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Sample records for quaternary ache inhibitors

  1. Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy

    PubMed Central

    Murray, Ana Paula; Faraoni, María Belén; Castro, María Julia; Alza, Natalia Paola; Cavallaro, Valeria

    2013-01-01

    As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition. PMID:24381530

  2. Electronic structure calculations toward new potentially AChE inhibitors

    NASA Astrophysics Data System (ADS)

    de Paula, A. A. N.; Martins, J. B. L.; Gargano, R.; dos Santos, M. L.; Romeiro, L. A. S.

    2007-10-01

    The main purpose of this study was the use of natural non-isoprenoid phenolic lipid of cashew nut shell liquid from Anacardium occidentale as lead material for generating new potentially candidates of acetylcholinesterase inhibitors. Therefore, we studied the electronic structure of 15 molecules derivatives from the cardanol using the following groups: methyl, acetyl, N, N-dimethylcarbamoyl, N, N-dimethylamine, N, N-diethylamine, piperidine, pyrrolidine, and N-benzylamine. The calculations were performed at RHF level using 6-31G, 6-31G(d), 6-31+G(d) and 6-311G(d,p) basis functions. Among the proposed compounds we found that the structures with substitution by acetyl, N, N-dimethylcarbamoyl, N, N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine indicating possible activity.

  3. Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.

    PubMed

    Tommonaro, Giuseppina; García-Font, Nuria; Vitale, Rosa Maria; Pejin, Boris; Iodice, Carmine; Cañadas, Sixta; Marco-Contelles, José; Oset-Gasque, María Jesús

    2016-10-21

    Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer's disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3'-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of

  4. Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.

    PubMed

    Tommonaro, Giuseppina; García-Font, Nuria; Vitale, Rosa Maria; Pejin, Boris; Iodice, Carmine; Cañadas, Sixta; Marco-Contelles, José; Oset-Gasque, María Jesús

    2016-10-21

    Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer's disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3'-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of

  5. Neurophysiological predictors of long term response to AChE inhibitors in AD patients

    PubMed Central

    Di, L; Oliviero, A; Pilato, F; Saturno, E; Dileone, M; Marra, C; Ghirlanda, S; Ranieri, F; Gainotti, G; Tonali, P

    2005-01-01

    Background: In vivo evaluation of cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with motor cortex TMS (short latency afferent inhibition, SAI). SAI is reduced in Alzheimer's disease (AD) and drugs enhancing cholinergic transmission increase SAI. Methods: We evaluated whether SAI testing, together with SAI test-retest, after a single dose of the acetylcholinesterase (AChE) inhibitor rivastigmine, might be useful in predicting the response after 1 year treatment with rivastigmine in 16 AD patients. Results: Fourteen AD patients had pathologically reduced SAI. SAI was increased after administration of a single oral dose of rivastigmine in AD patients with abnormal baseline SAI, but individual responses to rivastigmine varied widely, with SAI change ranging from an increase in inhibition of ∼50% of test size to no change. Baseline SAI and the increase in SAI after a single dose of rivastigmine were correlated with response to long term treatment. A normal SAI in baseline conditions, or an abnormal SAI in baseline conditions that was not greatly increased by a single oral dose of rivastigmine, were invariably associated with poor response to long term treatment, while an abnormal SAI in baseline conditions in conjunction with a large increase in SAI after a single dose of rivastigmine was associated with good response to long term treatment in most of the patients. Conclusions: Evaluation of SAI may be useful for identifying AD patients likely to respond to treatment with AChE inhibitors. PMID:16024879

  6. An in vitro AChE inhibition assay combined with UF-HPLC-ESI-Q-TOF/MS approach for screening and characterizing of AChE inhibitors from roots of Coptis chinensis Franch.

    PubMed

    Zhao, Hengqiang; Zhou, Siduo; Zhang, Minmin; Feng, Jinhong; Wang, Shanshan; Wang, Daijie; Geng, Yanling; Wang, Xiao

    2016-02-20

    In this study, an in vitro acetylcholinesterase (AChE) inhibition assay based on microplate reader combined with ultrafiltration high performance liquid chromatography-electrospray quadrupole time of flight mass (UF-HPLC-ESI-Q-TOF/MS) was developed for the rapid screening and identification of acetylcholinesterase inhibitors (AChEI) from roots of Coptis chinensis Franch. Incubation conditions such as enzyme concentration, incubation time, incubation temperature and co-solvent was optimized so as to get better screening results. Five alkaloids including columbamine, jatrorrhizine, coptisine, palmatine and berberine were found with AChE inhibition activity in the 80% ethanol extract of C. chinensis Franch. The screened compounds were identified by HPLC-DAD-ESI-Q-TOF/MS compared with the reference stands and literatures. The screened results were verified by in vitro AChE inhibition assays, palmatine showed the best AChE inhibitory activities with IC50 values of 36.6μM among the five compounds. Results of the present study indicated that the combinative method using in vitro AChE inhibition assay and UF-HPLC-ESI-Q-TOF/MS could be widely applied for rapid screening and identification of AChEI from complex TCM extract.

  7. Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease.

    PubMed

    Lemes, Laís Flávia Nunes; de Andrade Ramos, Giselle; de Oliveira, Andressa Souza; da Silva, Fernanda Motta R; de Castro Couto, Gina; da Silva Boni, Marina; Guimarães, Marcos Jorge R; Souza, Isis Nem O; Bartolini, Manuela; Andrisano, Vincenza; do Nascimento Nogueira, Patrícia Coelho; Silveira, Edilberto Rocha; Brand, Guilherme D; Soukup, Ondřej; Korábečný, Jan; Romeiro, Nelilma C; Castro, Newton G; Bolognesi, Maria Laura; Romeiro, Luiz Antonio Soares

    2016-01-27

    Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 μM, and a similar inhibition profile of the human isoform (IC50 = 5.7 μM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 μM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development. PMID:26735910

  8. Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease.

    PubMed

    Zhou, An; Hu, Jianping; Wang, Lirong; Zhong, Guochen; Pan, Jian; Wu, Zeyu; Hui, Ailing

    2015-10-01

    Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).

  9. Novel bis-(−)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property

    SciTech Connect

    Zheng, Wei; Li, Juan; Qiu, Zhuibai; Xia, Zheng; Li, Wei; Yu, Lining; Chen, Hailin; Chen, Jianxing; Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao; Xie, Qiong; Chen, Hongzhuan

    2012-10-01

    The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(−)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC{sub 50} values of 9.63 μM (for ZLA) and 8.64 μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC{sub 50} values of 49.1 μM (for ZLA) and 55.3 μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD. -- Highlights: ► Two novel bis-(−)-nor-meptazinol derivatives are designed and synthesized. ► ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency. ► They are potential leads for disease-modifying treatment of Alzheimer's disease.

  10. Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies.

    PubMed

    Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Martínez-Ramos, Federico; Padilla-Martínez, Itzia Irene; Benítez-Cardoza, Claudia G; Mera-Jiménez, Elvia; Rosales-Hernández, Martha Cecilia

    2014-01-01

    Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.

  11. Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies.

    PubMed

    Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Martínez-Ramos, Federico; Padilla-Martínez, Itzia Irene; Benítez-Cardoza, Claudia G; Mera-Jiménez, Elvia; Rosales-Hernández, Martha Cecilia

    2014-01-01

    Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models. PMID:24762947

  12. Quaternary ammonium sulfanilamide: a membrane-impermeant carbonic anhydrase inhibitor

    SciTech Connect

    Henry, R.P.

    1987-05-01

    A novel carbonic anhydrase (CA) inhibitor, quaternary ammonium sulfanilamide (QAS), was tested for potency as a CA inhibitor and for its ability to be excluded from permeating biological membranes. Inhibitor titration plots of QAS vs. pure bovine CA II and CA from the gills of the blue crab, Callinectes sapidus, yielded K/sub i/ values of approx. 15 ..mu..M; thus QAS is a relatively weak but effective CA inhibitor. Permeability of the QAS was directly tested by two independent methods. The inhibitor was excluded from human erythrocytes incubated in 5 mM QAS for 24 h as determined using an /sup 18/O-labeled mass spectrometer CA assay for intact cells. Also QAS injected into the hemolymph of C. sapidus (1 or 10 mM) did not cross the basal membrane of the gill. The compound was cleared from the hemolymph by 96 h after injection, and at no time during that period could the QAS be detected in homogenates of gill tissue. Total branchial CA activity was only slightly reduced following the QAS injection. These data indicate that QAS is a CA inhibitor to which biological membranes are impermeable and that can be used in vivo and in vitro in the study of membrane-associated CA.

  13. Quaternary ammonium sulfanilamide: a membrane-impermeant carbonic anhydrase inhibitor.

    PubMed

    Henry, R P

    1987-05-01

    A novel carbonic anhydrase (CA) inhibitor, quaternary ammonium sulfanilamide (QAS), was tested for potency as a CA inhibitor and for its ability to be excluded from permeating biological membranes. Inhibitor titration plots of QAS vs. pure bovine CA II and CA from the gills of the blue crab, Callinectes sapidus, yielded Ki values of approximately 15 microM; thus QAS is a relatively weak but effective CA inhibitor. Permeability of the QAS was directly tested by two independent methods. The inhibitor was excluded from human erythrocytes incubated in 5 mM QAS for 24 h as determined using an 18O-labeled mass spectrometer CA assay for intact cells. Also QAS injected into the hemolymph of C. sapidus (1 or 10 mM) did not cross the basal membrane of the gill. The compound was cleared from the hemolymph by 96 h after injection, and at no time during that period could the QAS be detected in homogenates of gill tissue. Total branchial CA activity was only slightly reduced following the QAS injection. These data indicate that QAS is a CA inhibitor to which biological membranes are impermeable and that can be used in vivo or in vitro in the study of membrane-associated CA.

  14. The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats.

    PubMed

    Khan, Nadia; Saad, Ali; Nurulain, Syed M; Darras, Fouad H; Decker, Michael; Sadek, Bassem

    2016-01-15

    Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual

  15. The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats.

    PubMed

    Sadek, Bassem; Khan, Nadia; Darras, Fouad H; Pockes, Steffen; Decker, Michael

    2016-10-15

    Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4μM on hAChE and hH3R antagonism with Ki of 2.54μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5mg/kg, i.p.) on memory deficits induced by the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2mg/kg, i.p.) and DIZ (0.1mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10mg/kg, i.p.) and SCO (1.0mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, observed through histaminergic H2R as well as

  16. Selection of a human butyrylcholinesterase-like antibody single-chain variable fragment resistant to AChE inhibitors from a phage library expressed in E. coli

    PubMed Central

    Podestà, Adriano; Rossi, Serena; Massarelli, Ilaria; Carpi, Sara; Adinolfi, Barbara; Fogli, Stefano; Bianucci, Anna Maria; Nieri, Paola

    2014-01-01

    Organophosphates are potent poisoning agents that cause severe cholinergic toxicity. Current treatment has been reported to be unsatisfactory and novel antidotes are needed. In this study, we used a single-chain variable fragment (scFv) library to select a recombinant antibody fragment (WZ1–14.2.1) with butyrylcholinesterase-like catalytic activity by using an innovative method integrating genetic selection and the bait-and-switch strategy. Ellman assay demonstrated that WZ1–14.2.1 has Michaelis-Menten kinetics in the hydrolysis of all the three substrates used, acetylthiocholine, propionylthiocholine and butyrylthiocholine. Notably, the catalytic activity was resistant to the following acetylcholinesterase inhibitors: neostigmine, iso-OMPA, chlorpyrifos oxon, dichlorvos, and paraoxon ethyl. Otherwise, the enzymatic activity of WZ1–14.2.1 was inhibited by the selective butyrylcholinesterase inhibitor, ethopropazine, and by the Ser-blocking agent phenylmethanesuphonyl fluoride. A hypothetical 3D structure of the WZ1–14.2.1 catalytic site, compatible with functional results, is proposed on the basis of a molecular modeling analysis. PMID:24675419

  17. Selection of a human butyrylcholinesterase-like antibody single-chain variable fragment resistant to AChE inhibitors from a phage library expressed in E. coli.

    PubMed

    Podestà, Adriano; Rossi, Serena; Massarelli, Ilaria; Carpi, Sara; Adinolfi, Barbara; Fogli, Stefano; Bianucci, Anna Maria; Nieri, Paola

    2014-01-01

    Organophosphates are potent poisoning agents that cause severe cholinergic toxicity. Current treatment has been reported to be unsatisfactory and novel antidotes are needed. In this study, we used a single-chain variable fragment (scFv) library to select a recombinant antibody fragment (WZ1-14.2.1) with butyrylcholinesterase-like catalytic activity by using an innovative method integrating genetic selection and the bait-and-switch strategy. Ellman assay demonstrated that WZ1-14.2.1 has Michaelis-Menten kinetics in the hydrolysis of all the three substrates used, acetylthiocholine, propionylthiocholine and butyrylthiocholine. Notably, the catalytic activity was resistant to the following acetylcholinesterase inhibitors: neostigmine, iso-OMPA, chlorpyrifos oxon, dichlorvos, and paraoxon ethyl. Otherwise, the enzymatic activity of WZ1-14.2.1 was inhibited by the selective butyrylcholinesterase inhibitor, ethopropazine, and by the Ser-blocking agent phenylmethanesuphonyl fluoride. A hypothetical 3D structure of the WZ1-14.2.1 catalytic site, compatible with functional results, is proposed on the basis of a molecular modeling analysis.

  18. AChE inhibition: one dominant factor for swimming behavior changes of Daphnia magna under DDVP exposure.

    PubMed

    Ren, Zongming; Zhang, Xu; Wang, Xiaoguang; Qi, Pingping; Zhang, Biao; Zeng, Yang; Fu, Rongshu; Miao, Mingsheng

    2015-02-01

    As a key enzyme that hydrolyzes the neurotransmitter acetylcholine in cholinergic synapses of both vertebrates and invertebrates, acetylcholinesterase (AChE) is strongly inhibited by organophosphates. AChE inhibition may induce the decrease of swimming ability. According to previous research, swimming behavior of different aquatic organisms could be affected by different chemicals, and there is a shortage of research on direct correlation analysis between swimming behavior and biochemical indicators. Therefore, swimming behavior and whole-body AChE activity of Daphnia magna under dichlorvos (DDVP) exposure were identified in order to clarify the relationship between behavioral responses and AChE inhibition in this study. In the beginning, AChE activity was similar in all treatments with the control. During all exposures, the tendency of AChE activity inhibition was the same as the behavioral responses of D. magna. The AChE activity of individuals without movement would decrease to about zero in several minutes. The correlation analysis between swimming behavior of D. magna and AChE activity showed that the stepwise behavioral response was mainly decided by AChE activity. All of these results suggested that the toxicity characteristics of DDVP as an inhibitor of AChE on the swimming behavior of organisms were the same, and the AChE activity inhibition could induce loss of the nerve conduction ability, causing hyperactivity, loss of coordination, convulsions, paralysis and other kinds of behavioral changes, which was illustrated by the stepwise behavioral responses under different environmental stresses.

  19. AChE for DNA degradation.

    PubMed

    Sánchez-Osuna, María; Yuste, Victor J

    2015-06-01

    DNA hydrolysis is a biochemical process often associated with different forms of cell death, including apoptosis. In a recent paper published in Cell Discovery, Du et al. report that synaptic acetylcholinesterase (AChE-S) shows an unexpected enzymatic activity as DNase switched on after cytotoxic insults. PMID:25930710

  20. Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels

    SciTech Connect

    Xia Menghang; Shahane, Sampada A.; Huang, Ruili; Titus, Steven A.; Shum, Enoch; Zhao Yong; Southall, Noel; Zheng, Wei; Witt, Kristine L.; Tice, Raymond R.; Austin, Christopher P.

    2011-05-01

    The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K{sup +}) channels, plays a critical role in the repolarization of the cardiac action potential. The reduction of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially leads to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity associated with the inhibition of hERG channels by environmental chemicals is also a public health concern. To assess the inhibitory effects of environmental chemicals on hERG channel function, we screened the National Toxicology Program (NTP) collection of 1408 compounds by measuring thallium influx into cells through hERG channels. Seventeen compounds with hERG channel inhibition were identified with IC{sub 50} potencies ranging from 0.26 to 22 {mu}M. Twelve of these compounds were confirmed as hERG channel blockers in an automated whole cell patch clamp experiment. In addition, we investigated the structure-activity relationship of seven compounds belonging to the quaternary ammonium compound (QAC) series on hERG channel inhibition. Among four active QAC compounds, tetra-n-octylammonium bromide was the most potent with an IC{sub 50} value of 260 nM in the thallium influx assay and 80 nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the number and length of their aliphatic side-chains surrounding the charged nitrogen. Profiling environmental compound libraries for hERG channel inhibition provides information useful in prioritizing these compounds for cardiotoxicity assessment in vivo.

  1. Searching for Multi-Targeting Neurotherapeutics against Alzheimer's: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif.

    PubMed

    Pisani, Leonardo; Farina, Roberta; Soto-Otero, Ramon; Denora, Nunzio; Mangiatordi, Giuseppe Felice; Nicolotti, Orazio; Mendez-Alvarez, Estefania; Altomare, Cosimo Damiano; Catto, Marco; Carotti, Angelo

    2016-03-17

    The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer's disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 µM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam.

  2. 3D MI-DRAGON: new model for the reconstruction of US FDA drug- target network and theoretical-experimental studies of inhibitors of rasagiline derivatives for AChE.

    PubMed

    Prado-Prado, Francisco; García-Mera, Xerardo; Escobar, Manuel; Alonso, Nerea; Caamaño, Olga; Yañez, Matilde; González-Díaz, Humberto

    2012-01-01

    The number of neurodegenerative diseases has been increasing in recent years. Many of the drug candidates to be used in the treatment of neurodegenerative diseases present specific 3D structural features. An important protein in this sense is the acetylcholinesterase (AChE), which is the target of many Alzheimer's dementia drugs. Consequently, the prediction of Drug-Protein Interactions (DPIs/nDPIs) between new drug candidates and specific 3D structure and targets is of major importance. To this end, we can use Quantitative Structure-Activity Relationships (QSAR) models to carry out a rational DPIs prediction. Unfortunately, many previous QSAR models developed to predict DPIs take into consideration only 2D structural information and codify the activity against only one target. To solve this problem we can develop some 3D multi-target QSAR (3D mt-QSAR) models. In this study, using the 3D MI-DRAGON technique, we have introduced a new predictor for DPIs based on two different well-known software. We have used the MARCH-INSIDE (MI) and DRAGON software to calculate 3D structural parameters for drugs and targets respectively. Both classes of 3D parameters were used as input to train Artificial Neuronal Network (ANN) algorithms using as benchmark dataset the complex network (CN) made up of all DPIs between US FDA approved drugs and their targets. The entire dataset was downloaded from the DrugBank database. The best 3D mt-QSAR predictor found was an ANN of Multi-Layer Perceptron-type (MLP) with profile MLP 37:37-24-1:1. This MLP classifies correctly 274 out of 321 DPIs (Sensitivity = 85.35%) and 1041 out of 1190 nDPIs (Specificity = 87.48%), corresponding to training Accuracy = 87.03%. We have validated the model with external predicting series with Sensitivity = 84.16% (542/644 DPIs; Specificity = 87.51% (2039/2330 nDPIs) and Accuracy = 86.78%. The new CNs of DPIs reconstructed from US FDA can be used to explore large DPI databases in order to discover both new drugs

  3. Quaternary and tertiary aldoxime antidotes for organophosphate exposure in a zebrafish model system

    SciTech Connect

    Schmidt, Hayden R.; Radić, Zoran; Taylor, Palmer; Fradinger, Erica A.

    2015-04-15

    The zebrafish is rapidly becoming an important model system for screening of new therapeutics. Here we evaluated the zebrafish as a potential pharmacological model for screening novel oxime antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE). The k{sub i} values determined for chlorpyrifos oxon (CPO) and dichlorvos (DDVP) showed that CPO was a more potent inhibitor of both human and zebrafish AChE, but overall zebrafish AChE was less sensitive to OP inhibition. In contrast, aldoxime antidotes, the quaternary ammonium 2-PAM and tertiary amine RS-194B, showed generally similar overall reactivation kinetics, k{sub r}, in both zebrafish and human AChE. However, differences between the K{sub ox} and k{sub 2} constants suggest that zebrafish AChE associates more tightly with oximes, but has a slower maximal reactivation rate than human AChE. Homology modeling suggests that these kinetic differences result from divergences in the amino acids lining the entrance to the active site gorge. Although 2-PAM had the more favorable in vitro reactivation kinetics, RS-194B was more effective antidote in vivo. In intact zebrafish embryos, antidotal treatment with RS-194B rescued embryos from OP toxicity, whereas 2-PAM had no effect. Dechorionation of the embryos prior to antidotal treatment allowed both 2-PAM and RS-194B to rescue zebrafish embryos from OP toxicity. Interestingly, RS-194B and 2-PAM alone increased cholinergic motor activity in dechorionated embryos possibly due to the reversible inhibition kinetics, K{sub i} and αK{sub i}, of the oximes. Together these results demonstrate that the zebrafish at various developmental stages provides an excellent model for investigating membrane penetrant antidotes to OP exposure. - Highlights: • Zebrafish AChE shares significant structural similarities with human AChE. • OP-inhibited zebrafish and human AChE exhibit similar reactivation kinetics. • The zebrafish chorion is permeable to BBB penetrant and not

  4. Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski's Rule of Five and ZINC Databank

    PubMed Central

    Nogara, Pablo Andrei; Saraiva, Rogério de Aquino; Caeran Bueno, Diones; Lissner, Lílian Juliana; Lenz Dalla Corte, Cristiane; Braga, Marcos M.; Rosemberg, Denis Broock; Rocha, João Batista Teixeira

    2015-01-01

    Alzheimer's disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski's rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) from Equus ferus (EfBChE), with IC50 ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms. PMID:25685814

  5. Synthesis, Biological Evaluation, and Molecular Docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease.

    PubMed

    Shaik, Jeelan Basha; Palaka, Bhagath Kumar; Penumala, Mohan; Eadlapalli, Siddhartha; Darla Mark, Manidhar; Ampasala, Dinakara Rao; Vadde, Ramakrishna; Amooru Gangaiah, Damu

    2016-07-01

    Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogs (4a-q) were synthesized and evaluated for their multitarget-directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, and amyloid-β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3-bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC50 value of 13 ± 1.4 nm which is 51-fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed-type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e, 4f, 4g, 4j, and 4k have shown 1.4- to 2.5-fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage-dependent acceleration of Aβ1-42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy. PMID:26833890

  6. Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver.

    PubMed

    Yokota, Shin-Ichi; Nakamura, Kaai; Ando, Midori; Kamei, Hiroyasu; Hakuno, Fumihiko; Takahashi, Shin-Ichiro; Shibata, Shigenobu

    2014-01-01

    Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism. PMID:25383314

  7. Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo.

    PubMed

    Chen, Heng-Wen; He, Xuan-Hui; Yuan, Rong; Wei, Ben-Jun; Chen, Zhong; Dong, Jun-Xing; Wang, Jie

    2016-04-01

    Acetylcholinesterase Inhibitor (AchEI) is the most extensive in all anti-dementia drugs. The extracts and isolated compounds from the Valeriana genus have shown anti-dementia bioactivity. Four new sesquiterpenoids (1-4) and a new monoterpenoid (5) were isolated from the root of Valeriana officinalis var. latiofolia. The acetylcholinesterase (AchE) inhibitory activity of isolates was evaluated by modified Ellman method in vitro. Learning and memory ability of compound 4 on mice was evaluated by the Morris water maze. The contents of acetylcholine (Ach), acetylcholine transferase (ChAT) and AchE in mice brains were determined by colorimetry. The results showed IC50 of compound 4 was 0.161 μM in vitro. Compared with the normal group, the learning and memory ability of mice and the contents of Ach and ChAT decreased in model group mice (P<0.01), while the AchE increased (P<0.01). Compared with the model group, Ach and ChAT in the positive control group, the high-dose group and the medium-dose group increased (P<0.01), while the AchE decreased (P<0.01). Compound 4 can improve the learning and memory abilities of APPswe/PSΔE9 double-transgenic mice, and the mechanism may be related to the regulation of the relative enzyme in the cholinergic system. PMID:26976216

  8. Screening of POP pollution by AChE and EROD activities in Zebra mussels from the Italian Great Lakes.

    PubMed

    Binelli, A; Ricciardi, Francesco; Riva, Consuelo; Provini, Alfredo

    2005-12-01

    The increase of ethoxyresorufin dealkylation (EROD) and the inhibition of acetylcholinesterase (AChE) as biomarkers have been commonly used in vertebrates for the persistent organic pollutants (POPs) biomonitoring of aquatic environments, but very few studies have been performed for invertebrates. Previous researches demonstrated the interference due to some chemicals on EROD and AChE activities of the freshwater bivalve Zebra mussel (Dreissena polymorpha) in laboratory and field studies, showing its possible use for the screening of POP effects. We investigated the contamination of the Italian sub-alpine great lakes (Maggiore, Lugano, Como, Iseo, Garda) by the biomarker approach on Zebra mussel specimens collected at 17 sampling sites with different morphometric characteristics and anthropization levels. Results showed a homogeneous contamination of AChE inhibitors in Lake Garda, Maggiore, Como and Iseo with values ranging from 0.5 to 3 nmol/min/mg proteins and with an average inhibition of about 66% to controls. The planar compounds pollution, able to activate the EROD activity, seems higher in some sampling stations of Lake Garda, Como and Iseo (2-4 pmol/min/mg proteins) than that measured in Lake Lugano (1.5-3 pmol/min/mg proteins). On the contrary, the enzyme activity in Lake Maggiore showed an interesting opposite effect of AhR-binding compounds and trace metals. Finally, the possible use of Zebra mussel specimens maintained at laboratory conditions as controls against the selection of the less polluted sampling site is discussed.

  9. Synthetic conversion of ACAT inhibitor to acetylcholinesterase inhibitor.

    PubMed

    Obata, R; Sunazuka, T; Otoguro, K; Tomoda, H; Harigaya, Y; Omura, S

    2000-06-19

    Natural product acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor pyripyropene A was synthetically converted to acetylcholinesterase (AChE) inhibitor via heterolitic cleavage of the 2-pyrone ring, followed by gamma-acylation/cyclization with several aroyl chlorides. The 4-pyridyl analogue selectively showed AChE inhibitory activity (IC50 7.9 microM) and no ACAT inhibitory activity IC50 = >1000 microM. PMID:10890154

  10. Quaternary investigation

    SciTech Connect

    Stieve, A.

    1991-05-15

    The primary purpose of the Quaternary investigation is to provide information on the location and age of Quaternary deposits for use in evaluating the presence or absence of neotectonic deformation or paleoliquefaction features within the Savannah River Site (SRS) region. The investigation will provide a basis for evaluating the potential for capable faults and associated deformation in the SRS vicinity. Particular attention will be paid to the Pen Branch fault.

