reiner

    2015-01-01

    Summary We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model. PMID:26317466

  18. Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility

    PubMed Central

    Takeuchi, Koji

    2012-01-01

    This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE2 and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E2 (PGE2) production and causes gastric hypermotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Helicobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition. PMID:22611307

  19. Selective attention and control of action: comparative psychology of an artificial, evolved agent and people.

    PubMed

    Ward, Robert; Ward, Ronnie

    2008-10-01

    This study examined the selective attention abilities of a simple, artificial, evolved agent and considered implications of the agent's performance for theories of selective attention and action. The agent processed two targets in continuous time, catching one and then the other. This task required many cognitive operations, including prioritizing the first target (T1) over the second (T2); selectively focusing responses on T1, while preventing T2 from interfering with responses; creating a memory for the unselected T2 item, so that it could be efficiently processed later; and reallocating processing towards T2 after catching T1. The evolved agent demonstrated all these abilities. Analysis shows that the agent used reactive inhibition to selectively focus behavior. That is, the more salient T2, the more strongly responses towards T2 were inhibited and the slower the agent was to subsequently reallocate processing towards T2. Reactive inhibition was also suggested in two experiments with people, performing a virtually identical catch task. The presence of reactive inhibition in the simple agent and in people suggests that it is an important mechanism for selective processing.

  20. ProBDNF inhibits collective migration and chemotaxis of rat Schwann cells.

    PubMed

    Ding, You-Quan; Li, Xuan-Yang; Xia, Guan-Nan; Ren, Hong-Yi; Zhou, Xin-Fu; Su, Bing-Yin; Qi, Jian-Guo

    2016-10-01

    Schwann cell migration, including collective migration and chemotaxis, is essential for the formation of coordinate interactions between Schwann cells and axons during peripheral nerve development and regeneration. Moreover, limited migration of Schwann cells imposed a serious obstacle on Schwann cell-astrocytes intermingling and spinal cord repair after Schwann cell transplantation into injured spinal cords. Recent studies have shown that mature brain-derived neurotrophic factor, a member of the neurotrophin family, inhibits Schwann cell migration. The precursor form of brain-derived neurotrophic factor, proBDNF, was expressed in the developing or degenerating peripheral nerves and the injured spinal cords. Since "the yin and yang of neurotrophin action" has been established as a common sense, proBDNF would be expected to promote Schwann cell migration. However, we found, in the present study, that exogenous proBDNF also inhibited in vitro collective migration and chemotaxis of RSC 96 cells, a spontaneously immortalized rat Schwann cell line. Moreover, proBDNF suppressed adhesion and spreading of those cells. At molecular level, proBDNF inhibits F-actin polymerization and focal adhesion dynamics in cultured RSC 96 cells. Therefore, our results suggested a special case against the classical opinion of "the yin and yang of neurotrophin action" and implied that proBDNF might modulate peripheral nerve development or regeneration and spinal cord repair through perturbing native or transplanted Schwann cell migration.