  11. Bactericidal activity of ACH-702 against nondividing and biofilm Staphylococci.

    PubMed

    Podos, Steven D; Thanassi, Jane A; Leggio, Melissa; Pucci, Michael J

    2012-07-01

    Many bacterial infections involve slow or nondividing bacterial growth states and localized high cell densities. Antibiotics with demonstrated bactericidal activity rarely remain bactericidal at therapeutic concentrations under these conditions. The isothiazoloquinolone (ITQ) ACH-702 is a potent, bactericidal compound with activity against many antibiotic-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We evaluated its bactericidal activity under conditions where bacterial cells were not dividing and/or had slowed their growth. Against S. aureus cultures in stationary phase, ACH-702 showed concentration-dependent bactericidal activity and achieved a 3-log-unit reduction in viable cell counts within 6 h of treatment at ≥ 16× MIC values; in comparison, the bactericidal quinolone moxifloxacin and the additional comparator compounds vancomycin, linezolid, and rifampin at 16× to 32× MICs showed little or no bactericidal activity against stationary-phase cells. ACH-702 at 32× MIC retained bactericidal activity against stationary-phase S. aureus across a range of inoculum densities. ACH-702 did not kill cold-arrested cells yet remained bactericidal against cells arrested by protein synthesis inhibitors, suggesting that its bactericidal activity against nondividing cells requires active metabolism but not de novo protein synthesis. ACH-702 also showed a degree of bactericidal activity at 16× MIC against S. epidermidis biofilm cells that was superior to that of moxifloxacin, rifampin, and vancomycin. The bactericidal activity of ACH-702 against stationary-phase staphylococci and biofilms suggests potential clinical utility in infections containing cells in these physiological states. PMID:22547614

  12. Anticholinesterase inhibitory activity of quaternary alkaloids from Tinospora crispa.

    PubMed

    Yusoff, Mashitah; Hamid, Hazrulrizawati; Houghton, Peter

    2014-01-01

    Quaternary alkaloids are the major alkaloids isolated from Tinospora species. A previous study pointed to the necessary presence of quaternary nitrogens for strong acetylcholinesterase (AChE) inhibitory activity in such alkaloids. Repeated column chromatography of the vine of Tinospora crispa extract led to the isolation of one new protoberberine alkaloid, 4,13-dihydroxy-2,8,9-trimethoxydibenzo[a,g]quinolizinium (1), along with six known alkaloids-dihydrodiscretamine (2), columbamine (3), magnoflorine (4), N-formylannonaine (5), N-formylnornuciferine (6), and N-trans-feruloyltyramine (7). The seven compounds were isolated and structurally elucidated by spectroscopic analysis. Two known alkaloids, namely, dihydrodiscretamine and columbamine are reported for the first time for this plant. The compounds were tested for AChE inhibitory activity using Ellman's method. In the AChE inhibition assay, only columbamine (3) showed strong activity with IC50 48.1 µM. The structure-activity relationships derived from these results suggest that the quaternary nitrogen in the skeleton has some effect, but that a high degree of methoxylation is more important for acetylcholinesterase inhibition. PMID:24448061

  13. Lysosomotropic N,N- dimethyl alpha-aminoacid N-alkyl esters and their quaternary ammonium salts as plasma membrane and mitochondrial ATPases inhibitors.

    PubMed

    Obłak, Ewa; Lachowicz, Tadeusz M; Łuczyński, Jacek; Witek, Stanisław

    2002-01-01

    A set of n-alkyl esters of N,N-dimethylglycine (DMG-n) and their methobromides (DMGM-n) was synthesized, and their activities on yeast Saccharomyces cerevisiae were compared. The compounds differ in the number of carbon atoms in the aliphatic chain. Aminoesters with 12 carbon atoms appeared to be most active. Unlike quaternary ammonium salts previously tested, the activities of the compounds were not pH-dependent; the minimal inhibitory concentrations (MIC) were identical at pH 8 and at pH 6. In contrast to quaternary ammonium salts, aminoesters showed similar effects on respiratory sufficient (rho+) and respiratory deficient (rho0) mutants. When tested on glucose stimulated proton extrusion, aminoesters applied at MIC increased external pH. Aminoesters inhibited the plasma membrane H+-ATPase, whereas they were less inhibitory on the mitochondrial ATPase. In order to further compare the aminoesters and their corresponding quaternary ammonium salts, derivatives of N,N-dimethylalanine (DMAL-n and DMALM-n, respectively) were synthesized. The quaternary ammonium salts appeared to have a higher inhibitory potency than aminoesters, especially at pH 8, and alanine derivatives inhibited growth at a lower concentration than glycine derivatives. Both alanine derivatives of the aminoester and the quaternary ammonium salt inhibited the plasma membrane H+- ATPase at lower concentrations than glycine derivatives, but the alanine aminoester was without a detectable effect on the mitochondrial ATPase.

  14. Searching for the Multi-Target-Directed Ligands against Alzheimer's disease: discovery of quinoxaline-based hybrid compounds with AChE, H₃R and BACE 1 inhibitory activities.

    PubMed

    Huang, Wenhai; Tang, Li; Shi, Ying; Huang, Shufang; Xu, Lei; Sheng, Rong; Wu, Peng; Li, Jia; Zhou, Naiming; Hu, Yongzhou

    2011-12-01

    A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H(3)R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H(3)R/AChE/BACE 1 (H(3)R antagonism, IC(50)=280.0 ± 98.0 nM; H(3)R inverse agonism, IC(50)=189.3 ± 95.7 nM; AChE, IC(50)=483 ± 5 nM; BACE 1, 46.64±2.55% inhibitory rate at 20 μM) and high selectivity over H(1)R/H(2)R/H(4)R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.

  15. Effect of pharmaceuticals exposure on acetylcholinesterase (AchE) activity and on the expression of AchE gene in the monogonont rotifer, Brachionus koreanus.

    PubMed

    Rhee, Jae-Sung; Kim, Bo-Mi; Jeong, Chang-Bum; Park, Heum Gi; Leung, Kenneth Mei Yee; Lee, Young-Mi; Lee, Jae-Seong

    2013-11-01

    Pharmaceuticals are widely used in human and veterinary medicine. However, they are emerging as a significant contaminant in aquatic environments through wastewater. Due to the persistent and accumulated properties of pharmaceuticals via the food web, their potential harmful effects on aquatic animals are a great concern. In this study, we investigated the effects of six pharmaceuticals: acetaminophen, ATP; atenolol, ATN; carbamazepine, CBZ; oxytetracycline, OTC; sulfamethoxazole, SMX; and trimethoprim, TMP on acetylcholinesterase (AChE; EC 3.1.1.7) activity and its transcript expression with chlorpyrifos (as a positive control) in the monogonont rotifer, Brachionus koreanus. ATP, CBZ, and TMP exposure also remarkably inhibited Bk-AChE activity at 100 μg/L (24 h) and 1000 μg/L (12 h and 24 h). ATP, CBZ, and TMP exposure showed a significant decrease in the Bk-AChE mRNA level in a concentration-dependent manner. However, in the case of OTC and SMX, a slight decrease in Bk-AChE mRNA expression was found but only at the highest concentration. The time-course experiments showed that ATP positively induced Bk-AChE mRNA 12 h after exposure at both 100 and 1000 μg/L, while the Bk-AChE mRNA expression was significantly downregulated over 6 to 24 h after exposure to 1000 μg/L of CBZ, OTC, SMX, and TMP. Our findings suggest that Bk-AChE would be a useful biomarker for risk assessment of pharmaceutical compounds as an early signal of their toxicity in aquatic environments. Particularly, ATP, CBZ, and TMP may have a toxic cholinergic effect on rotifer B. koreanus by inhibiting AChE activity. PMID:24028855

  16. Circannual rhythms of acetylcholinesterase (AChE) activity in the freshwater fish Cnesterodon decemmaculatus.

    PubMed

    Menéndez-Helman, Renata J; Ferreyroa, Gisele V; dos Santos Afonso, Maria; Salibián, Alfredo

    2015-01-01

    The use of biomarkers as a tool to assess responses of organisms exposed to pollutants in toxicity bioassays, as well as in aquatic environmental risk assessment protocols, requires the understanding of the natural fluctuation of the particular biomarker. The aim of this study was to characterize the intrinsic variations of acetylcholinesterase (AChE) activity in tissues of a native freshwater teleost fish to be used as biomarker in toxicity tests, taking into account both seasonal influence and fish size. Specific AChE activity was measured by the method of Ellman et al. (1961) in homogenates of fish anterior section finding a seasonal variability. The highest activity was observed in summer, decreasing significantly below 40% in winter. The annual AChE activity cycle in the anterior section was fitted to a sinusoidal function with a period of 11.2 months. Moreover, an inverse relationship between enzymatic activity and the animal size was established. The results showed that both the fish length and seasonal variability affect AChE activity. AChE activity in fish posterior section showed a similar trend to that in the anterior section, while seasonal variations of the activity in midsection were observed but differences were not statistically significant. In addition, no relationship between AChE and total tissue protein was established in the anterior and posterior sections suggesting that the circannual rhythms observed are AChE-specific responses. Results highlight the importance of considering both the fish size and season variations to reach valid conclusions when AChE activity is employed as neurotoxicity biomarker.

  17. Cholinesterases in development: AChE as a firewall to inhibit cell proliferation and support differentiation.

    PubMed

    Layer, Paul G; Klaczinski, Janine; Salfelder, Anika; Sperling, Laura E; Thangaraj, Gopenath; Tuschl, Corina; Vogel-Höpker, Astrid

    2013-03-25

    Acetylcholinesterase (AChE) is a most remarkable protein, not only because it is one of the fastest enzymes in nature, but also since it appears in many molecular forms and is regulated by elaborate genetic networks. AChE is expressed in many tissues during development and in mature organisms, as well as in healthy and diseased states. In search for alternative, "non-classical" functions of cholinesterases (ChEs), AChE could either work within the frame of classic cholinergic systems, but in non-neural tissues ("non-synaptic function"), or act non-enzymatically. Here, we review briefly some of the major ideas and advances of this field, and report on some recent progress from our own experimental work, e.g. that (i) non-neural ChEs have pronounced, predominantly enzymatic effects on early embryonic (limb) development in chick and mouse, that (ii) retinal R28 cells of the rat overexpressing synaptic AChE present a significantly decreased cell proliferation, and that (iii) in developing chick retina ACh-synthesizing and ACh-degrading cells originate from the same postmitotic precursor cells, which later form two locally opposing cell populations. We suggest that such distinct distributions of ChAT(+) vs. AChE(+) cells in the inner half retina provide graded distributions of ACh, which can direct cell differentiation and network formation. Thus, as corroborated by works from many labs, AChE can be considered a highly co-opting protein, which can combine enzymatic and non-enzymatic functions within one molecule. PMID:23047026

  18. Nanoparticles Ease Aching Joints in Mice

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_161188.html Nanoparticles Ease Aching Joints in Mice Treatment might one ... News) -- New research in mice suggests that tiny nanoparticles might one day be a better way to ...

  19. Analysis of AchE and LDH in mollusc, Lamellidens marginalis after exposure to chlorpyrifos.

    PubMed

    Amanullah, B; Stalin, A; Prabu, P; Dhanapal, S

    2010-07-01

    The enzymes Acetylcholinesterase (AchE) and Lactatedehydrogenase (LDH) are used as biological markers in the present study. Enzymes are highly sensitive and used to evaluate the biological effects of organophosphate pesticide chlorpyrifos in freshwater mussel Lamellidens marginalis. The test organisms were exposed to sub-lethal concentration (5 ppm) of chlorpyrifos for 30 days and allowed to recover for seven days. A distinct reduction of the enzyme AchE (34 +/- 3.3 U l(-1)) was found in the treated hepatopancreas. A significant increase in LDH activity in gill, hepatopancreas and muscle was observed. There was a significant recovery in AchE and LDH in the different tissues, after seven days recovery period.. Hence, the changes in the enzymes are found as the best biomarkering tool to evaluate the effect of organophosphate pesticide chlorpyrifos on the aquatic biota.

  20. mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells

    PubMed Central

    2014-01-01

    Background Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist. Methods Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses. Results Decreased E-cadherin expression and increased vimentin and α-SMA expression induced by TGF-β1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-β1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-β1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP. Conclusions Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs. PMID:24678619

  1. Can hydroxylamine be a more potent nucleophile for the reactivation of tabun-inhibited AChE than prototype oxime drugs? An answer derived from quantum chemical and steered molecular dynamics studies.

    PubMed

    Lo, Rabindranath; Ganguly, Bishwajit

    2014-07-29

    Organophosphorus nerve agents are highly toxic compounds which strongly inhibit acetylcholinesterase (AChE) in the blood and in the central nervous system (CNS). Tabun is one of the highly toxic organophosphorus (OP) compounds and is resistant to many oxime drugs formulated for the reactivation of AChE. The reactivation mechanism of tabun-conjugated AChE with various drugs has been examined with density functional theory and ab initio quantum chemical calculations. The presence of a lone-pair located on the amidic group resists the nucleophilic attack at the phosphorus center of the tabun-conjugated AChE. We have shown that the newly designed drug candidate N-(pyridin-2-yl)hydroxylamine, at the MP2/6-31+G*//M05-2X/6-31G* level in the aqueous phase with the polarizable continuum solvation model (PCM), is more effective in reactivating the tabun-conjugated AChE than typical oxime drugs. The rate determining activation barrier with N-(pyridin-2-yl)hydroxylamine was found to be ∼1.7 kcal mol(-1), which is 7.2 kcal mol(-1) lower than the charged oxime trimedoxime (one of the most efficient reactivators in tabun poisonings). The greater nucleophilicity index (ω(-)) and higher CHelpG charge of pyridinylhydroxylamine compared to TMB4 support this observation. Furthermore, we have also examined the reactivation process of tabun-inhibited AChE with some other bis-quaternary oxime drug candidates such as methoxime (MMB4) and obidoxime. The docking analysis suggests that charged bis-quaternary pyridinium oximes have greater binding affinity inside the active-site gorge of AChE compared to the neutral pyridinylhydroxylamine. The peripheral ligand attached to the neutral pyridinylhydroxylamine enhanced the binding with the aromatic residues in the active-site gorge of AChE through effective π-π interactions. Steered molecular dynamics (SMD) simulations have also been performed with the charged oxime (TMB4) and the neutral hydroxylamine. From protein-drug interaction

  2. AChE biosensor based on zinc oxide sol-gel for the detection of pesticides.

    PubMed

    Sinha, Ravi; Ganesana, Mallikarjunarao; Andreescu, Silvana; Stanciu, Lia

    2010-02-28

    Zinc oxide has been used as a matrix for immobilization of acetylcholinesterase (AChE) and detection of the pesticide paraoxon. The immobilized enzyme retained its enzymatic activity up to three months when stored in phosphate buffered saline (pH 7.4) at 4 degrees C. An amperometric biosensor for the detection of paraoxon was designed. The biosensor detected paraoxon in the range 0.035-1.38 ppm and can be used to detect other AChE inhibiting organophosphate pesticides. PMID:20113735

  3. Acetylcholinesterase liquid crystal biosensor based on modulated growth of gold nanoparticles for amplified detection of acetylcholine and inhibitor.

    PubMed

    Liao, Shuzhen; Qiao, Yanan; Han, Wenting; Xie, Zhaoxia; Wu, Zhaoyang; Shen, Guoli; Yu, Ruqin

    2012-01-01

    A novel acetylcholinesterase (AChE) liquid crystal (LC) biosensor based on enzymatic growth of gold nanoparticles (Au NPs) has been developed for amplified detection of acetylcholine (ACh) and AChE inhibitor. In this method, AChE mediates the hydrolysis of acetylthiocholine (ATCl) to form thiocholine, and the latter further reduces AuCl(4)(-) to Au NPs without Au nanoseeds. This process, termed biometallization, leads to a great enhancement in the optical signal of the LC biosensor due to the large size of Au NPs, which can greatly disrupt the orientational arrangement of LCs. On the other hand, the hydrolysis of ATCl is inhibited in the presence of ACh or organophosphate pesticides (OPs, a AChE inhibitor), which will decrease the catalytic growth of Au NPs and, as a result, reduce the orientational response of LCs. On the basis of such an inhibition mechanism, the AChE LC biosensor can be used as an effective way to realize the detection of ACh and AChE inhibitors. The results showed that the AChE LC biosensor was highly sensitive to ACh with a detection limit of 15 μmol/L and OPs with a detection limit of 0.3 nmol/L. This study provides a simple and sensitive AChE LC biosensing approach and offers effective signal enhanced strategies for the development of enzyme LC biosensors. PMID:22148672

  4. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  5. Identification of petrogenic produced water components as acetylcholine esterase inhibitors.

    PubMed

    Froment, Jean; Langford, Katherine; Tollefsen, Knut Erik; Bråte, Inger Lise N; Brooks, Steven J; Thomas, Kevin V

    2016-08-01

    Effect-directed analysis (EDA) was applied to identify acetylcholine esterase (AChE) inhibitors in produced water. Common produced water components from oil production activities, such as polycyclic aromatic hydrocarbons (PAHs), alkylphenols, and naphthenic acids were tested for AChE inhibition using a simple mixture of PAHs and naphthenic acids. Produced water samples collected from two offshore platforms in the Norwegian sector of the North Sea were extracted by solid phase extraction and fractionated by open-column liquid solid chromatography and high-performance liquid chromatography (HPLC) before being tested using a high-throughput and automated AChE assay. The HPLC fractions causing the strongest AChE inhibition were analysed by gas chromatography coupled to a high-resolution time-of-flight mass spectrometry (GC-HR-ToF-MS). Butylated hydroxytoluene and 4-phenyl-1,2-dihydronaphthalene were identified as two produced water components capable of inhibiting AChE at low concentrations. In order to assess the potential presence of such compounds discharged into aquatic ecosystems, AChE activity in fish tissues was measured. Saithe (Pollachius virens) caught near two offshore platforms showed lower enzymatic activity than those collected from a reference location. Target analysis of saithe did not detected the presence of these two putative AChE inhibitors and suggest that additional compounds such as PAHs, naphthenic acids and yet un-identified compounds may also contribute to the purported AChE inhibition observed in saithe. PMID:27176761

  6. Altered GPI modification of insect AChE improves tolerance to organophosphate insecticides.

    PubMed

    Kakani, Evdoxia G; Bon, Suzanne; Massoulié, Jean; Mathiopoulos, Kostas D

    2011-03-01

    The olive fruit fly Bactrocera oleae is the most destructive and intractable pest of olives. The management of B. oleae has been based on the use of organophosphate (OP) insecticides, a practice that induced resistance. OP-resistance in the olive fly was previously shown to be associated with two mutations in the acetylcholinesterase (AChE) enzyme that, apparently, hinder the entrance of the OP into the active site. The search for additional mutations in the ace gene that encodes AChE revealed a short deletion of three glutamines (Δ3Q) from a stretch of five glutamines, in the C-terminal peptide that is normally cleaved and substituted by a GPI anchor. We verified that AChEs from B. oleae and other Dipterans are actually GPI-anchored, although this is not predicted by the "big-PI" algorithm. The Δ3Q mutation shortens the unusually long hydrophilic spacer that follows the predicted GPI attachment site and may thus improve the efficiency of GPI anchor addition. We expressed the wild type B. oleae AChE, the natural mutant Δ3Q and a constructed mutant lacking all 5 consecutive glutamines (Δ5Q) in COS cells and compared their kinetic properties. All constructs presented identical K(m) and k(cat) values, in agreement with the fact that the mutations did not affect the catalytic domain of the enzyme. In contrast, the mutants produced higher AChE activity, suggesting that a higher proportion of the precursor protein becomes GPI-anchored. An increase in the number of GPI-anchored molecules in the synaptic cleft may reduce the sensitivity to insecticides.

  7. A selective molecularly imprinted polymer for immobilization of acetylcholinesterase (AChE): an active enzyme targeted and efficient method.

    PubMed

    Demirci, Gökhan; Doğaç, Yasemin İspirli; Teke, Mustafa

    2015-11-01

    In the present study, we immobilized acetylcholinesterase (AChE) enzyme onto acetylcholine removed imprinted polymer and acetylcholine containing polymer. First, the polymers were produced with acetylcholine, substrate of AChE, by dispersion polymerization. Then, the enzyme was immobilized onto the polymers by using two different methods: In the first method (method A), acetylcholine was removed from the polymer, and then AChE was immobilized onto this polymer (acetylcholine removed imprinted polymer). In the second method (method B), AChE was immobilized onto acetylcholine containing polymer by affinity. In method A, enzyme-specific species (binding sites) occurred by removing acetylcholine from the polymer. The immobilized AChE reached 240% relative specific activity comparison with free AChE because the active enzyme molecules bounded onto the polymer. Transmission electron microscopy results were taken before and after immobilization of AChE for the assessment of morphological structure of polymer. Also, the experiments, which include optimum temperature (25-65 °C), optimum pH (3-10), thermal stability (4-70 °C), kinetic parameters, operational stability and reusability, were performed to determine the characteristic of the immobilized AChE.

  8. Acetylcholinesterase-Fc Fusion Protein (AChE-Fc): A Novel Potential Organophosphate Bioscavenger with Extended Plasma Half-Life.

    PubMed

    Noy-Porat, Tal; Cohen, Ofer; Ehrlich, Sharon; Epstein, Eyal; Alcalay, Ron; Mazor, Ohad

    2015-08-19

    Acetylcholinesterase (AChE) is the physiological target of organophosphate nerve agent compounds. Currently, the development of a formulation for prophylactic administration of cholinesterases as bioscavengers in established risk situations of exposure to nerve agents is the incentive for many efforts. While cholinesterase bioscavengers were found to be highly effective in conferring protection against nerve agent exposure in animal models, their therapeutic use is complicated by short circulatory residence time. To create a bioscavenger with prolonged plasma half-life, compatible with biotechnological production and purification, a chimeric recombinant molecule of HuAChE coupled to the Fc region of human IgG1 was designed. The novel fusion protein, expressed in cultured cells under optimized conditions, maintains its full enzymatic activity, at levels similar to those of the recombinant AChE enzyme. Thus, this novel fusion product retained its binding affinity toward BW284c5 and propidium, and its bioscavenging reactivity toward the organophosphate-AChE inhibitors sarin and VX. Furthermore, when administered to mice, AChE-Fc exhibits exceptional circulatory residence longevity (MRT of 6000 min), superior to any other known cholinesterase-based recombinant bioscavengers. Owing to its optimized pharmacokinetic performance, high reactivity toward nerve agents, and ease of production, AChE-Fc emerges as a promising next-generation organophosphate bioscavenger.

  9. Activation of nicotinic ACh receptors with α4 subunits induces adenosine release at the rat carotid body

    PubMed Central

    Conde, Sílvia V; Monteiro, Emília C

    2006-01-01

    The effect of ACh on the release of adenosine was studied in rat whole carotid bodies, and the nicotinic ACh receptors involved in the stimulation of this release were characterized. ACh and nicotinic ACh receptor agonists, cytisine, DMPP and nicotine, caused a concentration-dependent increase in adenosine production during normoxia, with nicotine being more potent and efficient in stimulating adenosine release from rat CB than cytisine and DMPP. D-Tubocurarine, mecamylamine, DHβE and α-bungarotoxin, nicotinic ACh receptor antagonists, caused a concentration-dependent reduction in the release of adenosine evoked by hypoxia. The rank order of potency for nicotinic ACh receptor antagonists that inhibit adenosine release was DHβE>mecamylamine>D-tubocurarine>α-bungarotoxin. The effect of the endogenous agonist, ACh, which was mimicked by nicotine, was antagonized by DHβE, a selective nicotinic receptor antagonist. The ecto-5′-nucleotidase inhibitor AOPCP produces a 72% inhibition in the release of adenosine from CB evoked by nicotine. Taken together, these data indicate that ACh induced the production of adenosine, mainly from extracellular ATP catabolism at the CB through a mechanism that involves the activation of nicotinic receptors with α4 and β2 receptor subunits. PMID:16444287

  10. Oximes: inhibitors of human recombinant acetylcholinesterase. A structure-activity relationship (SAR) study.

    PubMed

    Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J; Kuca, Kamil

    2013-08-16

    Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

  11. Quaternary and Geomorphology.

    ERIC Educational Resources Information Center

    Andrews, J. T.; Graf, W. L.

    1983-01-01

    Highlights conferences and meetings of organizations involved with quaternary geology and geomorphology, including International Union of Quaternary Research Conference held in Moscow. The impetus of a revision of "The Quaternary of the United States" resulted from this conference. Includes activities/aims of "Friends of the Pleistocene"…

  12. Acetylcholine as a signaling system to environmental stimuli in plants. III. Asymmetric solute distribution controlled by ACh in gravistimulated maize seedlings.

    PubMed

    Momonoki, Y S; Hineno, C; Noguchi, K

    1998-01-01

    Asymmetric distribution of acetylcholinesterase (AChE) activity has previously been demonstrated to occur in the lower side of the gravity-stimulated maize shoot. The localization of immunoreacted IAA-inositol synthase, AChE and safranin was detected in selected organs of gravistimulated dark grown maize seedlings using a light microscope. Immunoreacted IAA-inositol synthase was asymmetrically distributed in the lower side of the stele of coleoptile node and mesocotyl in maize seedlings placed horizontally. The positive AChE spots in the coleoptile node and mesocotyl were apparently localized in the lower half of the gravistimulated seedlings. Safranin was also asymmetrically distributed in the lower half of the endodermis and stele cells of coleoptile node and mesocotyl. Namely, transport of safranin in the upper half of the coleoptile node and mesocotyl was blocked by gravistimulation. Furthermore, the asymmetric distribution of immunoreacted IAA-inositol synthase was inhibited by neostigmine bromide, AChE inhibitor. These results show that an asymmetric environmental stimulus induces changes in AChE activity, affecting IAA-inositol synthase localization and safranin transport. PMID:12162322

  13. Time Evolution of the Quaternary Structure of Escherichia Coli Aspartate Transcarbamoylase Upon Reaction With the Natural Substrates And a Slow Tight Binding Inhibitor

    SciTech Connect

    West, J.M.; Xia, J.; Tsuruta, H.; Guo, W.; O'Day, E.M.; Kantrowitz, E.R.

    2009-05-26

    Here, we present a study of the conformational changes of the quaternary structure of Escherichia coli aspartate transcarbamoylase, as monitored by time-resolved small-angle X-ray scattering, upon combining with substrates, substrate analogs, and nucleotide effectors at temperatures between 5 and 22 {sup o}C, obviating the need for ethylene glycol. Time-resolved small-angle X-ray scattering time courses tracking the T {yields} R structural change after mixing with substrates or substrate analogs appeared to be a single phase under some conditions and biphasic under other conditions, which we ascribe to multiple ligation states producing a time course composed of multiple rates. Increasing the concentration of substrates up to a certain point increased the T {yields} R transition rate, with no further increase in rate beyond that point. Most strikingly, after addition of N-phosphonacetyl-l-aspartate to the enzyme, the transition rate was more than 1 order of magnitude slower than with the natural substrates. These results on the homotropic mechanism are consistent with a concerted transition between structural and functional states of either low affinity, low activity or high affinity, high activity for aspartate. Addition of ATP along with the substrates increased the rate of the transition from the T to the R state and also decreased the duration of the R-state steady-state phase. Addition of CTP or the combination of CTP/UTP to the substrates significantly decreased the rate of the T {yields} R transition and caused a shift in the enzyme population towards the T state even at saturating substrate concentrations. These results on the heterotropic mechanism suggest a destabilization of the T state by ATP and a destabilization of the R state by CTP and CTP/UTP, consistent with the T and R state crystallographic structures of aspartate transcarbamoylase in the presence of the heterotropic effectors.

  14. In Vitro Anti-AChE, Anti-BuChE, and Antioxidant Activity of 12 Extracts of Eleutherococcus Species

    PubMed Central

    2016-01-01

    Neurodegenerative diseases are one of the most occurring diseases in developed and developing countries. The aim of this work focused on the screening of the natural inhibitors of AChE and BuChE and antioxidants in Eleutherococcus species. We found that the ethanol extracts of E. setchuenensis and E. sessiliflorus showed the strongest inhibition towards AChE (IC50: 0.3 and 0.3 mg/mL, resp.). Among chloroform extracts, the most active appeared to be E. gracilistylus (IC50: 0.37 mg/mL). In turn, the ethanol extract of E. henryi inhibited the strongest BuChE with IC50 value of 0.13 mg/mL. Among chloroform extracts, E. gracilistylus, E. setchuenensis, and E. sessiliflorus appeared to be the strongest with IC50 values of 0.12, 0.18, and 0.19 mg/mL. HPTLC screening confirmed the presence of inhibitors in extracts. All extracts exhibited anti-DPPH⁎ activity and single antioxidants have been identified. To the best of our knowledge, no information was available on this activity of compounds in Eleutherococcus. These studies provide a biochemical basis for the regulation of AChE and BuChE and encourage us to continue isolation of active compounds. PMID:27803761

  15. In silico methods to assist drug developers in acetylcholinesterase inhibitor design.

    PubMed

    Bermúdez-Lugo, J A; Rosales-Hernández, M C; Deeb, O; Trujillo-Ferrara, J; Correa-Basurto, J

    2011-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by a low acetylcholine (ACh) concentration in the hippocampus and cortex. ACh is a neurotransmitter hydrolyzed by acetylcholinesterase (AChE). Therefore, it is not surprising that AChE inhibitors (AChEIs) have shown better results in the treatment of AD than any other strategy. To improve the effects of AD, many researchers have focused on designing and testing new AChEIs. One of the principal strategies has been the use of computational methods (structural bioinformatics or in silico methods). In this review, we summarize the in silico methods used to enhance the understanding of AChE, particularly at the binding site, to design new AChEIs. Several computational methods have been used, such as docking approaches, molecular dynamics studies, quantum mechanical studies, electronic properties, hindrance effects, partition coefficients (Log P) and molecular electrostatic potentials surfaces, among other physicochemical methods that exhibit quantitative structure-activity relationships.

  16. Cholinesterase inhibitors from botanicals

    PubMed Central

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  17. Cholinesterase inhibitors from botanicals.

    PubMed

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P; Ahmed, K K Mueen

    2013-07-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  18. Acetylcholinesterase (AChE) gene modification in transgenic animals: functional consequences of selected exon and regulatory region deletion.

    PubMed

    Camp, Shelley; Zhang, Limin; Marquez, Michael; de la Torre, Brian; Long, Jeffery M; Bucht, Goran; Taylor, Palmer

    2005-12-15

    AChE is an alternatively spliced gene. Exons 2, 3 and 4 are invariantly spliced, and this sequence is responsible for catalytic function. The 3' alternatively spliced exons, 5 and 6, are responsible for AChE disposition in tissue [J. Massoulie, The origin of the molecular diversity and functional anchoring of cholinesterases. Neurosignals 11 (3) (2002) 130-143; Y. Li, S. Camp, P. Taylor, Tissue-specific expression and alternative mRNA processing of the mammalian acetylcholinesterase gene. J. Biol. Chem. 268 (8) (1993) 5790-5797]. The splice to exon 5 produces the GPI anchored form of AChE found in the hematopoietic system, whereas the splice to exon 6 produces a sequence that binds to the structural subunits PRiMA and ColQ, producing AChE expression in brain and muscle. A third alternative RNA species is present that is not spliced at the 3' end; the intron 3' of exon 4 is used as coding sequence and produces the read-through, unanchored form of AChE. In order to further understand the role of alternative splicing in the expression of the AChE gene, we have used homologous recombination in stem cells to produce gene specific deletions in mice. Alternatively and together exon 5 and exon 6 were deleted. A cassette containing the neomycin gene flanked by loxP sites was used to replace the exon(s) of interest. Tissue analysis of mice with exon 5 deleted and the neomycin cassette retained showed very low levels of AChE expression, far less than would have been anticipated. Only the read-through species of the enzyme was produced; clearly the inclusion of the selection cassette disrupted splicing of exon 4 to exon 6. The selection cassette was then deleted in exon 5, exon 6 and exons 5 + 6 deleted mice by breeding to Ella-cre transgenic mice. AChE expression in serum, brain and muscle has been analyzed. Another AChE gene targeted mouse strain involving a region in the first intron, found to be critical for AChE expression in muscle cells [S. Camp, L. Zhang, M. Marquez, B

  19. Selective and Irreversible Inhibitors of Aphid Acetylcholinesterases: Steps Toward Human-Safe Insecticides

    PubMed Central

    Pang, Yuan-Ping; Singh, Sanjay K.; Gao, Yang; Lassiter, T. Leon; Mishra, Rajesh K.; Zhu, Kun Yan; Brimijoin, Stephen

    2009-01-01

    Aphids, among the most destructive insects to world agriculture, are mainly controlled by organophosphate insecticides that disable the catalytic serine residue of acetylcholinesterase (AChE). Because these agents also affect vertebrate AChEs, they are toxic to non-target species including humans and birds. We previously reported that a cysteine residue (Cys), found at the AChE active site in aphids and other insects but not mammals, might serve as a target for insect-selective pesticides. However, aphids have two different AChEs (termed AP and AO), and only AP-AChE carries the unique Cys. The absence of the active-site Cys in AO-AChE might raise concerns about the utility of targeting that residue. Herein we report the development of a methanethiosulfonate-containing small molecule that, at 6.0 µM, irreversibly inhibits 99% of all AChE activity extracted from the greenbug aphid (Schizaphis graminum) without any measurable inhibition of the human AChE. Reactivation studies using β-mercaptoethanol confirm that the irreversible inhibition resulted from the conjugation of the inhibitor to the unique Cys. These results suggest that AO-AChE does not contribute significantly to the overall AChE activity in aphids, thus offering new insight into the relative functional importance of the two insect AChEs. More importantly, by demonstrating that the Cys-targeting inhibitor can abolish AChE activity in aphids, we can conclude that the unique Cys may be a viable target for species-selective agents to control aphids without causing human toxicity and resistance problems. PMID:19194505

  20. Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs

    PubMed Central

    Lin, Bo; Xiang, Shihua; Li, Mengsen

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) are targets for developing new drugs to treat severe pain, nicotine addiction, Alzheimer disease, epilepsy, etc. α-Conotoxins are biologically and chemically diverse. With 12–19 residues and two disulfides, they can be specifically selected for different nAChRs. Acetylcholine-binding proteins from Aplysia californica (Ac-AChBP) are homologous to the ligand-binding domains of nAChRs and pharmacologically similar. X-ray structures of the α-conotoxin in complex with Ac-AChBP in addition to computer modeling have helped to determine the binding site of the important residues of α-conotoxin and its affinity for nAChR subtypes. Here, we present the various α-conotoxin residues that are selective for Ac-AChBP or nAChRs by comparing the structures of α-conotoxins in complex with Ac-AChBP and by modeling α-conotoxins in complex with nAChRs. The knowledge of these binding sites will assist in the discovery and design of more potent and selective α-conotoxins as drug leads. PMID:27727162

  1. Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors.

    PubMed

    Mantoani, Susimaire P; Chierrito, Talita P C; Vilela, Adriana F L; Cardoso, Carmen L; Martínez, Ana; Carvalho, Ivone

    2016-02-05

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization.

  2. Anisotropic a-C:H from Compression of Polyacetylene

    NASA Astrophysics Data System (ADS)

    Bernasconi, M.; Parrinello, M.; Chiarotti, G. L.; Focher, P.; Tosatti, E.

    1996-03-01

    We have simulated the transformation of crystalline trans-polyacetylene into a-C:H under pressure by constant pressure ab initio molecular dynamics. Polyacetylene undergoes a gradual saturation of C-C bonds via chain interlinks, ending up at ~50 GPa with a-C:H containing 80% sp3 carbon atoms. The sp2-->sp3 conversion is irreversible and does not reverse by returning to zero pressure. The final a-C:H is a wide gap insulator and, at variance with the conventionally generated a-C:H, is highly anisotropic keeping some memory of the original polyacetylene chain axis.

  3. Modelling interactions between Loop1 of Fasciculin2 (Fas2) and Torpedo californica acetylcholinesterase ( Tc AChE)

    NASA Astrophysics Data System (ADS)

    Wang, Jing; Gu, Jiande; Leszczynski, Jerzy

    2006-11-01

    Four interaction models for the binding of Torpedo californica acetylcholinesterase ( TcAChE) with Loop1 of Fasciculin2 are investigated at the B3LYP/6-311G(d,p) level of theory. The total binding energy of three fragments (P1-P3) which belong to the omega loop Cys67-Cys94 of TcAChE contributes almost 67% of the entire binding, suggesting the domination of this omega loop on the interaction between AChE and Loop1 of Fas2. The energy decomposition illustrates that the interactions mainly consist of electrostatic components. The polar solvent which reduces the binding energies of the studied models implies the significant impact of the solvent on the binding of Fas2 and AChE.

  4. In vivo protection against soman toxicity by known inhibitors of acetylcholine synthesis in vitro.

    PubMed

    Sterling, G H; Doukas, P H; Sheldon, R J; O'Neill, J J

    1988-02-01

    Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 micrograms/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 mumol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2-3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinuclidinol, a potent HAChU inhibitor (1 mumol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30-60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of

  5. In vivo protection against soman toxicity by known inhibitors of acetylcholine synthesis in vitro.

    PubMed

    Sterling, G H; Doukas, P H; Sheldon, R J; O'Neill, J J

    1988-02-01

    Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 micrograms/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 mumol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2-3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinuclidinol, a potent HAChU inhibitor (1 mumol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30-60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of

  6. Affinity binding-guided fluorescent nanobiosensor for acetylcholinesterase inhibitors via distance modulation between the fluorophore and metallic nanoparticle.

    PubMed

    Zhang, Yaodong; Hei, Tingting; Cai, Yanan; Gao, Qunqun; Zhang, Qi

    2012-03-20

    The magnitude of fluorescence enhancement was found to depend strongly on the distance between fluorophores and metal nanostructures in metal-enhanced fluorescence (MEF). However, the precise placement of the particle in front of the molecule with nanometer accuracy and distance control is a great challenge. We describe a method using acetylcholinesterase (AChE) to modulate the distance between a gold nanoparticle (AuNP) and the fluorophore 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one) (DDAO). We found that DDAO is a reversible mixed type-I AChE inhibitor. DDAO binds to the peripheral anionic site and penetrates into the active gorge site of AChE via inhibition kinetics test and molecular docking study. The affinity ligand DDAO bound to AChE which was immobilized onto AuNPs, and its fluorescence was sharply enhanced due to MEF. The fluorescence was reduced by distance variations between the AuNP and DDAO, which resulted from other inhibitors competitively binding with AChE and partly or completely displacing DDAO. Experimental results show that changes in fluorescence intensity are related to the concentration of inhibitors present in the solution. In addition, the nanobiosensor has high sensitivity, with detection limits as low as 0.4 μM for paraoxon and 10 nM for tacrine, and also exhibits different reduction efficiencies for the two types of inhibitor. Thus, instead of an inhibition test, a new type of affinity binding-guided fluorescent nanobiosensor was fabricated to detect AChE inhibitors, determine AChE inhibitor binding mode, and screen more potent AChE inhibitors. The proposed strategy may be applied to other proteins or protein domains via changes in the affinity ligand.

  7. Salicylanilide diethyl phosphates as cholinesterases inhibitors.

    PubMed

    Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína; Vinšová, Jarmila

    2015-02-01

    Based on the presence of dialkyl phosphate moiety, we evaluated twenty-seven salicylanilide diethyl phosphates (diethyl [2-(phenylcarbamoyl)phenyl] phosphates) for the inhibition of acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.) and butyrylcholinesterase (BChE) from equine serum. Ellman's spectrophotometric method was used. The inhibitory activity (expressed as IC50 values) was compared with that of the established drugs galantamine and rivastigmine. Salicylanilide diethyl phosphates showed significant activity against both cholinesterases with IC50 values from 0.903 to 86.3 μM. IC50s for BChE were comparatively lower than those obtained for AChE. All of the investigated compounds showed higher inhibition of AChE than rivastigmine, and six of them inhibited BChE more effectively than both rivastigmine and galantamine. In general, derivatives of 4-chlorosalicylic acid showed enhanced activity when compared to derivatives of 5-halogenated salicylic acids, especially against BChE. The most effective inhibitor of AChE was O-{5-chloro-2-[(3-bromophenyl)carbamoyl]phenyl} O,O-diethyl phosphate with IC50 of 35.4 μM, which is also one of the most potent inhibitors of BChE. O-{5-Chloro-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphate exhibited in vitro the strongest inhibition of BChE (0.90 μM). Salicylanilide diethyl phosphates act as pseudo-irreversible cholinesterases inhibitors. PMID:25462625

  8. The herbicide glyphosate is a weak inhibitor of acetylcholinesterase in rats.

    PubMed

    Larsen, Karen E; Lifschitz, Adrián L; Lanusse, Carlos E; Virkel, Guillermo L

    2016-07-01

    The current work evaluated the inhibitory potency of the herbicide glyphosate (GLP) on acetylcholinesterase (AChE) activity in male and female rat tissues. The AChE activity in brain was higher (p<0.05) than those observed in kidney (females: 2.2-fold; males: 1.9-fold), liver (females: 6-fold; males: 6.9-fold) and plasma (females: 14.7-fold; males: 25.3-fold). Enzyme activities were higher in presence of 10mM GLP compared to those measured at an equimolar concentration of the potent AChE inhibitor dichlorvos (DDVP). Moreover, IC50s for GLP resulted between 6×10(4)- and 6.8×10(5)-fold higher than those observed for DDVP. In conclusion, GLP is a weak inhibitor of AChE in rats. PMID:27258137

  9. Serotonin syndrome: pills, thrills and shoulder aches.

    PubMed

    Proudfoot, Malcolm; Gormley, Joe

    2013-01-01

    This case demonstrates an acute presentation of unwitnessed seizure causing typical injuries. Progress in hospital was complicated by worsening autonomic disturbance and agitation, typical for serotonin syndrome, suspected in light of recent selective serotonin reuptake inhibitor antidepressant initiation. Supportive care required treatment in the intensive care unit setting but full recovery ensued. This case not only reminds clinicians of the potential pitfalls in assessing postictal injured patients, but also that serotonin syndrome requires a high-index of diagnostic suspicion given the range of presenting features. Management ranges from simple withdrawal of the offending agent to specific therapies such as a cyproheptadine. PMID:23429023

  10. Gripped by Gout: Avoiding the Ache and Agony

    MedlinePlus

    ... please review our exit disclaimer . Subscribe Gripped by Gout Avoiding the Ache and Agony Sudden, painful swelling ... toe is often the first warning sign of gout. It can affect other joints as well. Without ...

  11. Acetylcholinesterase (AChE) is an important link in the apoptotic pathway induced by hyperglycemia in Y79 retinoblastoma cell line

    PubMed Central

    Masha'our, R. Shehadeh; Heinrich, R.; Garzozi, H. J.; Perlman, I.

    2012-01-01

    Acetylcholinesterase (AChE) expression was found to be induced in the mammalian CNS, including the retina, by different types of stress leading to cellular apoptosis. Here, we tested possible involvement of AChE in hyperglycemia-induced apoptosis in a retinal cell line. Y79 retinoblastoma cells were incubated in starvation media (1% FBS and 1 mg/ml glucose) for 16–24 h, and then exposed to hyperglycemic environment by raising extracellular glucose concentrations to a final level of 3.5 mg/ml or 6 mg/ml. Similar levels of mannitol were used as control for hyperosmolarity. Cells were harvested at different time intervals for analysis of apoptosis and AChE protein expression. Apoptosis was detected by the cleavage of Poly ADP-ribose polymerase (PARP) using western blot, and by Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling (TUNEL) assay. AChE protein expression and activity was detected by western blot and by the Karnovsky and Roots method, respectively. MissionTM shRNA for AChE was used to inhibit AChE protein expression. Treating Y79 cells with 3.5 mg/ml of glucose, but not with 3.5 mg/ml mannitol, induced apoptosis which was confirmed by TUNEL assay and by cleavage of PARP. A part of the signaling pathway accompanying the apoptotic process involved up-regulation of the AChE-R variant and an N-extended AChE variant as verified at the mRNA and protein level. Inhibition of AChE protein expression by shRNA protected Y79 cell from entering the apoptotic pathway. Our data suggest that expression of an N-extended AChE variant, most probably an R isoform, is involved in the apoptotic pathway caused by hyperglycemia in Y79 cells. PMID:22685426

  12. Acetylcholinesterase (AChE) is an important link in the apoptotic pathway induced by hyperglycemia in Y79 retinoblastoma cell line.

    PubMed

    Masha'our, R Shehadeh; Heinrich, R; Garzozi, H J; Perlman, I

    2012-01-01

    Acetylcholinesterase (AChE) expression was found to be induced in the mammalian CNS, including the retina, by different types of stress leading to cellular apoptosis. Here, we tested possible involvement of AChE in hyperglycemia-induced apoptosis in a retinal cell line. Y79 retinoblastoma cells were incubated in starvation media (1% FBS and 1 mg/ml glucose) for 16-24 h, and then exposed to hyperglycemic environment by raising extracellular glucose concentrations to a final level of 3.5 mg/ml or 6 mg/ml. Similar levels of mannitol were used as control for hyperosmolarity. Cells were harvested at different time intervals for analysis of apoptosis and AChE protein expression. Apoptosis was detected by the cleavage of Poly ADP-ribose polymerase (PARP) using western blot, and by Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling (TUNEL) assay. AChE protein expression and activity was detected by western blot and by the Karnovsky and Roots method, respectively. Mission(TM) shRNA for AChE was used to inhibit AChE protein expression. Treating Y79 cells with 3.5 mg/ml of glucose, but not with 3.5 mg/ml mannitol, induced apoptosis which was confirmed by TUNEL assay and by cleavage of PARP. A part of the signaling pathway accompanying the apoptotic process involved up-regulation of the AChE-R variant and an N-extended AChE variant as verified at the mRNA and protein level. Inhibition of AChE protein expression by shRNA protected Y79 cell from entering the apoptotic pathway. Our data suggest that expression of an N-extended AChE variant, most probably an R isoform, is involved in the apoptotic pathway caused by hyperglycemia in Y79 cells. PMID:22685426

  13. Evaluation of the Toxicity, AChE Activity and DNA Damage Caused by Imidacloprid on Earthworms, Eisenia fetida.

    PubMed

    Wang, Kai; Qi, Suzhen; Mu, Xiyan; Chai, Tingting; Yang, Yang; Wang, Dandan; Li, Dongzhi; Che, Wunan; Wang, Chengju

    2015-10-01

    Imidacloprid is a well-known pesticide and it is timely to evaluate its toxicity to earthworms (Eisenia fetida). In the present study, the effect of imidacloprid on reproduction, growth, acetylcholinesterase (AChE) and DNA damage in earthworms was assessed using an artificial soil medium. The median lethal concentration (LC50) and the median number of hatched cocoons (EC50) of imidacloprid to earthworms was 3.05 and 0.92 mg/kg respectively, the lowest observed effect concentration of imidacloprid about hatchability, growth, AChE activity and DNA damage was 0.02, 0.5, 0.1 and 0.5 mg/kg, respectively.

  14. Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction

    PubMed Central

    Lin, T; Simchovitz, A; Shenhar-Tsarfaty, S; Vaisvaser, S; Admon, R; Hanin, G; Hanan, M; Kliper, E; Bar-Haim, Y; Shomron, N; Fernandez, G; Lubin, G; Fruchter, E; Hendler, T; Soreq, H

    2016-01-01

    Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome–neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility. PMID:27138800

  15. Alpha3* and alpha 7 nAChR-mediated Ca2+ transient generation in IMR-32 neuroblastoma cells.

    PubMed

    Ween, Hilde; Thorin-Hagene, Kirsten; Andersen, Elisabeth; Grønlien, Jens Halvard; Lee, Chih-Hung; Gopalakrishnan, Murali; Malysz, John

    2010-10-01

    Alpha3-containing (alpha 3*) and alpha 7 nicotinic acetylcholine receptors (nAChRs) are expressed in human IMR-32 neuroblastoma cells and implicated in Ca(2+) signaling. In this study, we investigated the intracellular Ca(2+) transient generation evoked by selective activation of alpha 3* (agonist potency rank order: epibatidine>varenicline>nicotine approximately cytisine) and alpha 7 (rank order in the presence of alpha 7 positive allosteric modulator or PAM: A-795723>NS6784 approximately PNU-282987) using, respectively, varenicline and NS6784 (+alpha 7 PAM) by Ca(2+) imaging. Effects of inhibitors of nAChRs (MLA and mecamylamine), ER Ca(2+) ATPase pump (CPA and thapsigargin), Ca(2+)-induced Ca(2+) release (ryanodine and dantrolene), Ca(2+) channels (nitrendipine, diltiazem, and Cd(2+)), and removal of extracellular Ca(2+) were examined. alpha 7 PAMs, when tested in the presence of NS6784, were more active when added first, followed by the agonist, than in the reverse order. Removal of extracellular Ca(2+) - but not CPA, thapsigargin, ryanodine, dantrolene, nitrendipine, diltiazem, or Cd(2+) - diminished the alpha 7 agonist-evoked Ca(2+) transients. In contrast, only diltiazem and nitrendipine and removal of extracellular Ca(2+) inhibited the alpha 3*-mediated Ca(2+) transients. The differential effect of diltiazem and nitrendipine versus Cd(2+) was due to direct inhibition of alpha 3* nAChRs as revealed by Ca(2+) imaging in HEK-293 cells expressing human alpha 3 beta 4 nAChRs and patch clamp in IMR-32 cells. In summary, this study provides evidence that alpha 3* and alpha 7 nAChR agonist-evoked global Ca(2+) transient generation in IMR-32 cells does not primarily involve voltage-dependent Ca(2+) channels, intracellular Ca(2+) stores, or Ca(2+)-induced Ca(2+) release. These mechanisms may, however, be still involved in other forms of nAChR-mediated Ca(2+) signaling.

  16. Acetylcholinesterase inhibitors and Gulf War illnesses

    PubMed Central

    Golomb, Beatrice Alexandra

    2008-01-01

    Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose–response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV. PMID:18332428

  17. An acetylcholinesterase (AChE) biosensor with enhanced solvent resistance based on chitosan for the detection of pesticides.

    PubMed

    Warner, John; Andreescu, Silvana

    2016-01-01

    Solvent tolerance of immobilized enzymes is important for many biosensing and biotechnological applications. In this paper we report an acetylcholinesterase (AChE) biosensor based on chitosan that exhibits high solvent resistance and enables sensitive detection of pesticides in presence of a high content of organic solvents. The solvent effect was established comparatively for the enzyme immobilized in chitosan and covalently cross-linked with glutaraldehyde. The activity of the immobilized AChE was dependent on the immobilization method and solvent type. The enzyme entrapped in chitosan fully conserved its activity in up to 25% methanol, 15% acetonitrile and 100% cyclohexane while the enzyme cross-linked with glutaraldehyde gradually lost its activity starting at 5% acetonitrile and methanol, and showed variable levels in cyclohexane. The detection limits of the biosensor for paraoxon were: 7.5 nM in 25% methanol, 100 nM in 15% acetonitrile and 2.5 μM in 100% cyclohexane. This study demonstrates that chitosan provides an excellent immobilization environment for AChE biosensors designed to operate in environments containing high amounts of organic solvents. It also highlights the effect of the immobilization material and solvent type on enzyme stability. These findings can enable future selection of the immobilization matrix and solvent type for the development of organic phase enzyme based systems.

  18. An acetylcholinesterase (AChE) biosensor with enhanced solvent resistance based on chitosan for the detection of pesticides.

    PubMed

    Warner, John; Andreescu, Silvana

    2016-01-01

    Solvent tolerance of immobilized enzymes is important for many biosensing and biotechnological applications. In this paper we report an acetylcholinesterase (AChE) biosensor based on chitosan that exhibits high solvent resistance and enables sensitive detection of pesticides in presence of a high content of organic solvents. The solvent effect was established comparatively for the enzyme immobilized in chitosan and covalently cross-linked with glutaraldehyde. The activity of the immobilized AChE was dependent on the immobilization method and solvent type. The enzyme entrapped in chitosan fully conserved its activity in up to 25% methanol, 15% acetonitrile and 100% cyclohexane while the enzyme cross-linked with glutaraldehyde gradually lost its activity starting at 5% acetonitrile and methanol, and showed variable levels in cyclohexane. The detection limits of the biosensor for paraoxon were: 7.5 nM in 25% methanol, 100 nM in 15% acetonitrile and 2.5 μM in 100% cyclohexane. This study demonstrates that chitosan provides an excellent immobilization environment for AChE biosensors designed to operate in environments containing high amounts of organic solvents. It also highlights the effect of the immobilization material and solvent type on enzyme stability. These findings can enable future selection of the immobilization matrix and solvent type for the development of organic phase enzyme based systems. PMID:26695264

  19. Selenofuranoside Ameliorates Memory Loss in Alzheimer-Like Sporadic Dementia: AChE Activity, Oxidative Stress, and Inflammation Involvement.

    PubMed

    Chiapinotto Spiazzi, Cristiano; Bucco Soares, Melina; Pinto Izaguirry, Aryele; Musacchio Vargas, Laura; Zanchi, Mariane Magalhães; Frasson Pavin, Natasha; Ferreira Affeldt, Ricardo; Seibert Lüdtke, Diogo; Prigol, Marina; Santos, Francielli Weber

    2015-01-01

    Alzheimer's disease (AD) is becoming more common due to the increase in life expectancy. This study evaluated the effect of selenofuranoside (Se) in an Alzheimer-like sporadic dementia animal model. Male mice were divided into 4 groups: control, Aβ, Se, and Aβ + Se. Single administration of Aβ peptide (fragments 25-35; 3 nmol/3 μL) or distilled water was administered via intracerebroventricular (i.c.v.) injection. Selenofuranoside (5 mg/kg) or vehicle (canola oil) was administered orally 30 min before Aβ and for 7 subsequent days. Memory was tested through the Morris water maze (MWM) and step-down passive-avoidance (SDPA) tests. Antioxidant defenses along with reactive species (RS) were assessed. Inflammatory cytokines levels and AChE activity were measured. SOD activity was inhibited in the Aβ group whereas RS were increased. AChE activity, GSH, and IL-6 levels were increased in the Aβ group. These changes were reflected in impaired cognition and memory loss, observed in both behavioral tests. Se compound was able to protect against memory loss in mice in both behavioral tests. SOD and AChE activities as well as RS and IL-6 levels were also protected by Se administration. Therefore, Se is promising for further studies.

  20. Toxicological and Biochemical Characterizations of AChE in Phosalone-Susceptible and Resistant Populations of the Common Pistachio Psyllid, Agonoscena pistaciae

    PubMed Central

    Alizadeh, Ali; Talebi-Jahromi, Khalil; Hosseininaveh, Vahid; Ghadamyari, Mohammad

    2014-01-01

    The toxicological and biochemical characteristics of acetylcholinesterases (AChE) in nine populations of the common pistachio psyllid, Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Psyllidae), were investigated in Kerman Province, Iran. Nine A. pistaciae populations were collected from pistachio orchards, Pistacia vera L. (Sapindales: Anacardiaceae), located in Rafsanjan, Anar, Bam, Kerman, Shahrbabak, Herat, Sirjan, Pariz, and Paghaleh regions of Kerman province. The previous bioassay results showed these populations were susceptible or resistant to phosalone, and the Rafsanjan population was most resistant, with a resistance ratio of 11.3. The specific activity of AChE in the Rafsanjan population was significantly higher than in the susceptible population (Bam). The affinity (KM) and hydrolyzing efficiency (Vmax) of AChE on acetylthiocholine iodide, butyrylthiocholine iodide, and propionylthiocholine odide as artificial substrates were clearly lower in the Bam population than that in the Rafsanjan population. These results indicated that the AChE of the Rafsanjan population had lower affinity to these substrates than that of the susceptible population. The higher Vmax value in the Rafsanjan population compared to the susceptible population suggests a possible over expression of AChE in the Rafsanjan population. The in vitro inhibitory effect of several organophosphates and carbamates on AChE of the Rafsanjan and Bam populations was determined. Based on I50, the results showed that the ratios of AChE insensitivity of the resistant to susceptible populations were 23 and 21.7-fold to monocrotophos and phosphamidon, respectively. Whereas, the insensitivity ratios for Rafsanjan population were 0.86, 0.8, 0.78, 0.46, and 0.43 for carbaryl, eserine, propoxur, m-tolyl methyl carbamate, and carbofuran, respectively, suggesting negatively correlated sensitivity to organophosphate-insensitive AChE. Therefore, AChE from the Rafsanjan population showed negatively

  1. Toxicological and biochemical characterizations of AChE in phosalone-susceptible and resistant populations of the common pistachio psyllid, Agonoscena pistaciae.

    PubMed

    Alizadeh, Ali; Talebi-Jahromi, Khalil; Hosseininaveh, Vahid; Ghadamyari, Mohammad

    2014-01-01

    The toxicological and biochemical characteristics of acetylcholinesterases (AChE) in nine populations of the common pistachio psyllid, Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Psyllidae), were investigated in Kerman Province, Iran. Nine A. pistaciae populations were collected from pistachio orchards, Pistacia vera L. (Sapindales: Anacardiaceae), located in Rafsanjan, Anar, Bam, Kerman, Shahrbabak, Herat, Sirjan, Pariz, and Paghaleh regions of Kerman province. The previous bioassay results showed these populations were susceptible or resistant to phosalone, and the Rafsanjan population was most resistant, with a resistance ratio of 11.3. The specific activity of AChE in the Rafsanjan population was significantly higher than in the susceptible population (Bam). The affinity (K(M)) and hydrolyzing efficiency (Vmax) of AChE on acetylthiocholine iodide, butyrylthiocholine iodide, and propionylthiocholine odide as artificial substrates were clearly lower in the Bam population than that in the Rafsanjan population. These results indicated that the AChE of the Rafsanjan population had lower affinity to these substrates than that of the susceptible population. The higher Vmax value in the Rafsanjan population compared to the susceptible population suggests a possible over expression of AChE in the Rafsanjan population. The in vitro inhibitory effect of several organophosphates and carbamates on AChE of the Rafsanjan and Bam populations was determined. Based on I50, the results showed that the ratios of AChE insensitivity of the resistant to susceptible populations were 23 and 21.7-fold to monocrotophos and phosphamidon, respectively. Whereas, the insensitivity ratios for Rafsanjan population were 0.86, 0.8, 0.78, 0.46, and 0.43 for carbaryl, eserine, propoxur, m-tolyl methyl carbamate, and carbofuran, respectively, suggesting negatively correlated sensitivity to organophosphate-insensitive AChE. Therefore, AChE from the Rafsanjan population showed negatively

  2. Quinoxaline derivatives: novel and selective butyrylcholinesterase inhibitors.

    PubMed

    Zeb, Aurang; Hameed, Abdul; Khan, Latifullah; Khan, Imran; Dalvandi, Kourosh; Choudhary, M Iqbal; Basha, Fatima Z

    2014-01-01

    Alzheimer's disease (AD) is a progressive brain disorder which occurs due to lower levels of acetylcholine (ACh) neurotransmitters, and results in a gradual decline in memory and other cognitive processes. Acetycholinesterase (AChE) and butyrylcholinesterase (BChE) are considered to be primary regulators of the ACh levels in the brain. Evidence shows that AChE activity decreases in AD, while activity of BChE does not change or even elevate in advanced AD, which suggests a key involvement of BChE in ACh hydrolysis during AD symptoms. Therefore, inhibiting the activity of BChE may be an effective way to control AD associated disorders. In this regard, a series of quinoxaline derivatives 1-17 was synthesized and biologically evaluated against cholinesterases (AChE and BChE) and as well as against α- chymotrypsin and urease. The compounds 1-17 were found to be selective inhibitors for BChE, as no activity was found against other enzymes. Among the series, compounds 6 (IC50 = 7.7 ± 1.0 µM) and 7 (IC50 = 9.7 ± 0.9 µM) were found to be the most active inhibitors against BChE. Their IC50 values are comparable to the standard, galantamine (IC50 = 6.6 ± 0.38 µM). Their considerable BChE inhibitory activity makes them selective candidates for the development of BChE inhibitors. Structure-activity relationship (SAR) of this new class of selective BChE inhibitors has been discussed.

  3. Comparative study on short- and long-term behavioral consequences of organophosphate exposure: relationship to AChE mRNA expression.

    PubMed

    López-Granero, Caridad; Cardona, Diana; Giménez, Estela; Lozano, Rafael; Barril, José; Aschner, Michael; Sánchez-Santed, Fernando; Cañadas, Fernando

    2014-01-01

    Organophosphates (OPs) affect behavior by inhibiting acetylcholinesterase (AChE). While the cognitive short-term effects may be directly attributed to this inhibition, the mechanisms that underlie OP's long-term cognitive effects remain controversial and poorly understood. Accordingly, two experiments were designed to assess the effects of OPs on cognition, and to ascertain whether both the short- and long-term effects of are AChE-dependent. A single subcutaneous dose of 250 mg/kg chlorpyrifos (CPF), 1.5mg/kg diisopropylphosphorofluoridate (DFP) or 15 mg/kg parathion (PTN) was administered to male Wistar rats. Spatial learning was evaluated 72 h or 23 weeks after exposure, and impulsive choice was tested at 10 and 30 weeks following OPs administration (experiment 1 and 2, respectively). Brain soluble and membrane-bound AChE activity, synaptic AChE-S mRNA, read-through AChE-R mRNA and brain acylpeptide hydrolase (APH) activity (as alternative non-cholinergic target) were analyzed upon completion of the behavioral testing (17 and 37 weeks after OPs exposure). Both short- and long-term CPF treatment caused statistically significant effects on spatial learning, while PTN treatment led only to statistically significant short-term effects. Neither CPF, DFP nor PTN affected the long-term impulsivity response. Long-term exposure to CPF and DFP significantly decreased AChE-S and AChE-R mRNA, while in the PTN treated group only AChE-S mRNA levels were decreased. However, after long-term OP exposure, soluble and membrane-bound AChE activity was indistinguishable from controls. Finally, no changes were noted in brain APH activity in response to OP treatment. Taken together, this study demonstrates long-term effects of OPs on AChE-S and AChE-R mRNA in the absence of changes in AChE soluble and membrane-bound activity. Thus, changes in AChE mRNA expression imply non-catalytic properties of the AChE enzyme.

  4. Muscarinic ACh Receptors Contribute to Aversive Olfactory Learning in Drosophila

    PubMed Central

    Silva, Bryon; Molina-Fernández, Claudia; Ugalde, María Beatriz; Tognarelli, Eduardo I.; Angel, Cristian; Campusano, Jorge M.

    2015-01-01

    The most studied form of associative learning in Drosophila consists in pairing an odorant, the conditioned stimulus (CS), with an unconditioned stimulus (US). The timely arrival of the CS and US information to a specific Drosophila brain association region, the mushroom bodies (MB), can induce new olfactory memories. Thus, the MB is considered a coincidence detector. It has been shown that olfactory information is conveyed to the MB through cholinergic inputs that activate acetylcholine (ACh) receptors, while the US is encoded by biogenic amine (BA) systems. In recent years, we have advanced our understanding on the specific neural BA pathways and receptors involved in olfactory learning and memory. However, little information exists on the contribution of cholinergic receptors to this process. Here we evaluate for the first time the proposition that, as in mammals, muscarinic ACh receptors (mAChRs) contribute to memory formation in Drosophila. Our results show that pharmacological and genetic blockade of mAChRs in MB disrupts olfactory aversive memory in larvae. This effect is not explained by an alteration in the ability of animals to respond to odorants or to execute motor programs. These results show that mAChRs in MB contribute to generating olfactory memories in Drosophila. PMID:26380118

  5. Nicotinic ACh receptors as therapeutic targets in CNS disorders.

    PubMed

    Dineley, Kelly T; Pandya, Anshul A; Yakel, Jerrel L

    2015-02-01

    The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however, the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer's disease, AD), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain.

  6. Mechanisms of flow and ACh-induced dilation in rat soleus arterioles are altered by hindlimb unweighting

    NASA Technical Reports Server (NTRS)

    Schrage, William G.; Woodman, Christopher R.; Laughlin, M. Harold

    2002-01-01

    The purpose of this study was to test the hypothesis that endothelium-dependent dilation (flow-induced dilation and ACh-induced dilation) in rat soleus muscle arterioles is impaired by hindlimb unweighting (HLU). Male Sprague-Dawley rats (approximately 300 g) were exposed to HLU or weight-bearing control (Con) conditions for 14 days. Soleus first-order (1A) and second-order (2A) arterioles were isolated, cannulated, and exposed to step increases in luminal flow at constant pressure. Flow-induced dilation was not impaired by HLU in 1A or 2A arterioles. The cyclooxygenase inhibitor indomethacin (Indo; 50 microM) did not alter flow-induced dilation in 1As or 2As. Inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine (L-NNA; 300 microM) reduced flow-induced dilation by 65-70% in Con and HLU 1As. In contrast, L-NNA abolished flow-induced dilation in 2As from Con rats but had no effect in HLU 2As. Combined treatment with L-NNA + Indo reduced tone in 1As and 2As from Con rats, but flow-induced dilation in the presence of L-NNA + Indo was not different from responses without inhibitors in either Con or HLU 1As or 2As. HLU also did not impair ACh-induced dilation (10(-9)-10(-4) M) in soleus 2As. L-NNA reduced ACh-induced dilation by approximately 40% in Con 2As but abolished dilation in HLU 2As. Indo did not alter ACh-induced dilation in Con or HLU 2As, whereas combined treatment with L-NNA + Indo abolished ACh-induced dilation in 2As from both groups. We conclude that flow-induced dilation (1As and 2As) was preserved after 2 wk HLU, but HLU decreased the contribution of NOS in mediating flow-induced dilation and increased the contribution of a NOS- and cyclooxygenase-independent mechanism (possibly endothelium-derived hyperpolarizing factor). In soleus 2As, ACh-induced dilation was preserved after 2-wk HLU but the contribution of NOS in mediating ACh-induced dilation was increased.

  7. Partitioning the Quaternary

    NASA Astrophysics Data System (ADS)

    Gibbard, Philip L.; Lewin, John

    2016-11-01

    We review the historical purposes and procedures for stratigraphical division and naming within the Quaternary, and summarize the current requirements for formal partitioning through the International Commission on Stratigraphy (ICS). A raft of new data and evidence has impacted traditional approaches: quasi-continuous records from ocean sediments and ice cores, new numerical dating techniques, and alternative macro-models, such as those provided through Sequence Stratigraphy and Earth-System Science. The practical usefulness of division remains, but there is now greater appreciation of complex Quaternary detail and the modelling of time continua, the latter also extending into the future. There are problems both of commission (what is done, but could be done better) and of omission (what gets left out) in partitioning the Quaternary. These include the challenge set by the use of unconformities as stage boundaries, how to deal with multiphase records in ocean and terrestrial sediments, what happened at the 'Early-Mid- (Middle) Pleistocene Transition', dealing with trends that cross phase boundaries, and the current controversial focus on how to subdivide the Holocene and formally define an 'Anthropocene'.

  8. Identification of 4-aminoquinoline core for the design of new cholinesterase inhibitors

    PubMed Central

    Chen, Yao; Bian, Yaoyao; Sun, Yuan; Kang, Chen; Yu, Sheng; Fu, Tingming; Li, Wei

    2016-01-01

    Inhibition of acetylcholinesterase (AChE) using small molecules is still one of the most successful therapeutic strategies in the treatment of Alzheimer’s disease (AD). Previously we reported compound T5369186 with a core of quinolone as a new cholinesterase inhibitor. In the present study, in order to identify new cores for the designing of AChE inhibitors, we screened different derivatives of this core with the aim to identify the best core as the starting point for further optimization. Based on the results, we confirmed that only 4-aminoquinoline (compound 04 and 07) had cholinesterase inhibitory effects. Considering the simple structure and high inhibitory potency against AChE, 4-aminoquinoline provides a good starting core for further designing novel multifunctional AChEIs. PMID:27441112

  9. Discovery of Potent Carbonic Anhydrase and Acetylcholinesterase Inhibitors: 2-Aminoindan β-Lactam Derivatives

    PubMed Central

    Genç, Hayriye; Kalin, Ramazan; Köksal, Zeynep; Sadeghian, Nastaran; Kocyigit, Umit M.; Zengin, Mustafa; Gülçin, İlhami; Özdemir, Hasan

    2016-01-01

    β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The Ki values of β-lactams (2a–k) were 0.44–6.29 nM against hCA I, 0.93–8.34 nM against hCA II, and 0.25–1.13 nM against AChE. Our findings indicate that β-lactams (2a–k) inhibit both carbonic anhydrases (CA) isoenzymes and AChE at low nanomolar concentrations. PMID:27775608

  10. Inhibitor profile of bis(n)-tacrines and N-methylcarbamates on acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi

    PubMed Central

    Swale, Daniel R.; Tong, Fan; Temeyer, Kevin B.; Li, Andrew; Lam, Polo C-H.; Totrov, Maxim M.; Carlier, Paul R.; Pérez de León, Adalberto A.; Bloomquist, Jeffrey R.

    2013-01-01

    The cattle tick, Rhipicephalus (Boophilus) microplus (Bm), and the sand fly, Phlebotomus papatasi (Pp), are disease vectors to cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases from Bm (BmAChE1) and Pp (PpAChE) compared to human and bovine AChE, in order to identify divergent pharmacology that might lead to selective inhibitors. Results indicate that BmAChE has low sensitivity (IC50 = 200 μM) toward tacrine, a monovalent catalytic site inhibitor with sub micromolar blocking potency in all previous species tested. Similarly, a series of bis(n)-tacrine dimer series, bivalent inhibitors and peripheral site AChE inhibitors possess poor potency toward BmAChE. Molecular homology models suggest the rBmAChE enzyme possesses a W384F orthologous substitution near the catalytic site, where the larger tryptophan side chain obstructs the access of larger ligands to the active site, but functional analysis of this mutation suggests it only partially explains the low sensitivity to tacrine. In addition, BmAChE1 and PpAChE have low nanomolar sensitivity to some experimental carbamate anticholinesterases originally designed for control of the malaria mosquito, Anopheles gambiae. One experimental compound, 2-((2-ethylbutyl)thio)phenyl methylcarbamate, possesses >300-fold selectivity for BmAChE1 and PpAChE over human AChE, and a mouse oral LD50 of >1500 mg/kg, thus providing an excellent new lead for vector control. PMID:24187393

  11. AChR-specific immunosuppressive therapy of myasthenia gravis.

    PubMed

    Luo, Jie; Lindstrom, Jon

    2015-10-15

    Myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by muscle fatigability. In most cases, it is mediated by autoantibodies targeting muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. Experimental autoimmune myasthenia gravis (EAMG) is an animal model for MG, which is usually induced by immunization with AChR purified from fish electric organ. Pathological autoantibodies to AChRs are directed at the extracellular surface, especially the main immunogenic region (MIR). Current treatments for MG can help many but not all patients. Antigen-specific immunosuppressive therapy for MG that specifically suppresses the autoimmune response without affecting the entire immune system and avoids side effects of general immunosuppression is currently unavailable. Early attempts at antigen-specific immunosuppression for EAMG using AChR extracellular domain sequences that form epitopes for pathological autoantibodies risked provoking autoimmunity rather than suppressing it. We discovered a novel approach to specific immunosuppression of EAMG with a therapeutic vaccine consisting of bacterially-expressed human AChR cytoplasmic domains, which has the potential to specifically suppress MG without danger of causing exacerbation. This approach prevents development of chronic EAMG when initiated immediately after the acute phase of EAMG, and rapidly reverses established chronic EAMG when started during the chronic phase of EAMG. Successfully treated rats exhibited long-term resistance to re-induction of EAMG. In this review we also discuss the current understanding of the mechanisms by which the therapy works. Vaccination with AChR cytoplasmic domains in adjuvant is promising as a safe, antigen-specific, potent, effective, rapidly acting, and long lasting approach to therapy of MG.

  12. Nicotine Inhibits Cisplatin-Induced Apoptosis via Regulating α5-nAChR/AKT Signaling in Human Gastric Cancer Cells

    PubMed Central

    Wu, Hongqiao; Zhang, Huilin; Zhang, Xiuping; Xiao, Dongjie; Ma, Xiaoli; Wang, Yunshan

    2016-01-01

    Gastric cancer incidence demonstrates a strong etiologic association with smoking. Nicotine, the major component in tobacco, is a survival agonist that inhibits apoptosis induced by certain chemotherapeutic agents, but the precise mechanisms involved remain largely unknown. Recently studies have indicated that α5-nicotinic acetylcholine receptor (α5-nAChR) is highly associated with lung cancer risk and nicotine dependence. Nevertheless, no information has been available about whether nicotine also affects proliferation of human gastric cancer cells through regulation of α5-nAChR. To evaluate the hypothesis that α5-nAChR may play a role in gastric cancer, we investigated its expression in gastric cancer tissues and cell lines. The expression of α5-nAChR increased in gastric cancer tissue compared with para-carcinoma tissues. In view of the results, we proceeded to investigate whether nicotine inhibits cisplatin-induced apoptosis via regulating α5-nAChR in gastric cancer cell. The results showed that nicotine significantly promoted cell proliferation in a dose and time-dependent manner through α5-nAChR activation in human gastric cells. Furthermore, nicotine inhibited apoptosis induced by cisplatin. Silence of α5-nAChR ablated the protective effects of nicotine. However, when co-administrating LY294002, an inhibitor of PI3K/AKT pathway, an increased apoptosis was observed. This effect correlated with the induction of Bcl-2, Bax, Survivin and Caspase-3 by nicotine in gastric cell lines. These results suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that α5-nAChR/AKT signaling plays a key role in the anti-apoptotic activity of nicotine induced by cisplatin. PMID:26909550

  13. Nicotine Inhibits Cisplatin-Induced Apoptosis via Regulating α5-nAChR/AKT Signaling in Human Gastric Cancer Cells.

    PubMed

    Jia, Yanfei; Sun, Haiji; Wu, Hongqiao; Zhang, Huilin; Zhang, Xiuping; Xiao, Dongjie; Ma, Xiaoli; Wang, Yunshan

    2016-01-01

    Gastric cancer incidence demonstrates a strong etiologic association with smoking. Nicotine, the major component in tobacco, is a survival agonist that inhibits apoptosis induced by certain chemotherapeutic agents, but the precise mechanisms involved remain largely unknown. Recently studies have indicated that α5-nicotinic acetylcholine receptor (α5-nAChR) is highly associated with lung cancer risk and nicotine dependence. Nevertheless, no information has been available about whether nicotine also affects proliferation of human gastric cancer cells through regulation of α5-nAChR. To evaluate the hypothesis that α5-nAChR may play a role in gastric cancer, we investigated its expression in gastric cancer tissues and cell lines. The expression of α5-nAChR increased in gastric cancer tissue compared with para-carcinoma tissues. In view of the results, we proceeded to investigate whether nicotine inhibits cisplatin-induced apoptosis via regulating α5-nAChR in gastric cancer cell. The results showed that nicotine significantly promoted cell proliferation in a dose and time-dependent manner through α5-nAChR activation in human gastric cells. Furthermore, nicotine inhibited apoptosis induced by cisplatin. Silence of α5-nAChR ablated the protective effects of nicotine. However, when co-administrating LY294002, an inhibitor of PI3K/AKT pathway, an increased apoptosis was observed. This effect correlated with the induction of Bcl-2, Bax, Survivin and Caspase-3 by nicotine in gastric cell lines. These results suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that α5-nAChR/AKT signaling plays a key role in the anti-apoptotic activity of nicotine induced by cisplatin. PMID:26909550

  14. The linoleic acid derivative DCP-LA increases membrane surface localization of the α7 ACh receptor in a protein 4.1N-dependent manner.

    PubMed

    Kanno, Takeshi; Tsuchiya, Ayako; Tanaka, Akito; Nishizaki, Tomoyuki

    2013-03-01

    In yeast two-hybrid screening, protein 4.1N, a scaffolding protein, was identified as a binding partner of the α7 ACh (acetylcholine) receptor. For rat hippocampal slices, the linoleic acid derivative DCP-LA {8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid} increased the association of the α7 ACh receptor with 4.1N, and the effect was inhibited by GF109203X, an inhibitor of PKC (protein kinase C), although DCP-LA did not induce PKC phosphorylation of 4.1N. For PC-12 cells, the presence of the α7 ACh receptor in the plasma membrane fraction was significantly suppressed by knocking down 4.1N. DCP-LA increased the presence of the α7 ACh receptor in the plasma membrane fraction, and the effect was still inhibited by knocking down 4.1N. In the monitoring of α7 ACh receptor mobilization, DCP-LA enhanced signal intensities for the α7 ACh receptor at the membrane surface in PC-12 cells, which was clearly prevented by knocking down 4.1N. Taken together, the results of the present study show that 4.1N interacts with the α7 ACh receptor and participates in the receptor tethering to the plasma membrane. The results also indicate that DCP-LA increases membrane surface localization of the α7 ACh receptor in a 4.1N-dependent manner under the control of PKC, but without phosphorylating 4.1N.

  15. Nicotine Inhibits Cisplatin-Induced Apoptosis via Regulating α5-nAChR/AKT Signaling in Human Gastric Cancer Cells.

    PubMed

    Jia, Yanfei; Sun, Haiji; Wu, Hongqiao; Zhang, Huilin; Zhang, Xiuping; Xiao, Dongjie; Ma, Xiaoli; Wang, Yunshan

    2016-01-01

    Gastric cancer incidence demonstrates a strong etiologic association with smoking. Nicotine, the major component in tobacco, is a survival agonist that inhibits apoptosis induced by certain chemotherapeutic agents, but the precise mechanisms involved remain largely unknown. Recently studies have indicated that α5-nicotinic acetylcholine receptor (α5-nAChR) is highly associated with lung cancer risk and nicotine dependence. Nevertheless, no information has been available about whether nicotine also affects proliferation of human gastric cancer cells through regulation of α5-nAChR. To evaluate the hypothesis that α5-nAChR may play a role in gastric cancer, we investigated its expression in gastric cancer tissues and cell lines. The expression of α5-nAChR increased in gastric cancer tissue compared with para-carcinoma tissues. In view of the results, we proceeded to investigate whether nicotine inhibits cisplatin-induced apoptosis via regulating α5-nAChR in gastric cancer cell. The results showed that nicotine significantly promoted cell proliferation in a dose and time-dependent manner through α5-nAChR activation in human gastric cells. Furthermore, nicotine inhibited apoptosis induced by cisplatin. Silence of α5-nAChR ablated the protective effects of nicotine. However, when co-administrating LY294002, an inhibitor of PI3K/AKT pathway, an increased apoptosis was observed. This effect correlated with the induction of Bcl-2, Bax, Survivin and Caspase-3 by nicotine in gastric cell lines. These results suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that α5-nAChR/AKT signaling plays a key role in the anti-apoptotic activity of nicotine induced by cisplatin.

  16. Screening of acetylcholinesterase inhibitors by CE after enzymatic reaction at capillary inlet.

    PubMed

    Martín-Biosca, Yolanda; Asensi-Bernardi, Lucia; Villanueva-Camañas, Rosa M; Sagrado, Salvador; Medina-Hernández, Maria J

    2009-05-01

    In this study the development of a procedure based on capillary electrophoresis after enzymatic reaction at capillary inlet methodology for the screening and in vitro evaluation of the biological activity of acetylcholinesterase (AChE) inhibitors is presented. The progress of the enzymatic reaction of the hydrolysis of acetylthiocholine at pH 8 in the presence of AChE and the inhibitor studied is determined by measuring at 230 nm the peak area of the reaction product thiocholine (TCh). In the method employed the capillary was first filled with 30 mM borate-phosphate buffer (pH 8.0) and subsequently, plugs of: (i) water, (ii) AChE solution, (iii) substrate solution with or without inhibitor, (iv) AChE solution, and (v) water, were hydrodynamically injected into the capillary, and were allowed to stand (and react) during a waiting period of 2 min. The applicability of the proposed methodology to estimate different kinetic parameters of interest such as inhibition constants K(i), identification of inhibitory action mechanism and IC(50), is evaluated using compounds with known activity, tacrine edrophonium, and neostigmine. The results obtained are compared with bibliographic values and confirm the effectiveness of the methodology proposed. Finally a method for AChE Inhibitor screening is proposed.

  17. Acetylcholinesterase Regulates Skeletal In Ovo Development of Chicken Limbs by ACh-Dependent and -Independent Mechanisms

    PubMed Central

    Spieker, Janine; Ackermann, Anica; Salfelder, Anika; Vogel-Höpker, Astrid; Layer, Paul G.

    2016-01-01

    Formation of the vertebrate limb presents an excellent model to analyze a non-neuronal cholinergic system (NNCS). Here, we first analyzed the expression of acetylcholinesterase (AChE) by IHC and of choline acetyltransferase (ChAT) by ISH in developing embryonic chicken limbs (stages HH17-37). AChE outlined formation of bones, being strongest at their distal tips, and later also marked areas of cell death. At onset, AChE and ChAT were elevated in two organizing centers of the limb anlage, the apical ectodermal ridge (AER) and zone of polarizing activity (ZPA), respectively. Thereby ChAT was expressed shortly after AChE, thus strongly supporting a leading role of AChE in limb formation. Then, we conducted loss-of-function studies via unilateral implantation of beads into chicken limb anlagen, which were soaked in cholinergic components. After varying periods, the formation of cartilage matrix and of mineralizing bones was followed by Alcian blue (AB) and Alizarin red (AR) stainings, respectively. Both acetylcholine (ACh)- and ChAT-soaked beads accelerated bone formation in ovo. Notably, inhibition of AChE by BW284c51, or by the monoclonal antibody MAB304 delayed cartilage formation. Since bead inhibition of BChE was mostly ineffective, an ACh-independent action during BW284c51 and MAB304 inhibition was indicated, which possibly could be due to an enzymatic side activity of AChE. In conclusion, skeletogenesis in chick is regulated by an ACh-dependent cholinergic system, but to some extent also by an ACh-independent aspect of the AChE protein. PMID:27574787

  18. Acetylcholinesterase Regulates Skeletal In Ovo Development of Chicken Limbs by ACh-Dependent and -Independent Mechanisms.

    PubMed

    Spieker, Janine; Ackermann, Anica; Salfelder, Anika; Vogel-Höpker, Astrid; Layer, Paul G

    2016-01-01

    Formation of the vertebrate limb presents an excellent model to analyze a non-neuronal cholinergic system (NNCS). Here, we first analyzed the expression of acetylcholinesterase (AChE) by IHC and of choline acetyltransferase (ChAT) by ISH in developing embryonic chicken limbs (stages HH17-37). AChE outlined formation of bones, being strongest at their distal tips, and later also marked areas of cell death. At onset, AChE and ChAT were elevated in two organizing centers of the limb anlage, the apical ectodermal ridge (AER) and zone of polarizing activity (ZPA), respectively. Thereby ChAT was expressed shortly after AChE, thus strongly supporting a leading role of AChE in limb formation. Then, we conducted loss-of-function studies via unilateral implantation of beads into chicken limb anlagen, which were soaked in cholinergic components. After varying periods, the formation of cartilage matrix and of mineralizing bones was followed by Alcian blue (AB) and Alizarin red (AR) stainings, respectively. Both acetylcholine (ACh)- and ChAT-soaked beads accelerated bone formation in ovo. Notably, inhibition of AChE by BW284c51, or by the monoclonal antibody MAB304 delayed cartilage formation. Since bead inhibition of BChE was mostly ineffective, an ACh-independent action during BW284c51 and MAB304 inhibition was indicated, which possibly could be due to an enzymatic side activity of AChE. In conclusion, skeletogenesis in chick is regulated by an ACh-dependent cholinergic system, but to some extent also by an ACh-independent aspect of the AChE protein. PMID:27574787

  19. Selective and irreversible inhibitors of mosquito acetylcholinesterases for controlling malaria and other mosquito-borne diseases.

    PubMed

    Pang, Yuan-Ping; Ekström, Fredrik; Polsinelli, Gregory A; Gao, Yang; Rana, Sandeep; Hua, Duy H; Andersson, Björn; Andersson, Per Ola; Peng, Lei; Singh, Sanjay K; Mishra, Rajesh K; Zhu, Kun Yan; Fallon, Ann M; Ragsdale, David W; Brimijoin, Stephen

    2009-01-01

    New insecticides are urgently needed because resistance to current insecticides allows resurgence of disease-transmitting mosquitoes while concerns for human toxicity from current compounds are growing. We previously reported the finding of a free cysteine (Cys) residue at the entrance of the active site of acetylcholinesterase (AChE) in some insects but not in mammals, birds, and fish. These insects have two AChE genes (AP and AO), and only AP-AChE carries the Cys residue. Most of these insects are disease vectors such as the African malaria mosquito (Anopheles gambiae sensu stricto) or crop pests such as aphids. Recently we reported a Cys-targeting small molecule that irreversibly inhibited all AChE activity extracted from aphids while an identical exposure caused no effect on the human AChE. Full inhibition of AChE in aphids indicates that AP-AChE contributes most of the enzymatic activity and suggests that the Cys residue might serve as a target for developing better aphicides. It is therefore worth investigating whether the Cys-targeting strategy is applicable to mosquitocides. Herein, we report that, under conditions that spare the human AChE, a methanethiosulfonate-containing molecule at 6 microM irreversibly inhibited 95% of the AChE activity extracted from An. gambiae s. str. and >80% of the activity from the yellow fever mosquito (Aedes aegypti L.) or the northern house mosquito (Culex pipiens L.) that is a vector of St. Louis encephalitis. This type of inhibition is fast ( approximately 30 min) and due to conjugation of the inhibitor to the active-site Cys of mosquito AP-AChE, according to our observed reactivation of the methanethiosulfonate-inhibited AChE by 2-mercaptoethanol. We also note that our sulfhydryl agents partially and irreversibly inhibited the human AChE after prolonged exposure (>4 hr). This slow inhibition is due to partial enzyme denaturation by the inhibitor and/or micelles of the inhibitor, according to our studies using atomic force

  20. Complete Genome Sequence of Agrobacterium tumefaciens Ach5.

    PubMed

    Huang, Ya-Yi; Cho, Shu-Ting; Lo, Wen-Sui; Wang, Yi-Chieh; Lai, Erh-Min; Kuo, Chih-Horng

    2015-01-01

    Agrobacterium tumefaciens is a phytopathogenic bacterium that causes crown gall disease. The strain Ach5 was isolated from yarrow (Achillea ptarmica L.) and is the wild-type progenitor of other derived strains widely used for plant transformation. Here, we report the complete genome sequence of this bacterium. PMID:26044425

  1. The Ache: Genocide Continues in Paraguay. IWGIA Document No. 17.

    ERIC Educational Resources Information Center

    Munzel, Mark

    In 1972, the Paraguayan Roman Catholic Church protested against the massacre of Indians in Paraguay. This was followed by further protests from Paraguayan intellectuals. These protests led to the removal of Jesus de Pereira, one of the executors of the official Ache policy. Thus, the critics were appeased. Since the beginning of 1973, new protests…

  2. [The biological activity of quaternary ammonium salts (QASs)].

    PubMed

    Obłak, Ewa; Gamian, Andrzej

    2010-01-01

    Quaternary ammonium salts (QASs), especially those of cationic surfactant character, are applied as antibacterial and antifungal disinfectants. QASs affect lipid-enveloped viruses, including human immunodeficiency virus (HIV) and hepatitis B virus (HBV), but not non-enveloped viruses. These compounds are extensively used in domestic (as ingredients of shampoos, hair conditioners), agricultural (as fungicides, pesticides, insecticides), healthcare (as medications), and industrial applications (as biocides, fabric softeners, corrosion inhibitors). The extensive use of quaternary ammonium disinfectants in recent years has led to the development of resistance in microorganisms to these drugs. Thus Staphylococcus aureus strains contain the plasmid-carrying genes qacA and qacB encoding resistance to quaternary ammonium compounds and acriflavine. The membrane proteins QacA and QacB confer multidrug resistance by exporting the compound by the proton motive force which is generated by the transmembrane electrochemical proton gradient. PMID:20400784

  3. Synthesis of aminoalkyl-substituted aurone derivatives as acetylcholinesterase inhibitors.

    PubMed

    Lee, Young Hun; Shin, Min Cheol; Yun, Yong Don; Shin, Seo Young; Kim, Jong Min; Seo, Jeong Moo; Kim, Nam-Jung; Ryu, Jong Hoon; Lee, Yong Sup

    2015-01-01

    Alzheimer's disease (AD), a progressive and neurodegenerative disorder of the brain, is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, aurone derivatives were designed and synthesized as AChE inhibitors based on the lead structure of sulfuretin. Of those synthesized, compound 10d showed ca. 1700-fold and 6-fold higher AChE inhibitory activity than sulfuretin and galantamine, respectively. This compound also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2mg/kg. PMID:25468034

  4. Magnetism of quaternary sediments

    NASA Astrophysics Data System (ADS)

    Heller, Friedrich

    Magnetism of Quaternary sediments was the topic of a well-attended symposium held during the 13th INQUA (International Union of Quaternary Research) congress in Beijing, China, August 2-9. More than 40 papers were delivered by scientists from Belgium, England, France, Germany, Japan, New Zealand, Sweden, Switzerland, Taiwan, the United States, the Soviet Union, Yugoslavia, and other countries. The host country contributed to a productive session that was part of the first large scientific meeting to take place in Beijing after the June 4, 1989, upheaval.Nearly half of the studies focused on paleomagnetic and rock magnetic properties of loess in Alaska, Central Asia, China, and New Zealand. Magnetostratigraphic polarity dating was done at some sections in the western (Shaw et al.) and central Chinese loess plateau (Bai and Hus; Wang and Evans; Yue). The interpretation of the polarity pattern found in the western loess plateau still is not unambiguous. In the central part, certain polarity boundaries, such as the Brunhes/Matuyama (B/M) boundary, are found in slightly different stratigraphic positions (Hus et al.; Yue). In deep-sea sediments the lock-in depth of natural remanent magnetization (NRM) at the B/M boundary seems to be a linear function of sedimentation rate (de Menocal et al.). Although the magnetization process in the Chinese loess is not well understood, detailed records of polarity transitions have been reported for the B/M and the Jaramillo R→N transition (Ma et al.; Rolph).

  5. Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody

    PubMed Central

    Morsch, Marco; Reddel, Stephen W; Ghazanfari, Nazanin; Toyka, Klaus V; Phillips, William D

    2013-01-01

    In myasthenia gravis, the neuromuscular junction is impaired by the antibody-mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4-diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK-induced AChR loss by prolonging the activity of ACh in the synaptic cleft. PMID:23440963

  6. Exposure to Acetylcholinesterase Inhibitors Alters the Physiology and Motor Function of Honeybees

    PubMed Central

    Williamson, Sally M.; Moffat, Christopher; Gomersall, Martha A. E.; Saranzewa, Nastja; Connolly, Christopher N.; Wright, Geraldine A.

    2013-01-01

    Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. PMID:23386834

  7. Exposure to acetylcholinesterase inhibitors alters the physiology and motor function of honeybees.

    PubMed

    Williamson, Sally M; Moffat, Christopher; Gomersall, Martha A E; Saranzewa, Nastja; Connolly, Christopher N; Wright, Geraldine A

    2013-01-01

    Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival.

  8. Photolabeling a Nicotinic Acetylcholine Receptor (nAChR) with an (α4)3(β2)2 nAChR-Selective Positive Allosteric Modulator.

    PubMed

    Hamouda, Ayman K; Deba, Farah; Wang, Ze-Jun; Cohen, Jonathan B

    2016-05-01

    Positive allosteric modulators (PAMs) of nicotinic acetylcholine (ACh) receptors (nAChRs) have potential clinical applications in the treatment of nicotine dependence and many neuropsychiatric conditions associated with decreased brain cholinergic activity, and 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrrazol-4-yl)isoxazole (CMPI) has been identified as a PAM selective for neuronal nAChRs containing theα4 subunit. In this report, we compare CMPI interactions with low-sensitivity (α4)3(β2)2 and high-sensitivity (α4)2(β2)3 nAChRs, and with muscle-type nAChRs. In addition, we use the intrinsic reactivity of [(3)H]CMPI upon photolysis at 312 nm to identify its binding sites inTorpedonAChRs. Recording fromXenopusoocytes, we found that CMPI potentiated maximally the responses of (α4)3(β2)2nAChR to 10μM ACh (EC10) by 400% and with anEC50of ∼1µM. CMPI produced a left shift of the ACh concentration-response curve without altering ACh efficacy. In contrast, CMPI inhibited (∼35% at 10µM) ACh responses of (α4)2(β2)3nAChRs and fully inhibited human muscle andTorpedonAChRs with IC50values of ∼0.5µM. Upon irradiation at 312 nm, [(3)H]CMPI photoincorporated into eachTorpedo[(α1)2β1γδ] nAChR subunit. Sequencing of peptide fragments isolated from [(3)H]CMPI-photolabeled nAChR subunits established photolabeling of amino acids contributing to the ACh binding sites (αTyr(190),αTyr(198),γTrp(55),γTyr(111),γTyr(117),δTrp(57)) that was fully inhibitable by agonist and lower-efficiency, state-dependent [(3)H]CMPI photolabeling within the ion channel. Our results establish that CMPI is a potent potentiator of nAChRs containing anα4:α4 subunit interface, and that its intrinsic photoreactivy makes it of potential use to identify its binding sites in the (α4)3(β2)2nAChR. PMID:26976945

  9. Kinetics and molecular docking studies of cholinesterase inhibitors derived from water layer of Lycopodiella cernua (L.) Pic. Serm. (II).

    PubMed

    Hung, Tran Manh; Lee, Joo Sang; Chuong, Nguyen Ngoc; Kim, Jeong Ah; Oh, Sang Ho; Woo, Mi Hee; Choi, Jae Sue; Min, Byung Sun

    2015-10-01

    Acetylcholinesterase (AChE) inhibitors increase the availability of acetylcholine in central cholinergic synapses and are the most promising drugs currently available for the treatment of Alzheimer's disease (AD). Our screening study indicated that the water fraction of the methanolic extract of Lycopodiella cernua (L.) Pic. Serm. significantly inhibited AChE in vitro. Bioassay-guided fractionation led to the isolation of a new lignan glycoside, lycocernuaside A (12), and fourteen known compounds (1-11 and 13-15). Compound 7 exhibited the most potent AChE inhibitory activity with an IC50 value of 0.23 μM. Compound 15 had the most potent inhibitory activity against BChE and BACE1 with IC50 values of 0.62 and 2.16 μM, respectively. Compounds 4 and 7 showed mixed- and competitive-type AChE inhibition. Compound 7 noncompetitively inhibited BChE whereas 15 showed competitive and 8, 13, and 14 showed mixed-type inhibition. The docking results for complexes with AChE or BChE revealed that inhibitors 4, 7, and 15 stably positioned themselves in several pocket/catalytic domains of the AChE and BChE residues. PMID:26297990

  10. Kinetics and molecular docking studies of cholinesterase inhibitors derived from water layer of Lycopodiella cernua (L.) Pic. Serm. (II).

    PubMed

    Hung, Tran Manh; Lee, Joo Sang; Chuong, Nguyen Ngoc; Kim, Jeong Ah; Oh, Sang Ho; Woo, Mi Hee; Choi, Jae Sue; Min, Byung Sun

    2015-10-01

    Acetylcholinesterase (AChE) inhibitors increase the availability of acetylcholine in central cholinergic synapses and are the most promising drugs currently available for the treatment of Alzheimer's disease (AD). Our screening study indicated that the water fraction of the methanolic extract of Lycopodiella cernua (L.) Pic. Serm. significantly inhibited AChE in vitro. Bioassay-guided fractionation led to the isolation of a new lignan glycoside, lycocernuaside A (12), and fourteen known compounds (1-11 and 13-15). Compound 7 exhibited the most potent AChE inhibitory activity with an IC50 value of 0.23 μM. Compound 15 had the most potent inhibitory activity against BChE and BACE1 with IC50 values of 0.62 and 2.16 μM, respectively. Compounds 4 and 7 showed mixed- and competitive-type AChE inhibition. Compound 7 noncompetitively inhibited BChE whereas 15 showed competitive and 8, 13, and 14 showed mixed-type inhibition. The docking results for complexes with AChE or BChE revealed that inhibitors 4, 7, and 15 stably positioned themselves in several pocket/catalytic domains of the AChE and BChE residues.

  11. Functional Analysis and Molecular Docking studies of Medicinal Compounds for AChE and BChE in Alzheimer’s Disease and Type 2 Diabetes Mellitus

    PubMed Central

    Kaladhar, Dowluru SVGK; Yarla, Nagendra Sastry; Anusha, N.

    2013-01-01

    Acetylcholinesterase and Butyrylcholinesterase share unravelling link with components of metabolic syndromes that’s characterised by low levels of HDL cholesterol, obesity, high fast aldohexose levels, hyper-trigliceridaemia and high blood pressure, by regulation of cholinergic transmission and therefore the enzyme activity within a living system. The phosphomotifs associated with amino acid and tyrosine binding motifs in AChE and BChE were known to be common. Phylogenetic tree was constructed to these proteins usinf UPGMA and Maximum Likelihood methods in MEGA software has shown interaction of AChE and BChE with ageing diseases like Alzheimer’s disease and Diabetes. AChE has shown closely related to BChE, retinol dehydrogenase and β-polypeptide. The present studies is also accomplished that AChE, BChE, COLQ, HAND1, APP, NLGN2 and NGF proteins has interactions with diseases such as Alzheimer’s and D2M using Pathwaylinker and STRING. Medicinal compounds like Ortho-7, Dibucaine and HI-6 are predicted as good targets for modeled AChE and BChE proteins based on docking studies. Hence perceptive studies of cholinesterase structure and the biological mechanisms of inhibition are necessary for effective drug development. PMID:23936743

  12. Solanocapsine derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular docking and biological studies.

    PubMed

    García, Manuela E; Borioni, José L; Cavallaro, Valeria; Puiatti, Marcelo; Pierini, Adriana B; Murray, Ana P; Peñéñory, Alicia B

    2015-12-01

    The investigation of natural products in medicinal chemistry is essential today. In this context, acetylcholinesterase (AChE) inhibitors comprise one type of the compounds most actively studied in the search for an effective treatment of symptoms of Alzheimer's disease. This work describes the isolation of a natural compound, solanocapsine, the preparation of its chemical derivatives, the evaluation of AChE inhibitory activity, and the structure-activity analysis of relevant cases. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different reactive parts of the parent molecule. A theoretical study was also carried out into the binding mode of representative compounds to the enzyme through molecular modeling. The biological properties of the series were investigated. Through this study valuable information was obtained of steroidal alkaloid-type compounds as a starting point for the synthesis of AChE inhibitors. PMID:26362598

  13. Natural compounds endowed with cholinergic or anticholinergic activity. Enhancement of acetylcholine release by a quaternary derivative of L-hyoscyamine.

    PubMed

    Souccar, Caden; Salamanca, Ana Lucia V; Tanae, Mirtes M; Lima-Landman, Maria Teresa R; Lapa, Antonio José

    2010-01-01

    New compounds that target nicotinic receptors (nAChRs) have been sought to correct disorders affecting cholinergic transmission in central and peripheral synapses. A quaternary derivate of l-hyoscyamine, phenthonium (Phen), was shown by our group to enhance the spontaneous acetylcholine (ACh) release without altering the nerve-induced transmitter release at the neuromuscular junction. The effect was unrelated to membrane depolarization, and was not induced by an increase of calcium influx into the nerve terminal. Phen also presented a competitive antimuscarinic activity and blocked noncompetitively the neuromuscular transmission. In this work we re-examined the mechanisms underlying the facilitatory actions of Phen on [(3)H]-ACh release in isolated ganglia of the guinea pig ileal myenteric plexus. Exposure of the preparations to Phen (10-50 microM) increased the release of [(3)H]-ACh by 81 to 68% over the basal. The effect was not affected by the ganglionic nAChR antagonist hexamethonium (1 nM) at a concentration that inhibited the increase of [(3)H]-ACh release induced by the nicotinic agonist dimethylphenylpiperazinium (DMPP, 30 microM). Association of Phen (10 microM) with DMPP potentiated the facilitatory effect of Phen. [(3)H]-ACh release was not altered by the muscarinic antagonists atropine (1 nM) or pirenzepine (1 microM). However, both antagonists inhibited the release of [(3)H]-ACh induced by either the muscarinic M1 agonist McN-343 (10 microM) or Phen (20 microM). The facilitatory effect of Phen was not altered by CdCl(2) (50 mM), but it was potentiated in the presence of tetraethylammonium (40 mM). The results indicate that the facilitatory action of Phen appears to be mediated by an increase of the inwardly rectifying potassium channels conductance probably related to the compound antimuscarinic activity.

  14. Real Time Ligand-Induced Motion Mappings of AChBP and nAChR Using X-ray Single Molecule Tracking

    PubMed Central

    Sekiguchi, Hiroshi; Suzuki, Yasuhito; Nishino, Yuri; Kobayashi, Suzuko; Shimoyama, Yoshiko; Cai, Weiyan; Nagata, Kenji; Okada, Masato; Ichiyanagi, Kouhei; Ohta, Noboru; Yagi, Naoto; Miyazawa, Atsuo; Kubo, Tai; Sasaki, Yuji C.

    2014-01-01

    We observed the dynamic three-dimensional (3D) single molecule behaviour of acetylcholine-binding protein (AChBP) and nicotinic acetylcholine receptor (nAChR) using a single molecule tracking technique, diffracted X-ray tracking (DXT) with atomic scale and 100 μs time resolution. We found that the combined tilting and twisting motions of the proteins were enhanced upon acetylcholine (ACh) binding. We present the internal motion maps of AChBP and nAChR in the presence of either ACh or α-bungarotoxin (αBtx), with views from two rotational axes. Our findings indicate that specific motion patterns represented as biaxial angular motion maps are associated with channel function in real time and on an atomic scale. PMID:25223459

  15. Kinetic evidence that desensitized nAChR may promote transitions of active nAChR to desensitized states during sustained exposure to agonists in skeletal muscle.

    PubMed

    Manthey, Arthur A

    2006-06-01

    During prolonged exposure of postjunctional nicotinic acetylcholine receptors (nAChR) of skeletal muscle to acetylcholine (ACh), agonist-activated nAChR (nAChRa) gradually fall into a refractory "desensitized" state (nAChRd), which no longer supports the high-conductance channel openings characteristic of the initially active nAChRa. In the present study, the possibility was examined that nAChRd, rather than simply constituting a passive "trap" for nAChRa, may actively promote further conversions of nAChRa to nAChRd in a formally autocatalytic manner. Single-ion whole-cell voltage-clamp currents (Na+ and Li+ in separate trials) were measured using two KCl-filled capillary electrodes (5-10 MOmega) implanted at the postjunctional locus of single frog skeletal muscle fibers (Rana pipiens) equilibrated in 30 mM K+ bath media to eliminate mechanical responses. Various nAChR agonists (carbamylcholine, acetylcholine, suberyldicholine) at different concentrations were delivered focally by positive pressure microjet. It was found that the decline of postmaximal agonist-induced currents under these different conditions (driven by the growth of the subpool of nAChRd) consistently followed an autocatalytic logistic rule modified for population growth of fixed units in a planar array: [Formula: see text] (where y represents the remaining agonist-induced current at time t, A=initial maximum current, and n is a constant). Some further experimental features that might result from a self-promoting growth of nAChRd were also tested, namely, (1) the effect of increased nAChRa and (2) the effect of increased nAChRd. Increase in agonist concentration of the superfusate, by increasing the planar density of active nAChRa at the outset, should enhance the probability of autocatalytic interactions with emerging nAChRd, hence, the rate of decline of agonist-induced current, and this was a consistent finding under all conditions tested. Raising the initial level of desensitized nAChRd by

  16. Acetylcholinesterase (AChE) and heat shock proteins (Hsp70) of gypsy moth (Lymantria dispar L.) larvae in response to long-term fluoranthene exposure.

    PubMed

    Mrdaković, Marija; Ilijin, Larisa; Vlahović, Milena; Matić, Dragana; Gavrilović, Anja; Mrkonja, Aleksandra; Perić-Mataruga, Vesna

    2016-09-01

    Polycyclic aromatic hydrocarbons (PAHs) may affect biochemical and physiological processes in living organisms, thus impairing fitness related traits and influencing their populations. This imposes the need for providing early-warning signals of pollution. Our study aimed to examine changes in the activity of acetylcholinesterase (AChE) and the concentration of heat shock proteins (Hsp70) in homogenates of brain tissues of fifth instar gypsy moth (Lymantria dispar L.) larvae, exposed to the ubiquitous PAH, fluoranthene, supplemented to the rearing diet. Significantly increased activity of AChE in larvae fed on the diets with high fluoranthene concentrations suggests the necessity for elucidation of the role of AChE in these insects when exposed to PAH pollution. Significant induction of Hsp70 in gypsy moth larvae reared on the diets containing low fluoranthene concentrations, indicate that changes in the level of Hsp70 might be useful as an indicator of pollution in this widespread forest species. PMID:27343862

  17. Acetylcholinesterase (AChE) and heat shock proteins (Hsp70) of gypsy moth (Lymantria dispar L.) larvae in response to long-term fluoranthene exposure.

    PubMed

    Mrdaković, Marija; Ilijin, Larisa; Vlahović, Milena; Matić, Dragana; Gavrilović, Anja; Mrkonja, Aleksandra; Perić-Mataruga, Vesna

    2016-09-01

    Polycyclic aromatic hydrocarbons (PAHs) may affect biochemical and physiological processes in living organisms, thus impairing fitness related traits and influencing their populations. This imposes the need for providing early-warning signals of pollution. Our study aimed to examine changes in the activity of acetylcholinesterase (AChE) and the concentration of heat shock proteins (Hsp70) in homogenates of brain tissues of fifth instar gypsy moth (Lymantria dispar L.) larvae, exposed to the ubiquitous PAH, fluoranthene, supplemented to the rearing diet. Significantly increased activity of AChE in larvae fed on the diets with high fluoranthene concentrations suggests the necessity for elucidation of the role of AChE in these insects when exposed to PAH pollution. Significant induction of Hsp70 in gypsy moth larvae reared on the diets containing low fluoranthene concentrations, indicate that changes in the level of Hsp70 might be useful as an indicator of pollution in this widespread forest species.

  18. Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

    PubMed Central

    2013-01-01

    The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2–7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14–18), and quinolinodonepezils (19–21) are described. Pyridonepezils 15–18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19–21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC50 (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15–18 and quinolinodonepezils 20–21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC50 (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ1–42. All compounds were effective in preventing the enhancement of AChE activity induced by Aβ1–42. Compounds 2–7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ1–42. Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive

  19. Target site insensitivity mutations in the AChE enzyme confer resistance to organophosphorous insecticides in Leptinotarsa decemlineata (Say).

    PubMed

    Malekmohammadi, M; Galehdari, H

    2016-01-01

    In the present study, we demonstrated the use and optimization of the tetra-primer ARMS-PCR procedure to detect and analyze the frequency of the R30K and I392T mutations in resistant field populations of CPB. The R30K mutation was detected in 72%, 84%, 52% and 64% of Bahar, Dehpiaz, Aliabad and Yengijeh populations, respectively. Overall frequencies of the I392T mutation were 12%, 8% and 16% of Bahar, Aliabad and Yengijeh populations, respectively. No I392T point mutation was found among samples from Dehpiaz field population. Moreover, only 31% and 2% of samples from the resistant field populations were homozygous for R30K and I392T mutations, respectively. No individual simultaneously had both I392T and S291G/R30K point mutations. The incidence of individuals with both S291G and R30K point mutations in the samples from Bahar, Dehpiaz, Aliabad, and Yengijeh populations were 31.5%, 44.7%, 41.6%, and 27.3% respectively. Genotypes determined by the tetra-primer ARMS-PCR method were consistent with those determined by PCR sequencing. There was no significant correlation between the mutation frequencies and resistance levels in the resistant populations, indicating that other mutations may contribute to this variation. Polymorphism in the partial L. decemlineata cDNA AChE gene Ldace2 of four field populations was identified by direct sequencing of PCR-amplified fragments. Among 45 novel mutations detected in this study, T29P mutation was found across all four field populations that likely contribute to the AChE insensitivity. Site-directed mutagenesis and protein expression experiments are needed for a more complete evaluation. PMID:26778439

  20. The regulation of hippocampal nicotinic acetylcholine receptors (nAChRs) after a protracted treatment with selective or nonselective nAChR agonists.

    PubMed

    Auta, J; Longone, P; Guidotti, A; Costa, E

    1999-01-01

    In rats, 1 mg/kg twice daily for 10 d of nicotine, a nonselective agonist of nicotinic acetylcholine receptors (nAChRs), fails to change alpha4 and beta2 nAChR subunit mRNA but significantly decreased alpha7 nAChR subunit mRNA and protein expression, which is associated with a 35-40% decrease in the number of 125I-alpha-Bgtx binding sites in hippocampus. In addition, this schedule of nicotine treatment produced a 40% increase in the number of high- (K(D) 1 nM), but decreased by 25% the number of low-affinity (K(D) 30 nM) binding sites for 3H-epibatidine in hippocampus. In contrast, repeated treatment with lobeline (2.7 mg/kg twice daily for 10 d), which selectively binds to high-affinity binding nAChRs, fails to change the expression of high- or low-affinity nAChRs. These data suggest that a simultaneous upregulation of high-affinity nAChRs and downregulation of low-affinity nAChRs is elicited by ligands that can bind to both low- and high-affinity nAChRs, but not by selective agonists of high-affinity nAChRs. One might infer that in hippocampus, high- and low-affinity nAChRs may be located in the same cells. When these two receptor types are stimulated simultaneously by nonselective ligands for high- and low-affinity nAChRs, they interact, bringing about an increase in binding site density of the high-affinity nAChRs.

  1. Steric and Dynamic Parameters Influencing In Situ Cycloadditions to Form Triazole Inhibitors with Crystalline Acetylcholinesterase.

    PubMed

    Bourne, Yves; Sharpless, K Barry; Taylor, Palmer; Marchot, Pascale

    2016-02-10

    Ligand binding sites on acetylcholinesterase (AChE) comprise an active center, at the base of a deep and narrow gorge lined by aromatic residues, and a peripheral site at the gorge entry. These features launched AChE as a reaction vessel for in situ click-chemistry synthesis of high-affinity TZ2PA6 and TZ2PA5 inhibitors, forming a syn-triazole upon cycloaddition within the gorge from alkyne and azide reactants bound at the two sites, respectively. Subsequent crystallographic analyses of AChE complexes with the TZ2PA6 regioisomers demonstrated that syn product association is accompanied by side chain reorganization within the gorge, freezing-in-frame a conformation distinct from an unbound state or anti complex. To correlate inhibitor dimensions with reactivity and explore whether in situ cycloaddition could be accelerated in a concentrated, crystalline template, we developed crystal-soaking procedures and solved structures of AChE complexes with the TZ2PA5 regioisomers and their TZ2/PA5 precursors (2.1-2.7 Å resolution). The structures reveal motions of residue His447 in the active site and, unprecedentedly, residue Tyr341 at the gorge mouth, associated with TZ2 binding and coordinated with other side chain motions in the gorge that may guide AChE toward a transient state favoring syn-triazole formation. Despite precursor binding to crystalline AChE, coupling of rapid electric field fluctuations in the gorge with proper alignments of the azide and alkyne reactants to form the triazole remains a likely limiting step. These observations point to a prime requirement for AChE to interconvert dynamically between sequential conformations to promote favorable electrostatic factors enabling a productive apposition of the reactants for reactivity. PMID:26731630

  2. Identification of non-alkaloid acetylcholinesterase inhibitors from Ferulago campestris (Besser) Grecescu (Apiaceae).

    PubMed

    Dall'Acqua, Stefano; Maggi, Filippo; Minesso, Paola; Salvagno, Marina; Papa, Fabrizio; Vittori, Sauro; Innocenti, Gabbriella

    2010-12-01

    Inhibition of Acetylcholinesterase (AChE) is still considered as a strategy for the treatment of neurological disorders such as Alzheimer's disease. Many plant derived alkaloids (such as galantamine and rivastigmine) are known for their AChE inhibitory activity. Recently, other classes of natural compounds such as terpenoids, sesquiterpene glycosides and coumarins have been studied as new AChE inhibitors, with the aim to discover less toxic compounds compared to alkaloidal ones. The Ferulago campestris roots dichloromethane extract was used for a bioassay-guided fractionation for the search of AChE inhibitors. Three coumarin derivatives (umbelliprenin 1, coladonin 2 and coladin 3), three daucane ester derivatives (siol anisate 4, ferutinin 5 and 1-acetyl-5-angeloyl lapiferol 6), two phenol derivatives (2-epilaserine 7 and epielmanticine 8) and one polyacetylene (9-epoxyfalcarindiol 9) were isolated by the bioassay-guided approach. Their structures were characterized on the basis of spectral methods (1D and 2D NMR, and MS spectroscopy). All the isolated compounds were able to inhibit the AChE (IC(50) 1.2-0.1mM) although at higher doses if compared to galantamine (6.7 μM) measured in the same conditions. The most active compounds were the daucane derivative siol anisate 4 and the epielmanticine 8, with IC(50) of 0.172 and 0.175 mM respectively.

  3. The natural product dihydrotanshinone I provides a prototype for uncharged inhibitors that bind specifically to the acetylcholinesterase peripheral site with nanomolar affinity.

    PubMed

    Beri, Veena; Wildman, Scott A; Shiomi, Kazuro; Al-Rashid, Ziyad F; Cheung, Jonah; Rosenberry, Terrone L

    2013-10-22

    Cholinergic synaptic transmission often requires extremely rapid hydrolysis of acetylcholine by acetylcholinesterase (AChE). AChE is inactivated by organophosphates (OPs) in chemical warfare nerve agents. The resulting accumulation of acetylcholine disrupts cholinergic synaptic transmission and can lead to death. A potential long-term strategy for preventing AChE inactivation by OPs is based on evidence that OPs must pass through a peripheral site or P-site near the mouth of the AChE active site gorge before reacting with a catalytic serine in an acylation site or A-site at the base of the gorge. An ultimate goal of this strategy is to design compounds that bind tightly at or near the P-site and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site with ligands and potential drugs that selectively restrict access, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. We apply here an inhibitor competition assay that can correctly determine whether an AChE inhibitor binds to the P-site, the A-site, or both sites. We have used this assay to examine three uncharged, natural product inhibitors of AChE, including aflatoxin B1, dihydrotanshinone I, and territrem B. The first two of these inhibitors are predicted by the competition assay to bind selectively to the P-site, while territrem B is predicted to span both the P- and A-sites. These predictions have recently been confirmed by X-ray crystallography. Dihydrotanshinone I, with an observed binding constant (KI) of 750 nM, provides a good lead compound for the development of high-affinity, uncharged inhibitors with specificity for the P-site. PMID:24040835

  4. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies

    PubMed Central

    2011-01-01

    Background Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. Methods In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors. Results The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R2 = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site. Conclusions The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites. PMID:21251245

  5. Some new carbacylamidophosphates as inhibitors of acetylcholinesterase and butyrylcholinesterase.

    PubMed

    Gholivand, Khodayar; Alizadehgan, Ahlam Madani; Mojahed, Fresia; Dehghan, Gholamreza; Mohammadirad, Azadeh; Abdollahi, Mohammad

    2008-01-01

    The differences in the inhibition activity of organophosphorus agents are a manifestation of different molecular properties of the inhibitors involved in the interaction with the active site of enzyme. We were interested in comparing the inhibition potency of four known synthesized carbacylamidophosphates with the general formula RC(O)NHP(O)Cl2, constituting organophosphorus compounds, where R = CCl3 (1), CHCl2 (2), CH2Cl (3) and CF3 (4), and four new ones with the general formula RC(O)NHP(O)(R')2, where R' = morpholine and R = CCl3 (5), CHCl2 (6), CH2Cl (7), CF3 (8), on AChE and BuChE activities. In addition, in vitro activities of all eight compounds on BuChE were determined. Besides, in vivo inhibition potency of compounds 2 and 6, which had the highest inhibition potency among the tested compounds, was studied. The data demonstrated that compound 2 from the compound series 1 to 4 and compound 6 from the compound series 5 to 8 are the most sensitive as AChE and BuChE inhibitors, respectively. Comparing the IC50 values of these compounds, it was clear that the inhibition potency of these compounds for AChE are 2- to 100-fold greater than for BuChE inhibition. Comparison of the kinetics (IC50, Ki, kp, KA and KD) of AChE and BuChE inactivation by these compounds resulted in no significant difference for the measured variables except for compounds 2 and 6, which appeared to be more sensitive to AChE and BuChE by significantly higher kp and Ki values and a lower IC50 value in comparison with the other compounds. The LD50 value of compounds 2 and 6, after oral administration, and the changes of erythrocyte AChE and plasma BuChE activities in albino mice were studied. The in vivo experiments, similar to the in vitro results, showed that compound 2 is a stronger AChE and BuChE inhibitor than the other synthesized carbacylamidophosphates. Furthermore, in this study, the importance of electropositivity of the phosphorus atom, steric hindrance and leaving group specificity

  6. Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

    PubMed

    Wang, Zhi-Min; Cai, Pei; Liu, Qiao-Hong; Xu, Ding-Qiao; Yang, Xue-Lian; Wu, Jia-Jia; Kong, Ling-Yi; Wang, Xiao-Bing

    2016-11-10

    A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aβ1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy. PMID:27484514

  7. Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals

    PubMed Central

    Amat-ur-Rasool, Hafsa; Ahmed, Mehboob

    2015-01-01

    Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD. PMID:26325402

  8. Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.

    PubMed

    Amat-Ur-Rasool, Hafsa; Ahmed, Mehboob

    2015-01-01

    Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD. PMID:26325402

  9. Chlorpyrifos and Malathion have opposite effects on behaviors and brain size that are not correlated to changes in AChE activity

    PubMed Central

    Richendrfer, Holly; Creton, Robbert

    2015-01-01

    Organophosphates, a type of neurotoxicant pesticide, are used globally for the treatment of pests on croplands and are therefore found in a large number of conventional foods. These pesticides are harmful and potentially deadly if ingested or inhaled in large quantities by causing a significant reduction in acetylcholinesterase (AChE) activity in the central and peripheral nervous system. However, much less is known about the effects of exposure to small quantities of the pesticides on neural systems and behavior during development. In the current study we used zebrafish larvae in order to determine the effects of two of the most widely used organophosphates, chlorpyrifos and malathion, on zebrafish behavior and AChE activity. Embryos and larvae were exposed to the organophosphates during different time points in development and then tested at 5 days post-fertilization for behavioral, neurodevelopmental and AChE abnormalities. The results of the study indicate that chlorpyrifos and malathion cause opposing behaviors in the larvae such as swim speed (hypoactivity vs. hyperactivity) and rest. Additionally, the pesticides affect only certain behaviors, such as thigmotaxis, during specific time points in development that are unrelated to changes in AChE activity. Larvae treated with malathion but not chlorpyrifos also had significantly smaller forebrain and hindbrain regions compared to controls by 5 days post-fertilization. We conclude that exposure to very low concentrations of organophosphate pesticides during development cause abnormalities in behavior and brain size. PMID:25983063

  10. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation.

    PubMed

    Bourne, Yves; Kolb, Hartmuth C; Radić, Zoran; Sharpless, K Barry; Taylor, Palmer; Marchot, Pascale

    2004-02-10

    The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template.

  11. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation

    PubMed Central

    Bourne, Yves; Kolb, Hartmuth C.; Radić, Zoran; Sharpless, K. Barry; Taylor, Palmer; Marchot, Pascale

    2004-01-01

    The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-Å resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template. PMID:14757816

  12. Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward.

    PubMed

    Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M; Kim, Charlene H; Nichols, Weston A; Moaddel, Ruin; Xiao, Cheng; Lester, Henry A

    2016-03-01

    Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway.

  13. Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase.

    PubMed

    Sun, Qi; Peng, Da-Yong; Yang, Sheng-Gang; Zhu, Xiao-Lei; Yang, Wen-Chao; Yang, Guang-Fu

    2014-09-01

    Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.

  14. Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

    PubMed Central

    2014-01-01

    Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved “photoswitchable”. The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ1–40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays. PMID:24628027

  15. Escherichia coli Protein Expression System for Acetylcholine Binding Proteins (AChBPs)

    PubMed Central

    Abraham, Nikita; Paul, Blessy; Ragnarsson, Lotten; Lewis, Richard J.

    2016-01-01

    Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels, identified as therapeutic targets for a range of human diseases. Drug design for nAChR related disorders is increasingly using structure-based approaches. Many of these structural insights for therapeutic lead development have been obtained from co-crystal structures of nAChR agonists and antagonists with the acetylcholine binding protein (AChBP). AChBP is a water soluble, structural and functional homolog of the extracellular, ligand-binding domain of nAChRs. Currently, AChBPs are recombinantly expressed in eukaryotic expression systems for structural and biophysical studies. Here, we report the establishment of an Escherichia coli (E. coli) expression system that significantly reduces the cost and time of production compared to the existing expression systems. E. coli can efficiently express unglycosylated AChBP for crystallography and makes the expression of isotopically labelled forms feasible for NMR. We used a pHUE vector containing an N-terminal His-tagged ubiquitin fusion protein to facilitate AChBP expression in the soluble fractions, and thus avoid the need to recover protein from inclusion bodies. The purified protein yield obtained from the E. coli expression system is comparable to that obtained from existing AChBP expression systems. E. coli expressed AChBP bound nAChR agonists and antagonists with affinities matching those previously reported. Thus, the E. coli expression system significantly simplifies the expression and purification of functional AChBP for structural and biophysical studies. PMID:27304486

  16. Phe362Tyr in AChE: A Major Factor Responsible for Azamethiphos Resistance in Lepeophtheirus salmonis in Norway

    PubMed Central

    Kaur, Kiranpreet; Jansen, Peder Andreas; Aspehaug, Vidar Teis; Horsberg, Tor Einar

    2016-01-01

    Organophosphates (OP) are one of the major treatments used against the salmon louse (Lepeophtherius salmonis) in Norwegian salmonid aquaculture. The use of OP since the late 1970s has resulted in widespread resistant parasites. Recently, we reported a single mutation (Phe362Tyr) in acetylcholinesterase (AChE) as the major mechanism behind resistance in salmon louse towards OP. The present study was carried out to validate this mechanism at the field level. A total of 6658 salmon louse samples were enrolled from 56 different fish farms across the Norwegian coast, from Vest Agder in the south to Finnmark in the north. All the samples were genotyped using a TaqMan probe assay for the Phe362Tyr mutation. A strong association was observed between areas with frequent use of the OP (azamethiphos) and the Phe362Tyr mutation. This was confirmed at 15 sites where results from independently conducted bioassays and genotyping of parasites correlated well. Furthermore, genotyping of surviving and moribund parasites from six bioassay experiments demonstrated a highly significant negative correlation between the frequency of resistance alleles and the probability of dying when exposed to azamethiphos in a bioassay. Based on these observations, we could strongly conclude that the Phe362Tyr mutation is a major factor responsible for OP resistance in salmon louse on Norwegian fish farms. PMID:26882536

  17. Phe362Tyr in AChE: A Major Factor Responsible for Azamethiphos Resistance in Lepeophtheirus salmonis in Norway.

    PubMed

    Kaur, Kiranpreet; Jansen, Peder Andreas; Aspehaug, Vidar Teis; Horsberg, Tor Einar

    2016-01-01

    Organophosphates (OP) are one of the major treatments used against the salmon louse (Lepeophtherius salmonis) in Norwegian salmonid aquaculture. The use of OP since the late 1970s has resulted in widespread resistant parasites. Recently, we reported a single mutation (Phe362Tyr) in acetylcholinesterase (AChE) as the major mechanism behind resistance in salmon louse towards OP. The present study was carried out to validate this mechanism at the field level. A total of 6658 salmon louse samples were enrolled from 56 different fish farms across the Norwegian coast, from Vest Agder in the south to Finnmark in the north. All the samples were genotyped using a TaqMan probe assay for the Phe362Tyr mutation. A strong association was observed between areas with frequent use of the OP (azamethiphos) and the Phe362Tyr mutation. This was confirmed at 15 sites where results from independently conducted bioassays and genotyping of parasites correlated well. Furthermore, genotyping of surviving and moribund parasites from six bioassay experiments demonstrated a highly significant negative correlation between the frequency of resistance alleles and the probability of dying when exposed to azamethiphos in a bioassay. Based on these observations, we could strongly conclude that the Phe362Tyr mutation is a major factor responsible for OP resistance in salmon louse on Norwegian fish farms. PMID:26882536

  18. Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes.

    PubMed

    Wang, Shuo; Du, Tianpeng; Liu, Zhuguo; Wang, Sheng; Wu, Ying; Ding, Jiuping; Jiang, Ling; Dai, Qiuyun

    2014-11-01

    T-superfamily conotoxins have a typical cysteine pattern of "CC-CC", and are known to mainly target calcium or sodium ion channels. Recently, we screened the targets of a series of T-superfamily conotoxins and found that a new T-superfamily conotoxin TxVC (KPCCSIHDNSCCGL-NH2) from the venom of Conus textile. It selectively targeted the neuronal nicotinic acetylcholine receptor (nAChR) subtypes α4β2 and α3β2, with IC50 values of 343.4 and 1047.2nM, respectively, but did not exhibit obvious pharmacological effects on voltage-gated potassium, sodium or calcium channel in DRG cells, the BK channels expressed in HEK293 cells, or the Kv channels in LβT2 cells. The changes in the inhibitory activities of its Ala mutants, the NMR structure, and molecular simulation results based on other conotoxins targeting nAChR α4β2, all demonstrated that the residues Ile(6) and Leu(14) were the main hydrophobic pharmacophores. To our best knowledge, this is the first T-superfamily conotoxin that inhibits neuronal nAChRs and possesses high binding affinity to α4β2. This finding will expand the knowledge of the targets of T-superfamily conotoxins and the motif information could help the design of new nAChR inhibitors.

  19. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity.

    PubMed

    Pohanka, Miroslav

    2014-06-02

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.

  20. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

    PubMed Central

    Pohanka, Miroslav

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

  1. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity.

    PubMed

    Pohanka, Miroslav

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

  2. 1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies.

    PubMed

    Di Pietro, Ornella; Viayna, Elisabet; Vicente-García, Esther; Bartolini, Manuela; Ramón, Rosario; Juárez-Jiménez, Jordi; Clos, M Victòria; Pérez, Belén; Andrisano, Vincenza; Luque, F Javier; Lavilla, Rodolfo; Muñoz-Torrero, Diego

    2014-02-12

    A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (>11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities. PMID:24389509

  3. Quaternary alkaloids of tinospora species.

    PubMed

    Bisset, N G; Nwaiwu, J

    1983-08-01

    The occurrence of quaternary alkaloids in TINOSPORA (and PARABAENA) species (Menispermaceae) has been studied. The main components were generally the protoberberine bases berberine and palmatine, with jatrorrhizine an occasional minor constituent, and the aporphine base magnoflorine. Choline was also often present. Only magnoflorine was detected in the PARABAENA material examined. PMID:17404996

  4. Role of acetylcholinesterase inhibitors in the metabolism of amyloid precursor protein.

    PubMed

    Pakaski, M; Kasa, P

    2003-06-01

    Potentiation of central cholinergic activity has been proposed as a therapeutic approach for improving the cognitive function in patients with Alzheimer's disease (AD). Increasing the acetylcholine concentration in the brain by modulating acetylcholine-sterase (AChE) activity is among the most promising therapeutic strategies. Efforts to treat the underlying pathology based on the modulation of amyloid precursor protein (APP) processing in order to decrease the accumulation of beta-amyloid are also very important. Alterations in APP metabolism have recently been proposed to play a key role in the long-lasting effects of AChE inhibitors. This review surveys recent data from in vivo and in vitro studies that have contributed to our understanding of the role of AChE inhibitors in APP processing. The regulatory mechanisms relating to the muscarinic agonist effect, protein kinase C activation and mitogen-activated protein kinase phosphorylation, involving the alpha-secretase or the 5 -UTR region of the APP gene, are also discussed. Further work is warranted to elucidate the exact roles in APP metabolism of the AChE inhibitors used in AD therapy at present. PMID:12769797

  5. Novel Selective and Irreversible Mosquito Acetylcholinesterase Inhibitors for Controlling Malaria and Other Mosquito-Borne Diseases

    NASA Astrophysics Data System (ADS)

    Dou, Dengfeng; Park, Jewn Giew; Rana, Sandeep; Madden, Benjamin J.; Jiang, Haobo; Pang, Yuan-Ping

    2013-01-01

    We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (kinact/KI) of 3,604-458,597 M-1sec-1 but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with kinact/KI values of 1,915 and 1,507 M-1sec-1, respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases.

  6. α7nAchR/NMDAR coupling affects NMDAR function and object recognition.

    PubMed

    Li, Shupeng; Nai, Qiang; Lipina, Tatiana V; Roder, John C; Liu, Fang

    2013-12-20

    The α7 nicotinic acetylcholine receptor (nAchR) and NMDA glutamate receptor (NMDAR) are both ligand-gated ion channels permeable to Ca2+ and Na+. Previous studies have demonstrated functional modulation of NMDARs by nAchRs, although the molecular mechanism remains largely unknown. We have previously reported that α7nAchR forms a protein complex with the NMDAR through a protein-protein interaction. We also developed an interfering peptide that is able to disrupt the α7nAchR-NMDAR complex and blocks cue-induced reinstatement of nicotine-seeking in rat models of relapse. In the present study, we investigated whether the α7nAchR-NMDAR interaction is responsible for the functional modulation of NMDAR by α7nAchR using both electrophysiological and behavioral tests. We have found that activation of α7nAchR upregulates NMDAR-mediated whole cell currents and LTP of mEPSC in cultured hippocampal neurons, which can be abolished by the interfering peptide that disrupts the α7nAchR-NMDAR interaction. Moreover, administration of the interfering peptide in mice impairs novel object recognition but not Morris water maze performance. Our results suggest that α7nAchR/NMDAR coupling may selectively affect some aspects of learning and memory.

  7. Clinical application of clustered-AChR for the detection of SNMG

    PubMed Central

    Zhao, Guang; Wang, Xiaoqing; Yu, Xiaowen; Zhang, Xiutian; Guan, Yangtai; Jiang, Jianming

    2015-01-01

    Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction (NMJ). However, accumulating evidence has indicated that MG patients whose serum anti-acetylcholine receptor (AChR) antibodies are not detectable (serumnegative MG; SNMG) in routine assays share similar clinical features with anti-AChR antibody-positive MG patients. We hypothesized that SNMG patients would have low-affinity antibodies to AChRs that would not be detectable using traditional methods but that might be detected by binding to AChR on the cell membrane, particularly if they were clustered at the high density observed at the NMJ. We expressed AChR subunits with the clustering protein rapsyn (an AChR-associated protein at the synapse) in human embryonic kidney (HEK) cells, and we tested the binding of the antibodies using immunofluorescence. With this approach, AChR antibodies to rapsyn-clustered AChR could be detected in the sera from 45.83% (11/24) of SNMG patients, as confirmed with fluorescence-activated cell sorting (FACS). This was the first application in China of cell-based AChR antibody detection. More importantly, this sensitive (and specific) approach could significantly increase the diagnosis rate of SNMG. PMID:26068604

  8. Synthesis of Novel 3-Aryl-N-Methyl-1,2,5,6-Tetrahydropyridine Derivatives by Suzuki coupling: As Acetyl Cholinesterase Inhibitors

    PubMed Central

    Prasad, S.B. Benaka; Kumar, Y.C. Sunil; Kumar, C.S. Ananda; Sadashiva, C.T; Vinaya, K; Rangappa, K.S

    2007-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder affecting the central nervous system, which is also associated with progressive loss of memory and cognition. The development of numerous structural classes of compounds with different pharmacological profile could be an evolving, promising therapeutic approach for the treatment of AD. Thus, providing a symptomatic treatment for this disease are cholinomimetics with the pharmacological profile of Acetylcholinesterase (AChE) inhibitors. In view of this, we have synthesized novel 3-aryl-N-methyl-1,2,5,6-tetrahydropyridine derivatives 5a-k by Suzuki coupling and screened the efficacy of these derivatives for their AChE inhibitor activity. PMID:19662135

  9. Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward

    PubMed Central

    Henderson, Brandon J.; Wall, Teagan R.; Henley, Beverley M.; Kim, Charlene H.; Nichols, Weston A.; Moaddel, Ruin; Xiao, Cheng

    2016-01-01

    Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. SIGNIFICANCE STATEMENT Menthol, the most popular flavorant for tobacco products, has been considered simply a benign flavor additive. However, as we show here

  10. Nicotine activates YAP1 through nAChRs mediated signaling in esophageal squamous cell cancer (ESCC).

    PubMed

    Zhao, Yue; Zhou, Wei; Xue, Liyan; Zhang, Weimin; Zhan, Qimin

    2014-01-01

    Cigarette smoking is an established risk factor for esophageal cancers. Yes-associated protein 1 (YAP1), the key transcription factor of the mammalian Hippo pathway, has been reported to be an oncogenic factor for many cancers. In this study, we find nicotine administration can induce nuclear translocation and activation of YAP1 in ESCC. Consistently, we observed nuclear translocation and activation of YAP1 by knockdown of CHRNA3, which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells. Nicotine administration or CHRNA3 depletion substantially increased proliferation and migration in esophageal cancer cells. Interestingly, we find that YAP1 physically interacts with nAChRs, and nAChRs-signaling dissociates YAP1 from its negative regulatory complex composed with α-catenin, β-catenin and 14-3-3 in the cytoplasm, leading to upregulation and nuclear translocation of YAP1. This process likely requires PKC activation, as PKC specific inhibitor Enzastaurin can block nicotine induced YAP1 activation. In addition, we find nicotine signaling also inhibits the interaction of YAP1 with P63, which contributes to the inhibitory effect of nicotine on apoptosis. Using immunohistochemistry analysis we observed upregulation of YAP1 in a significant portion of esophageal cancer samples. Consistently, we have found a significant association between YAP1 upregulation and cigarette smoking in the clinical esophageal cancer samples. Together, these findings suggest that the nicotine activated nAChRs signaling pathway which further activates YAP1 plays an important role in the development of esophageal cancer, and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers.

  11. Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: Brain ACh increasing and memory improving properties

    PubMed Central

    Hornick, Ariane; Schwaiger, Stefan; Rollinger, Judith M.; Vo, Nguyen Phung; Prast, Helmut; Stuppner, Hermann

    2012-01-01

    Leontopodium alpinum (‘Edelweiss’) was phytochemically investigated for constituents that might enhance cholinergic neurotransmission. The potency to increase synaptic availability of acetylcholine (ACh) in rat brain served as key property for the bioguided isolation of cholinergically active compounds using different chromatographic techniques. The dichlormethane (DCM) extract of the root, fractions and isolated constituents were injected i.c.v. and the effect on brain ACh was detected via the push–pull technique. The DCM extract enhanced extracellular ACh concentration in rat brain and inhibited acetylcholinesterase (AChE) in vitro. The extracellular level of brain ACh was significantly increased by the isolated sesquiterpenes, isocomene and 14-acetoxyisocomene, while silphiperfolene acetate and silphinene caused a small increasing tendency. Only silphiperfolene acetate showed in vitro AChE inhibitory activity, thus suggesting the other sesquiterpenes to stimulate cholinergic transmission by an alternative mechanism of action. Isocomene was further investigated with behavioural tasks in mice. It restored object recognition in scopolamine-impaired mice and showed nootropic effects in the T-maze alternation task in normal and scopolamine-treated mice. Additionally, this sesquiterpene reduced locomotor activity of untreated mice in the open field task, while the activity induced by scopolamine was abolished. The enhancement of synaptic availability of ACh, the promotion of alternation, and the amelioration of scopolamine-induced deficit are in accordance with a substance that amplifies cholinergic transmission. Whether the mechanism of action is inhibition of AChE or another pro-cholinergic property remains to be elucidated. Taken together, isocomene and related constituents of L. alpinum deserve further interest as potential antidementia agents in brain diseases associated with cholinergic deficits. PMID:18541221

  12. Analysis of free ACh and 5-HT in milk from four different species and their bioactivity on 5-HT(3) and nACh receptors.

    PubMed

    Gallegos-Perez, Jose-Luis; Limon, Agenor; Reyes-Ruiz, Jorge M; Alshanqeeti, Ali S; Aljohi, Mohammad A; Miledi, Ricardo

    2014-07-25

    Milk is one of the most beneficial aliments and is highly recommended in normal conditions; however, in certain disorders, like irritable bowel syndrome, cow milk and dairy products worsen the gastric symptoms and their use is not recommended. Among the most recognized milk-induced gatrointestinal symptoms are abdominal pain, nausea and vomiting, which are processes controlled by cholinergic and serotonergic transmission. Whether the presence of bioavailable ACh and 5-HT in milk may contribute to normal peristalsis, or to the developing of these symptoms, is not known. In this work we attempt to determine whether the content of free ACh and 5-HT is of physiological significance in milk from four different species: cow (bovine), goat, camel and human. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to identify and quantify free ACh and 5-HT in milk, and activation of the serotonergic and cholinergic ionotropic receptors was investigated using electrophysiological experiments. Our principal hypothesis was that milk from these four species had sufficient free ACh and 5-HT to activate their correspondent receptors expressed in a heterologous system. Our results showed a more complex picture, in which free ACh and 5-HT and their ability to activate cholinergic and serotonergic receptors are not correlated. This work is a first step to elucidate whether 5-HT and ACh, at the concentrations present in the milk, can be associated to a direct function in the GI.

  13. Inhibitor Profile of bis(n)-tacrines and N-methylcarbamates on Acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cattle tick, Rhipicephalus (Boophilus) microplus (Bm), and the sand fly, Phlebotomus papatasi (Pp), are disease vectors to cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases from Bm (BmAChE1) and Pp (PpAchE) compared to h...

  14. The 3D-QSAR study of 110 diverse, dual binding, acetylcholinesterase inhibitors based on alignment independent descriptors (GRIND-2). The effects of conformation on predictive power and interpretability of the models.

    PubMed

    Vitorović-Todorović, Maja D; Cvijetić, Ilija N; Juranić, Ivan O; Drakulić, Branko J

    2012-09-01

    The 3D-QSAR analysis based on alignment independent descriptors (GRIND-2) was performed on the set of 110 structurally diverse, dual binding AChE reversible inhibitors. Three separate models were built, based on different conformations, generated following next criteria: (i) minimum energy conformations, (ii) conformation most similar to the co-crystalized ligand conformation, and (iii) docked conformation. We found that regardless on conformation used, all the three models had good statistic and predictivity. The models revealed the importance of protonated pyridine nitrogen of tacrine moiety for anti AChE activity, and recognized HBA and HBD interactions as highly important for the potency. This was revealed by the variables associated with protonated pyridinium nitrogen, and the two amino groups of the linker. MIFs calculated with the N1 (pyridinium nitrogen) and the DRY GRID probes in the AChE active site enabled us to establish the relationship between amino acid residues within AChE active site and the variables having high impact on models. External predictive power of the models was tested on the set of 40 AChE reversible inhibitors, most of them structurally different from the training set. Some of those compounds were tested on the different enzyme source. We found that external predictivity was highly sensitive on conformations used. Model based on docked conformations had superior predictive ability, emphasizing the need for the employment of conformations built by taking into account geometrical restrictions of AChE active site gorge.

  15. Insect-specific irreversible inhibitors of acetylcholinesterase in pests including the bed bug, the eastern yellowjacket, German and American cockroaches, and the confused flour beetle.

    PubMed

    Polsinelli, Gregory A; Singh, Sanjay K; Mishra, Rajesh K; Suranyi, Robert; Ragsdale, David W; Pang, Yuan-Ping; Brimijoin, Stephen

    2010-09-01

    Insecticides directed against acetylcholinesterase (AChE) are facing increased resistance among target species as well as increasing concerns for human toxicity. The result has been a resurgence of disease vectors, insects destructive to agriculture, and residential pests. We previously reported a free cysteine (Cys) residue at the entrance to the AChE active site in some insects but not higher vertebrates. We also reported Cys-targeting methanethiosulfonate molecules (AMTSn), which, under conditions that spared human AChE, caused total irreversible inhibition of aphid AChE, 95% inhibition of AChE from the malaria vector mosquito (Anopheles gambia), and >80% inhibition of activity from the yellow fever mosquito (Aedes aegypti) and northern house mosquito (Culex pipiens). We now find the same compounds inhibit AChE from cockroaches (Blattella germanica and Periplaneta americana), the flour beetle (Tribolium confusum), the multi-colored Asian ladybird beetle (Harmonia axyridis), the bed bug (Cimex lectularius), and a wasp (Vespula maculifrons), with IC(50) values of approximately 1-11muM. Our results support further study of Cys-targeting inhibitors as conceptually novel insecticides that may be free of resistance in a range of insect pests and disease vectors and, compared with current compounds, should demonstrate much lower toxicity to mammals, birds, and fish. PMID:20109441

  16. Andrei Sher and Quaternary science

    NASA Astrophysics Data System (ADS)

    Kuzmina, Svetlana; Lister, Adrian M.; Edwards, Mary E.

    2011-08-01

    Andrei Sher (1939-2008) was a key individual in Beringian studies who made substantial and original contributions, but also, importantly, built bridges between western and eastern Beringian scientists spanning some five decades of research. He is perhaps best known as a Quaternary palaeontologist, specializing in large mammals, and mammoths in particular, but his field of his scientific research was much broader, encompassing Quaternary geology, stratigraphy, geocryology, and paleoenvironmental reconstructions. He worked mainly in Siberia, in the Kolyma and Indigirka lowlands, and Chukotka, but also completed fieldwork in Alaska and Yukon through joint projects with American and Canadian scientists. Andrei was an active scientist until the last days of his life. He was involved in many different research projects ranging from mammoth evolution, fossil insects and environmental changes and ancient DNA. Without Andrei's connections between researchers, many unique discoveries would likely be unknown.

  17. Quaternary ecology: A paleoecological perspective

    SciTech Connect

    Delcourt, H.R.; Delcourt, P.A.

    1991-01-01

    This book considers issues and problems in ecology which may be illuminated, if not solved, by considering paleoecology. The five central chapters include a discussion of application of Quaternary ecology to future global climate change, including global warming. Other areas presented include: population dispersal, invasions, expansions, and migrations; plant successions; ecotones; factors in community structure; ecosystem patterns and processes. Published case studies are numerous. The role played by continuing climatic change in vegetation change is acknowledged but not stressed.

  18. THE ACHES THAT TAKE YOUR BREATH (AND TEARS) AWAY.

    PubMed

    Becerril, J; Gonzales, H; Saketkoo, L A

    2015-01-01

    An 80-year-old man presented with a complaint of three months of fatigue and aching of his shoulders and hips, as well as pain, swelling, and stiffness in bilateral fingers that was worse in the morning but improved with movement. Associated symptoms included worsening dry mouth and eyes, dysphagia, exertional dyspnea, and right foot drop. Physical exam was significant for edematous and tender bilateral proximal interphalangeal joints, metacarpophalangeal joints and wrists with decreased grip, extension and flexion, as well as bilateral pulmonary crackles. Laboratory analysis revealed Anti-Ro (SSA) and Anti-La (SSB) positivity with elevated erythrocyte sedimentation rate (70mm/hr) and C-reactive peptide (13mg/L). Pulmonary function testing was notable for a forced vital capacity (FVC) of 64% and carbon monoxide diffusing capacity (DLCO) of 44%. High resolution chest computed tomography demonstrated fibrotic changes consistent with nonspecific interstitial pneumonitis. The patient was started on mycophenolate mofetil, hydroxychloroquine, and prednisone for Sjögren's syndrome (SjS). Symptoms improved and repeat FVC revealed a 20 percent improvement, however subsequent tapering of prednisone resulted in worsening dyspnea and increase of FVC to 60 prcent. Prednisone was restarted and rituximab 2g divided in two doses was administered with overall symptom improvement. Symptoms and FVC continued to wax and wane over the following 18 months requiring re-dosing of rituximab with most recent FVC improved to 71 percent and DLCO 41 percent. PMID:27159479

  19. Acetylcholinesterase biosensor for inhibitor measurements based on glassy carbon electrode modified with carbon black and pillar[5]arene.

    PubMed

    Shamagsumova, Rezeda V; Shurpik, Dmitry N; Padnya, Pavel L; Stoikov, Ivan I; Evtugyn, Gennady A

    2015-11-01

    New acetylcholinesterase (AChE) biosensor based on unsubstituted pillar[5]arene (P[5]A) as electron mediator was developed and successfully used for highly sensitive detection of organophosphate and carbamate pesticides. The AChE from electric eel was immobilized by carbodiimide binding on carbon black (CB) placed on glassy carbon electrode. The working potential of 200mV was obtained in chronoamperometric mode with the measurement time of 180 s providing best inter-biosensors precision of the results. The AChE biosensor developed made it possible to detect 1×10(-11)-1×10(-6) M of malaoxon, 1×10(-8)-7×10(-6) M of methyl-paraoxon, 1×10(-10)-2×10(-6) M of carbofuran and 7×10(-9)-1×10(-5) M of aldicarb with 10 min incubation. The limits of detection were 4×10(-12), 5×10(-9), 2×10(-11) and 6×10(-10) M, respectively. The AChE biosensor was tested in the analysis of pesticide residuals in spiked samples of peanut and beetroot. The protecting effect of P[5]A derivative bearing quaternary ammonia groups on malaoxon inhibition was shown. PMID:26452862

  20. Acetylcholinesterase biosensor for inhibitor measurements based on glassy carbon electrode modified with carbon black and pillar[5]arene.

    PubMed

    Shamagsumova, Rezeda V; Shurpik, Dmitry N; Padnya, Pavel L; Stoikov, Ivan I; Evtugyn, Gennady A

    2015-11-01

    New acetylcholinesterase (AChE) biosensor based on unsubstituted pillar[5]arene (P[5]A) as electron mediator was developed and successfully used for highly sensitive detection of organophosphate and carbamate pesticides. The AChE from electric eel was immobilized by carbodiimide binding on carbon black (CB) placed on glassy carbon electrode. The working potential of 200mV was obtained in chronoamperometric mode with the measurement time of 180 s providing best inter-biosensors precision of the results. The AChE biosensor developed made it possible to detect 1×10(-11)-1×10(-6) M of malaoxon, 1×10(-8)-7×10(-6) M of methyl-paraoxon, 1×10(-10)-2×10(-6) M of carbofuran and 7×10(-9)-1×10(-5) M of aldicarb with 10 min incubation. The limits of detection were 4×10(-12), 5×10(-9), 2×10(-11) and 6×10(-10) M, respectively. The AChE biosensor was tested in the analysis of pesticide residuals in spiked samples of peanut and beetroot. The protecting effect of P[5]A derivative bearing quaternary ammonia groups on malaoxon inhibition was shown.

  1. Screening of β-secretase and acetylcholinesterase inhibitors from plant resources.

    PubMed

    Murata, Kazuya; Matsumura, Shinichi; Yoshioka, Yuri; Ueno, Yoshihiro; Matsuda, Hideaki

    2015-01-01

    The therapeutic agents for dementia are limited due to the complex system underlying the mechanisms. Taking a preventive point of view, we focused on the inhibition of β-secretase and acetylcholinesterase (AChE). In addition, plant resources including herbs and spices have been widely consumed, and further, may be consumed for a long period over a lifetime. Considering this background, we screened β-secretase and AChE inhibitors from curry spices. Amongst them, curry leaf, black pepper, and turmeric extracts were effective to inhibit β-secretase. Furthermore, black pepper and turmeric extracts were also effective to inhibit AChE. Having these results in hand, we focused on the investigation of β-secretase inhibitors since the inhibitor of this enzyme has not previously been well investigated. As a result, α- and β-caryophyllene, β-caryophyllene oxide (from curry leaf), piperine (from black pepper), curcumin, demethoxycurcumin, and bisdemethoxycurcumin (from turmeric) were successfully identified as low molecular inhibitors. This is the first report to determine α- and β-caryophyllene, β-caryophyllene oxide, and piperine as β-secretase inhibitors. These compounds may pass through the blood brain barrier since their molecular weights are relatively low. PMID:25119528

  2. Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques.

    PubMed

    Gupta, Shikhar; Fallarero, Adyary; Järvinen, Päivi; Karlsson, Daniela; Johnson, Mark S; Vuorela, Pia M; Mohan, C Gopi

    2011-02-15

    Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer's disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads--Specs1 (IC(50)=3.279 μM) and Spec2 (IC(50)=5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity. PMID:21273074

  3. Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques.

    PubMed

    Gupta, Shikhar; Fallarero, Adyary; Järvinen, Päivi; Karlsson, Daniela; Johnson, Mark S; Vuorela, Pia M; Mohan, C Gopi

    2011-02-15

    Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer's disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads--Specs1 (IC(50)=3.279 μM) and Spec2 (IC(50)=5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity.

  4. Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [¹¹C] Radiosynthesis and Biological Evaluation.

    PubMed

    Bohn, Pierre; Gourand, Fabienne; Papamicaël, Cyril; Ibazizène, Méziane; Dhilly, Martine; Gembus, Vincent; Alix, Florent; Ţînţaş, Mihaela-Liliana; Marsais, Francis; Barré, Louisa; Levacher, Vincent

    2015-05-20

    With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug 1a [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of 1a. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [(11)C]1a, while identification of [(11)C]2a and [(11)C]3a both accounts for central redox activation of 1a and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors. PMID:25695305

  5. 40 CFR 721.4095 - Quaternary ammonium alkyltherpropyl trialkylamine halides.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Quaternary ammonium alkyltherpropyl... Specific Chemical Substances § 721.4095 Quaternary ammonium alkyltherpropyl trialkylamine halides. (a... generically as quaternary ammonium alkyltherpropyl trialkylamine halides (PMNs...

  6. 40 CFR 721.4095 - Quaternary ammonium alkyltherpropyl trialkylamine halides.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Quaternary ammonium alkyltherpropyl... Specific Chemical Substances § 721.4095 Quaternary ammonium alkyltherpropyl trialkylamine halides. (a... generically as quaternary ammonium alkyltherpropyl trialkylamine halides (PMNs...

  7. 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

    PubMed

    Semenov, Vyacheslav E; Zueva, Irina V; Mukhamedyarov, Marat A; Lushchekina, Sofya V; Kharlamova, Alexandra D; Petukhova, Elena O; Mikhailov, Anatoly S; Podyachev, Sergey N; Saifina, Lilya F; Petrov, Konstantin A; Minnekhanova, Oksana A; Zobov, Vladimir V; Nikolsky, Evgeny E; Masson, Patrick; Reznik, Vladimir S

    2015-11-01

    Novel 6-methyluracil derivatives with ω-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10,000-fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6-methyluracil derivatives are able to penetrate the blood-brain barrier (BBB), inhibiting brain-tissue AChE. The most potent AChE inhibitor, 3 d (1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of β-amyloid peptide plaques in the brain. PMID:26412714

  8. Ni nanoparticle catalyzed growth of MWCNTs on Cu NPs @ a-C:H substrate

    NASA Astrophysics Data System (ADS)

    Ghodselahi, T.; Solaymani, S.; Akbarzadeh Pasha, M.; Vesaghi, M. A.

    2012-11-01

    NiCu NPs @ a-C:H thin films with different Cu content were prepared by co-deposition by RF-sputtering and RF-plasma enhanced chemical vapor deposition (RF-PECVD) from acetylene gas and Cu and Ni targets. The prepared samples were used as catalysts for growing multi-wall carbon nanotubes (MWCNTs) from liquid petroleum gas (LPG) at 825 °C by thermal chemical vapor deposition (TCVD). By addition of Cu NPs @ a-C:H thin layer as substrate for Ni NPs catalyst, the density of the grown CNTs is greatly enhanced in comparison to bare Si substrate. Furthermore the average diameter of the grown CNTs decreases by decreasing of Cu content of Cu NPs @ a-C:H thin layer. However Cu NPs @ a-C:H by itself has no catalytic property in MWCNTs growth. Morphology and electrical and optical properties of Cu NPs @ a-C:H thin layer is affected by Cu content and each of them is effective parameter on growth of MWCNTs based on Ni NPs catalyst. Moreover, adding of a low amount of Ni NPs doesn't vary optical, electrical and morphology properties of Cu NPs @ a-C:H thin layer but it has a profound effect on its catalytic activity. Finally the density and diameter of MWCNTs can be optimized by selection of the Cu NPs @ a-C:H thin layer as substrate of Ni NPs.

  9. A cationic surfactant-decorated liquid crystal sensing platform for simple and sensitive detection of acetylcholinesterase and its inhibitor.

    PubMed

    Wang, Yi; Hu, Qiongzheng; Guo, Yongxian; Yu, Li

    2015-10-15

    In this paper, construction of the liquid crystal (LC)-based sensing platform for simple and sensitive detection of acetylcholinesterase (AChE) and its inhibitor using a cationic surfactant-decorated LC interface was demonstrated. A change of the optical images of LCs from bright to dark appearance was observed when the cationic surfactant, myristoylcholine chloride (Myr), was transferred onto the aqueous/LC interface, due to the formation of a stable surfactant monolayer at the interface. A dark-to-bright change of the optical appearance was then observed when AChE was transferred onto the Myr-decorated LC interface. The sensitivity of this new type of LC-based sensor is 3 orders of magnitude higher in the serum albumin solution than that only in the buffer solution. Noteworthy is that the AChE LC sensor shows a very high sensitivity for the detection of the enzyme inhibitor, which is around 1 fM. The constructed low-cost LC-based sensor is quite simple and convenient, showing high promise for label-free detection of AChE and its inhibitors. PMID:25957073

  10. Ancient biomolecules in Quaternary palaeoecology

    NASA Astrophysics Data System (ADS)

    Hofreiter, Michael; Collins, Matthew; Stewart, John R.

    2012-02-01

    The last few years have seen an enormous proliferation of ancient biomolecules research, especially in the field of ancient DNA. Ancient DNA studies have been transformed by the advent of next generation sequencing, with the first Pleistocene sample being analysed in 2005, and several complete and draft genomes that have been compiled from ancient DNA to date. At the same time, although less conspicuous, research on ancient proteins has also seen advances, with the time limit for research on ancient biomolecules now extending to over 1 million years. Here we review which effects these developments have on research in Quaternary science. We identify several lines of research that have the potential to profit substantially from these recent developments in ancient biomolecules research. First, the identification of taxa can be made using ancient biomolecules, and in the case of ancient DNA, specimens can even be assigned to specific populations within a species. Second, increasingly large DNA data sets from Pleistocene animals allow the elucidation of ever more precise pictures of the population dynamic processes whereby organisms respond to climate and environmental change. With the accompanying better understanding of process in the Quaternary, past ecologies can also more realistically be interpreted from proxy data sets. The dominant message from this research so far is that the Quaternary saw a great deal more dynamism in populations than had been forecast by conventional palaeoecology. This suggests that reconstructions of past environmental conditions need to be done with caution. Third, ancient DNA can also now be obtained directly from sediments to elucidate the presence of both plant and animal species in an area even in the absence of identifiable fossils, be it macro- or micro-fossils. Finally, the analysis of proteins enables the identification of bone remains to genus and sometimes species level far beyond the survival time of DNA, at least in temperate

  11. Stereoselective Synthesis of Quaternary Proline Analogues

    PubMed Central

    Calaza, M. Isabel

    2009-01-01

    This review describes available methods for the diastereoselective and asymmetric synthesis of quaternary prolines. The focus is on the preparation of α-functionalized prolines with the pyrrolidine moiety not embedded in a polycyclic frame. The diverse synthetic approaches are classified according to the bond which is formed to complete the quaternary skeleton. PMID:19655047

  12. Quaternary faults of west Texas

    SciTech Connect

    Collins, E.W.; Raney, J.A. . Bureau of Economic Geology)

    1993-04-01

    North- and northwest-striking intermontane basins and associated normal faults in West Texas and adjacent Chihuahua, Mexico, formed in response to Basin and Range tectonism that began about 24 Ma ago. Data on the precise ages of faulted and unfaulted Quaternary deposits are sparse. However, age estimates made on the basis of field stratigraphic relationships and the degree of calcic soil development have helped determine that many of the faults that bound the basin margins ruptured since the middle Pleistocene and that some faults probably ruptured during the Holocene. Average recurrence intervals between surface ruptures since the middle Pleistocene appear to be relatively long, about 10,000 to 100,000 yr. Maximum throw during single rupture events have been between 1 and 3 m. Historic seismicity in West Texas is low compared to seismicity in many parts of the Basin and Range province. The largest historic earthquake, the 1931 Valentine earthquake in Ryan Flat/Lobo Valley, had a magnitude of 6.4 and no reported surface rupture. The most active Quaternary faults occur within the 120-km-long Hueco Bolson, the 70-km-long Red Light Bolson, and the > 200-km-long Salt Basins/Wild Horse Flat/Lobo Valley/Ryan Flat.

  13. Remarkably increased resistin levels in anti-AChR antibody-positive myasthenia gravis.

    PubMed

    Zhang, Da-Qi; Wang, Rong; Li, Ting; Li, Xin; Qi, Yuan; Wang, Jing; Yang, Li

    2015-06-15

    Resistin is a pro-inflammatory cytokine involved in the pathogenesis of autoimmune diseases. To investigate serum resistin levels in patients with myasthenia gravis (MG) and determine if there are associations between resistin levels and disease severity, we measured serum resistin levels in 102 patients with anti-acetylcholine receptor antibody-positive MG (AChR-MG). We further analyzed associations between serum resistin levels and clinical variables in patients with MG. Our findings demonstrate that serum resistin levels are elevated in patients with AChR-generalized MG and AChR-MG with thymoma and are correlated with disease severity. Resistin has potential as a useful serum biomarker for inflammation in AChR-MG.

  14. Gypsogenin derivatives: an unexpected class of inhibitors of cholinesterases.

    PubMed

    Heller, Lucie; Schwarz, Stefan; Weber, Björn A; Csuk, René

    2014-10-01

    Gypsogenin (1) was obtained by acidic hydrolysis from its saponin. While the parent compound 1 acted as a selective inhibitor for butyrylcholinesterase (from equus) possessing a moderate mixed-type inhibition of the enzyme, Ki values as low as 2.67 ± 0.59 μM were determined for (3β,4α) 3-O-acetyl-olean-12-ene-23,28-dinitrile (11) and acetylcholinesterase (AChE, from electric eel). Thus, 11 possesses one-fifth of the inhibitory activity of the "gold standard" galantamine hydrobromide; this compound is one of the first pentacyclic triterpenoids described as a potent AChE-selective inhibitor. PMID:25042600

  15. Lymphocyte-derived ACh regulates local innate but not adaptive immunity

    PubMed Central

    Reardon, Colin; Duncan, Gordon S.; Brüstle, Anne; Brenner, Dirk; Tusche, Michael W.; Olofsson, Peder S.; Rosas-Ballina, Mauricio; Tracey, Kevin J.; Mak, Tak W.

    2013-01-01

    Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4+ T-cell population that is stimulated by norepinephrine to release ACh, ChAT+ B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT+ B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT+ B cells controlling the local recruitment of neutrophils. PMID:23297238

  16. From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR

    PubMed Central

    Lin, Bo; Xu, Manyu; Zhu, Xiaopeng; Wu, Yong; Liu, Xi; Zhangsun, Dongting; Hu, Yuanyan; Xiang, Shi-Hua; Kasheverov, Igor E.; Tsetlin, Victor I.; Wang, Xinquan; Luo, Sulan

    2016-01-01

    Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of AСhBP in complex with α-conotoxins provide important insights into the interactions of α-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why α-conotoxin GIC is strongly selective for α3β2 nAChR, this question has not yet been solved. Here we present the structure of α-conotoxin GIC in complex with Aplysia californica AChBP (Ac-AChBP) at a resolution of 2.1 Å. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human α3β2 vs α3β4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and α3β2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and α3β2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes. PMID:26925840

  17. Kinetics and Molecular Docking Study of an Anti-diabetic Drug Glimepiride as Acetylcholinesterase Inhibitor: Implication for Alzheimer's Disease-Diabetes Dual Therapy.

    PubMed

    Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Naaz, Deeba; Shakil, Shazi; Ahmad, Adnan; Haneef, Mohd; Abuzenadah, Adel M

    2016-06-01

    At the present time, treatment of two most common degenerative disorders of elderly population i.e., Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) is a major concern worldwide. As there are several evidences that proved strong linkages between these two disorders, the idea of using dual therapeutic agent for both the diseases might be considered as a good initiative. Earlier reports have revealed that oral anti-diabetic drugs such as peroxisome proliferator activated receptor γ (PPARγ) agonists (thiazolidinediones) when used in T2DM patients suffering from AD showed improved memory and cognition. However, the underlying mechanism still needs to be deciphered. Therefore, the present study was carried out to find whether glimepiride, an oral antidiabetic drug which is a PPARγ agonist could inhibit the activity of acetylcholine esterase (AChE) enzyme. Actually, AChE inhibitors seize the breakdown of acetylcholine which forms the main therapeutic strategy for AD. Here, glimepiride showed dose dependent inhibitory activity against AChE enzyme with IC50 value of 235 μM. Kinetic analysis showed competitive inhibition, which was verified by in silico docking studies. Glimepiride was found to interact with AChE enzyme at the same locus as that of substrate acetylcholine iodide (AChI). Interestingly, amino acid residues, Q71, Y72, V73, D74, W86, N87, Y124, S125, W286, F295, F297, Y337, F338 and Y341 of AChE were found to be common for 'glimepiride-AChE interaction' as well as 'AChI-AChE interaction'. Thus the present computational and kinetics study concludes that glimepiride and other thiazolidinediones derivatives could form the basis of future dual therapy against diabetes associated neurological disorders. PMID:26886763

  18. Gold nanoclusters-Cu(2+) ensemble-based fluorescence turn-on and real-time assay for acetylcholinesterase activity and inhibitor screening.

    PubMed

    Sun, Jian; Yang, Xiurong

    2015-12-15

    Based on the specific binding of Cu(2+) ions to the 11-mercaptoundecanoic acid (11-MUA)-protected AuNCs with intense orange-red emission, we have proposed and constructed a novel fluorescent nanomaterials-metal ions ensemble at a nonfluorescence off-state. Subsequently, an AuNCs@11-MUA-Cu(2+) ensemble-based fluorescent chemosensor, which is amenable to convenient, sensitive, selective, turn-on and real-time assay of acetylcholinesterase (AChE), could be developed by using acetylthiocholine (ATCh) as the substrate. Herein, the sensing ensemble solution exhibits a marvelous fluorescent enhancement in the presence of AChE and ATCh, where AChE hydrolyzes its active substrate ATCh into thiocholine (TCh), and then TCh captures Cu(2+) from the ensemble, accompanied by the conversion from fluorescence off-state to on-state of the AuNCs. The AChE activity could be detected less than 0.05 mU/mL within a good linear range from 0.05 to 2.5 mU/mL. Our proposed fluorescence assay can be utilized to evaluate the AChE activity quantitatively in real biological sample, and furthermore to screen the inhibitor of AChE. As far as we know, the present study has reported the first analytical proposal for sensing AChE activity in real time by using a fluorescent nanomaterials-Cu(2+) ensemble or focusing on the Cu(2+)-triggered fluorescence quenching/recovery. This strategy paves a new avenue for exploring the biosensing applications of fluorescent AuNCs, and presents the prospect of AuNCs@11-MUA-Cu(2+) ensemble as versatile enzyme activity assay platforms by means of other appropriate substrates/analytes. PMID:26141104

  19. Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones.

    PubMed

    Akıncıoğlu, Akın; Akıncıoğlu, Hülya; Gülçin, İlhami; Durdagi, Serdar; Supuran, Claudiu T; Göksu, Süleyman

    2015-07-01

    In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9±8.9-687.5±84.3 pM for hCA I, and 48.80±8.2-672.2±71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52±0.61-38.28±6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity. PMID:25921269

  20. Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli.

    PubMed

    Tillman, Tommy S; Alvarez, Frances J D; Reinert, Nathan J; Liu, Chuang; Wang, Dawei; Xu, Yan; Xiao, Kunhong; Zhang, Peijun; Tang, Pei

    2016-08-26

    Human Cys-loop receptors are important therapeutic targets. High-resolution structures are essential for rational drug design, but only a few are available due to difficulties in obtaining sufficient quantities of protein suitable for structural studies. Although expression of proteins in E. coli offers advantages of high yield, low cost, and fast turnover, this approach has not been thoroughly explored for full-length human Cys-loop receptors because of the conventional wisdom that E. coli lacks the specific chaperones and post-translational modifications potentially required for expression of human Cys-loop receptors. Here we report the successful production of full-length wild type human α7nAChR from E. coli Chemically induced chaperones promote high expression levels of well-folded proteins. The choice of detergents, lipids, and ligands during purification determines the final protein quality. The purified α7nAChR not only forms pentamers as imaged by negative-stain electron microscopy, but also retains pharmacological characteristics of native α7nAChR, including binding to bungarotoxin and positive allosteric modulators specific to α7nAChR. Moreover, the purified α7nAChR injected into Xenopus oocytes can be activated by acetylcholine, choline, and nicotine, inhibited by the channel blockers QX-222 and phencyclidine, and potentiated by the α7nAChR specific modulators PNU-120596 and TQS. The successful generation of functional human α7nAChR from E. coli opens a new avenue for producing mammalian Cys-loop receptors to facilitate structure-based rational drug design. PMID:27385587

  1. Identification and Expression of Acetylcholinesterase in Octopus vulgaris Arm Development and Regeneration: a Conserved Role for ACHE?

    PubMed

    Fossati, Sara Maria; Candiani, Simona; Nödl, Marie-Therese; Maragliano, Luca; Pennuto, Maria; Domingues, Pedro; Benfenati, Fabio; Pestarino, Mario; Zullo, Letizia

    2015-08-01

    Acetylcholinesterase (ACHE) is a glycoprotein with a key role in terminating synaptic transmission in cholinergic neurons of both vertebrates and invertebrates. ACHE is also involved in the regulation of cell growth and morphogenesis during embryogenesis and regeneration acting through its non-cholinergic sites. The mollusk Octopus vulgaris provides a powerful model for investigating the mechanisms underlying tissue morphogenesis due to its high regenerative power. Here, we performed a comparative investigation of arm morphogenesis during adult arm regeneration and embryonic arm development which may provide insights on the conserved ACHE pathways. In this study, we cloned and characterized O. vulgaris ACHE, finding a single highly conserved ACHE hydrophobic variant, characterized by prototypical catalytic sites and a putative consensus region for a glycosylphosphatidylinositol (GPI)-anchor attachment at the COOH-terminus. We then show that its expression level is correlated to the stage of morphogenesis in both adult and embryonic arm. In particular, ACHE is localized in typical neuronal sites when adult-like arm morphology is established and in differentiating cell locations during the early stages of arm morphogenesis. This possibility is also supported by the presence in the ACHE sequence and model structure of both cholinergic and non-cholinergic sites. This study provides insights into ACHE conserved roles during processes of arm morphogenesis. In addition, our modeling study offers a solid basis for predicting the interaction of the ACHE domains with pharmacological blockers for in vivo investigations. We therefore suggest ACHE as a target for the regulation of tissue morphogenesis.

  2. Identification and Expression of Acetylcholinesterase in Octopus vulgaris Arm Development and Regeneration: a Conserved Role for ACHE?

    PubMed

    Fossati, Sara Maria; Candiani, Simona; Nödl, Marie-Therese; Maragliano, Luca; Pennuto, Maria; Domingues, Pedro; Benfenati, Fabio; Pestarino, Mario; Zullo, Letizia

    2015-08-01

    Acetylcholinesterase (ACHE) is a glycoprotein with a key role in terminating synaptic transmission in cholinergic neurons of both vertebrates and invertebrates. ACHE is also involved in the regulation of cell growth and morphogenesis during embryogenesis and regeneration acting through its non-cholinergic sites. The mollusk Octopus vulgaris provides a powerful model for investigating the mechanisms underlying tissue morphogenesis due to its high regenerative power. Here, we performed a comparative investigation of arm morphogenesis during adult arm regeneration and embryonic arm development which may provide insights on the conserved ACHE pathways. In this study, we cloned and characterized O. vulgaris ACHE, finding a single highly conserved ACHE hydrophobic variant, characterized by prototypical catalytic sites and a putative consensus region for a glycosylphosphatidylinositol (GPI)-anchor attachment at the COOH-terminus. We then show that its expression level is correlated to the stage of morphogenesis in both adult and embryonic arm. In particular, ACHE is localized in typical neuronal sites when adult-like arm morphology is established and in differentiating cell locations during the early stages of arm morphogenesis. This possibility is also supported by the presence in the ACHE sequence and model structure of both cholinergic and non-cholinergic sites. This study provides insights into ACHE conserved roles during processes of arm morphogenesis. In addition, our modeling study offers a solid basis for predicting the interaction of the ACHE domains with pharmacological blockers for in vivo investigations. We therefore suggest ACHE as a target for the regulation of tissue morphogenesis. PMID:25112677

  3. 3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

    PubMed Central

    Verma, Astha; Wong, Dawn M.; Islam, Rafique; Tong, Fan; Ghavami, Maryam; Mutunga, James M.; Slebodnick, Carla; Li, Jianyong; Viayna, Elisabet; Lam, Polo C.-H.; Totrov, Maxim M.; Bloomquist, Jeffrey R.; Carlier, Paul R.

    2015-01-01

    To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification. PMID:25684426

  4. Identification of Potential Herbal Inhibitor of Acetylcholinesterase Associated Alzheimer's Disorders Using Molecular Docking and Molecular Dynamics Simulation

    PubMed Central

    Seniya, Chandrabhan; Khan, Ghulam Jilani; Uchadia, Kuldeep

    2014-01-01

    Cholinesterase inhibitors (ChE-Is) are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA). Additionally, acetylcholinesterase (AChE) is the target for many Alzheimer's dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000 ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6) to AChE. Further, molecular dynamics simulations for 1000 ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential. PMID:25054066

  5. Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore

    SciTech Connect

    Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radi, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer

    2008-07-28

    Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 {angstrom} in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids.

  6. Hologram QSAR models of 4-[(diethylamino)methyl]-phenol inhibitors of acetyl/butyrylcholinesterase enzymes as potential anti-Alzheimer agents.

    PubMed

    de Souza, Simone Decembrino; de Souza, Alessandra Mendonça Teles; de Sousa, Ana Carolina Corrêa; Sodero, Ana Carolina Rennó; Cabral, Lúcio Mendes; Albuquerque, Magaly Girão; Castro, Helena Carla; Rodrigues, Carlos Rangel

    2012-01-01

    Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer's disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0. 904) and non-cross-validated (AChE, r2 = 0.965; BChE, r2= 0.952) correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.

  7. Expression of APP, BACE1, AChE and ChAT in an AD model in rats and the effect of donepezil hydrochloride treatment.

    PubMed

    Li, Qiang; Chen, Min; Liu, Hongmin; Yang, Liqun; Yang, Guiying

    2012-12-01

    The aim of this study was to investigate the pathological changes in a rat model of Alzheimer's disease (AD) and the effect of donepezil hydrochloride (HCl) treatment. The rat model of AD was established by the bilateral injection of amyloid β₁₋₄₀ (Aβ₁₋₄₀) into the hippocampus. Changes in spatial learning and memory functions were examined using the Morris water maze test and changes in catalase (CAT) and glutathione peroxidase (GSH-Px) activities were determined using chemical colorimetry. Moreover, the changes in acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) expression were analyzed using immunohistochemical staining. The mRNA expression levels of the amyloid precursor protein (APP) and β-secreted enzyme 1 (BACE1) were evaluated using RT-PCR. The effects of donepezil HCl on the aforementioned indices were also observed. The rat memories of the platform quadrants in the blank, sham and donepezil HCl groups were improved compared with those of the rats in the model group. The ratio of swim distance in the fourth platform quadrant (l₄) to the total swim distance (l total) for the model group rats (l₄/l total) was significantly decreased compared with that for the blank and sham group rats. Following donepezil HCl treatment, the ratio of l₄/l total significantly increased. AD modeling caused a significant decrease in the CAT and GSH-Px activities in the brain tissues of the rats. The CAT and GSH-Px activities in the AD model rats significantly increased following donepezil HCl treatment. Moreover, donepezil HCl treatment significantly decreased the AChE, APP and BACE1 mRNA expression levels and increased the ChAT expression levels. Therefore, donepezil HCl was able to significantly decrease learning and memory damage in a rat model of AD.

  8. Book Review: Reconstructing Quaternary Environments

    NASA Astrophysics Data System (ADS)

    Bridgland, David R.; Evans, David J. A.; Roberts, David H.

    2016-02-01

    A third edition of this, the foremost Quaternary textbook, is most welcome, coming seventeen years after the 1997 second edition (which was 13 years after the first). The general impression is one of advancement, not least because of the extensive updating of literature cited and examples used, with the status maintained of an impressive compendium of a specialism with a very wide subject base. Some changes are cosmetic, with chapter and section headers having a more modern style and a profusion of new colour photographs and diagrams. Some of the latter are redrawn from black and white figures in the previous edition, although not all have been improved, as some are smaller and have been simplified. For example, black and white Fig. 3.10 of the Second Edition compares very favourably with the much smaller colour 3.17 in this latest volume (erratic sources). On the plus side, the number change, for a figure that appears in the same place within the chapter, shows that the latest edition is considerably better illustrated than its predecessor, perhaps accounting for a significant proportion of the increased page total (up from 446 to 538).

  9. The Irish quaternary fauna project

    NASA Astrophysics Data System (ADS)

    Woodman, Peter; Mccarthy, Margaret; Monaghan, Nigel

    Much of Ireland's Pleistocene and Early Holocene mammalian faunas are derived from a series of late 19th/early 20th century cave excavations. In many instances it would appear that the deposits containing these faunal remains were disturbed. This project assessed the chronological range of the mammalian species present in the caves using 14C dating, in particular accelerator mass spectrometry (AMS). The research has shown that (1) a wide range of mammals colonised Ireland in the period between at least 45 ka and 20 ka, with some elements surviving until close to the Last Glacial Maximum; (2) a more restricted range of species re-colonised Ireland during the Lateglacial period, with evidence for a slightly more temperature fauna being replaced by an Arctic fauna at about 11 ka; (3) certain elements of Ireland's Holocene fauna may have survived through from the Lateglacial into the Holocene; (4) there is a lack of evidence for red deer, Cervus elaphus, being present in the Early Holocene in Ireland; and (5) horse is only documented in the Irish Holocene from 4 ka. The paper also discusses the implications of the Quaternary Fauna Project for the Late Pleistocene of Ireland, the mechanism and period of colonisation of Ireland as well as the introduction of domesticates in the Mid Holocene.

  10. Erosion of a-C:H films under interaction with nitrous oxide afterglow discharge

    NASA Astrophysics Data System (ADS)

    Zalavutdinov, R. Kh.; Gorodetsky, A. E.; Bukhovets, V. L.; Zakharov, A. P.; Mazul, I. V.

    2009-06-01

    Hydrocarbon film removal using chemically active oxygen formed in a direct current glow discharge with a hollow cathode in nitrous oxide was investigated. In the afterglow region sufficiently fast removal of a-C:H films about 500 nm thick during about 8 h was achieved at N 2O pressure of 12 Pa and 370 K. The erosion rate in the afterglow region was directly proportional to the initial pressure and increased two orders of magnitude at temperature rising from 300 to 500 K. The products of a-C:H film plasmolysis were CO, CO 2, H 2O, and H 2. After removal of a-C:H films previously deposited on stainless steel, molybdenum or tungsten 3-30 nm thick oxide films were formed on the substrates. Reactions of oxygen ion neutralization and atomic oxygen recombination suppressed further oxidation of the materials.

  11. Double layer structure-based virtual screening reveals 3'-Hydroxy-A-Naphthoflavone as novel inhibitor candidate of human acetylcholinesterase

    NASA Astrophysics Data System (ADS)

    Ichsan, Mochammad; Pangastuti, Ardini; Habibi, Mohammad Wildan; Juliana, Kartika

    2016-03-01

    One of the most effective target for Alzheimer's disease's (AD) treatment is the inhibition of human acetylcholinesterase (hAChE) eventhough it has many side effects. So that, this study was aimed to discover a new candidate of hAChE's inhibitor that has more negative binding affinity than existing drugs. hAChE's 3D model used in this study has a good quality according to its number of residues in most favoured regions (92%), three bad contacts, >50 ERRAT's score (85,870) and successfully passed the VERIFY 3D threshold (>80%). Based on the first layer of SBVS againts more than 12.180.630 ligands, we discovered 11.806 hits and then we found 359 hits from the second layer of SBVS. Based on our previous steps, we found that 3'-Hydroxy-a-Naphthoflavone was the only one candidate, that directly interacted with Trp286 via hydrogen bond and hydrophobic interactions and also has the most negative binding affinity (-10,6 kcal/mol) and also has more negative than existing hAChE's inhibitors, such as tacrine, donepezil, etc. 3'-Hydroxy-a-Naphthoflavone is the best candidate of hAChE's inhibitor based on its binding affinity (-10,6 kcal/mol) that is more negative than existing hAChE's inhibitors, such as tacrine, donepezil, etc.

  12. Intracellular activity of tedizolid phosphate and ACH-702 versus Mycobacterium tuberculosis infected macrophages

    PubMed Central

    2014-01-01

    Background Due to the emergency of multidrug-resistant strains of Mycobacterium tuberculosis, is necessary the evaluation of new compounds. Findings Tedizolid, a novel oxazolidinone, and ACH-702, a new isothiazoloquinolone, were tested against M. tuberculosis infected THP-1 macrophages. These two compounds significantly decreased the number of intracellular mycobacteria at 0.25X, 1X, 4X and 16X the MIC value. The drugs were tested either in nanoparticules or in free solution. Conclusion Tedizolid and ACH-702 have a good intracellular killing activity comparable to that of rifampin or moxifloxacin. PMID:24708819

  13. Ice Age refugia and Quaternary extinctions: An issue of Quaternary evolutionary palaeoecology

    NASA Astrophysics Data System (ADS)

    Stewart, John R.; Cooper, Alan

    2008-12-01

    Quaternary palaeoecology, as a discipline, involves the analysis of a large range of fossil organisms from the last ca. 2 million years. This paper considers the role that these Quaternary records can take in better understanding the evolution of those organisms. We also discuss the surprisingly low uptake of evolutionary biology in Quaternary palaeoecological studies. This leads us to encourage an advance on both these fronts with a greater degree of collaboration with phylogeographic and ancient DNA researchers. These discussions accompany a summary of a special issue of Quaternary Science Reviews representing the proceedings of the XVII INQUA held in Cairns Australia in 2007. This special issue includes papers on a wide variety of Quaternary evolutionary palaeoecological and population dynamic subjects including extinct Pacific Island palm trees, Beringian beetles, Scandinavian trees, and the effects on human and animal populations of an extraterrestrial impact event in the Late Glacial of North America.

  14. Molecular Docking Guided Comparative GFA, G/PLS, SVM and ANN Models of Structurally Diverse Dual Binding Site Acetylcholinesterase Inhibitors.

    PubMed

    Gupta, Shikhar; Fallarero, Adyary; Vainio, Mikko J; Saravanan, P; Santeri Puranen, J; Järvinen, Päivi; Johnson, Mark S; Vuorela, Pia M; Mohan, C Gopi

    2011-08-01

    Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were identified on the basis of molecular docking approach, and its comparative quantitative structure-activity relationship (QSAR) models were developed. These structurally diverse inhibitors were obtained by our previously reported high-throughput in vitro screening technique using 384-well plate's assay based on colorimetric method of Ellman. QSAR models were developed using (i) genetic function algorithm, (ii) genetic partial least squares, (iii) support vector machine and (iv) artificial neural network techniques. The QSAR model robustness and significance was critically assessed using different cross-validation techniques on test data set. The generated QSAR models using thermodynamic, electrotopological and electronic descriptors showed that nonlinear methods are more robust than linear methods, and provide insight into the structural features of compounds that are important for AChE inhibition.

  15. nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms.

    PubMed

    Sarter, Martin; Parikh, Vinay; Howe, William M

    2009-10-01

    The identification and characterization of drugs for the treatment of cognitive disorders has been hampered by the absence of comprehensive hypotheses. Such hypotheses consist of (a) a precisely defined cognitive operation that fundamentally underlies a range of cognitive abilities and capacities and, if impaired, contributes to the manifestation of diverse cognitive symptoms; (b) defined neuronal mechanisms proposed to mediate the cognitive operation of interest; (c) evidence indicating that the putative cognition enhancer facilitates these neuronal mechanisms; (d) and evidence indicating that the cognition enhancer facilitates cognitive performance by modulating these underlying neuronal mechanisms. The evidence on the neuronal and attentional effects of nAChR agonists, specifically agonists selective for alpha4beta2* nAChRs, has begun to support such a hypothesis. nAChR agonists facilitate the detection of signals by augmenting the transient increases in prefrontal cholinergic activity that are necessary for a signal to gain control over behavior in attentional contexts. The prefrontal microcircuitry mediating these effects include alpha4beta2* nAChRs situated on the terminals of thalamic inputs and the glutamatergic stimulation of cholinergic terminals via ionotropic glutamate receptors. Collectively, this evidence forms the basis for hypothesis-guided development and characterization of cognition enhancers.

  16. Genome Sequence of the Mycorrhiza Helper Bacterium Streptomyces sp. Strain AcH 505.

    PubMed

    Tarkka, M T; Feldhahn, L; Buscot, F; Wubet, T

    2015-04-02

    A draft genome sequence of Streptomyces sp. strain AcH 505 is presented here. The genome encodes 22 secondary metabolite gene clusters and a large arsenal of secreted proteins, and their comparative and functional analyses will help to advance our knowledge of symbiotic interactions and fungal and plant biomass degradation.

  17. Genome Sequence of the Mycorrhiza Helper Bacterium Streptomyces sp. Strain AcH 505

    PubMed Central

    Feldhahn, L.; Buscot, F.; Wubet, T.

    2015-01-01

    A draft genome sequence of Streptomyces sp. strain AcH 505 is presented here. The genome encodes 22 secondary metabolite gene clusters and a large arsenal of secreted proteins, and their comparative and functional analyses will help to advance our knowledge of symbiotic interactions and fungal and plant biomass degradation. PMID:25838498

  18. Carbonaceous dust in interstellar shock waves: hydrogenated amorphous carbon (a-C:H) vs. graphite

    NASA Astrophysics Data System (ADS)

    Serra Díaz-Cano, L.; Jones, A. P.

    2008-12-01

    Context: Observations of regions of the interstellar medium affected by shock waves indicate gas phase abundances of carbon that are close to solar. In quiescent regions less than half of the carbon is in the gas phase. Aims: We propose that hydrogenated amorphous carbon (a-C:H), in its many guises, is the most probable form of carbonaceous grain material in the interstellar medium and study its erosion in shock waves. Methods: We have used the physical properties typical of a-C:H materials, rather than graphite/amorphous carbon, to study a-C:H erosion during ion irradiation and fragmentation in grain-grain collisions. Using SRIM we study material-, surface- and size-dependent sputtering effects and introduce these effects into a shock model. Results: We find significantly greater destruction for a-C:H, than for graphite, a result that brings the models into better agreement with existing observations of shocked regions of the ISM. Carbon grain erosion in shock waves therefore appears to be much more efficient than predicted by existing models. Conclusions: Interstellar hydrogenated amorphous carbon dust is, apparently, rather easily destroyed in shocks and must therefore be more rapidly re-cycled and re-formed during its journey through the interstellar medium than previously-thought.

  19. Draft Genome Sequence of Aldehyde-Degrading Strain Halomonas axialensis ACH-L-8

    PubMed Central

    Ye, Jun; Ren, Chong; Shan, Xiexie

    2016-01-01

    Halomonas axialensis ACH-L-8, a deep-sea strain isolated from the South China Sea, has the ability to degrade aldehydes. Here, we present an annotated draft genome sequence of this species, which could provide fundamental molecular information on the aldehydes-degrading mechanism. PMID:27081145

  20. Molecular recognition of thiaclopride by Aplysia californica AChBP: new insights from a computational investigation.

    PubMed

    Alamiddine, Zakaria; Selvam, Balaji; Cerón-Carrasco, José P; Mathé-Allainmat, Monique; Lebreton, Jacques; Thany, Steeve H; Laurent, Adèle D; Graton, Jérôme; Le Questel, Jean-Yves

    2015-12-01

    The binding of thiaclopride (THI), a neonicotinoid insecticide, with Aplysia californica acetylcholine binding protein (Ac-AChBP), the surrogate of the extracellular domain of insects nicotinic acetylcholine receptors, has been studied with a QM/QM' hybrid methodology using the ONIOM approach (M06-2X/6-311G(d):PM6). The contributions of Ac-AChBP key residues for THI binding are accurately quantified from a structural and energetic point of view. The importance of water mediated hydrogen-bond (H-bond) interactions involving two water molecules and Tyr55 and Ser189 residues in the vicinity of the THI nitrile group, is specially highlighted. A larger stabilization energy is obtained with the THI-Ac-AChBP complex compared to imidacloprid (IMI), the forerunner of neonicotinoid insecticides. Pairwise interaction energy calculations rationalize this result with, in particular, a significantly more important contribution of the pivotal aromatic residues Trp147 and Tyr188 with THI through CH···π/CH···O and π-π stacking interactions, respectively. These trends are confirmed through a complementary non-covalent interaction (NCI) analysis of selected THI-Ac-AChBP amino acid pairs. PMID:26589615

  1. 31 CFR 363.41 - What happens if an ACH payment is returned to Public Debt?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... returned to Public Debt? 363.41 Section 363.41 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE PUBLIC DEBT... TreasuryDirect § 363.41 What happens if an ACH payment is returned to Public Debt? We will notify...

  2. 31 CFR 363.41 - What happens if an ACH payment is returned to Public Debt?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... returned to Public Debt? 363.41 Section 363.41 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE PUBLIC DEBT... TreasuryDirect § 363.41 What happens if an ACH payment is returned to Public Debt? We will notify...

  3. 31 CFR 363.41 - What happens if an ACH payment is returned to Public Debt?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... returned to Public Debt? 363.41 Section 363.41 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE PUBLIC DEBT... TreasuryDirect § 363.41 What happens if an ACH payment is returned to Public Debt? We will notify...

  4. 31 CFR 363.41 - What happens if an ACH payment is returned to Public Debt?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... returned to Public Debt? 363.41 Section 363.41 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE PUBLIC DEBT... TreasuryDirect § 363.41 What happens if an ACH payment is returned to Public Debt? We will notify...

  5. Draft Genome Sequence of Aldehyde-Degrading Strain Halomonas axialensis ACH-L-8.

    PubMed

    Ye, Jun; Ren, Chong; Shan, Xiexie; Zeng, Runying

    2016-01-01

    Halomonas axialensisACH-L-8, a deep-sea strain isolated from the South China Sea, has the ability to degrade aldehydes. Here, we present an annotated draft genome sequence of this species, which could provide fundamental molecular information on the aldehydes-degrading mechanism.

  6. Non-neuronal release of ACh plays a key role in secretory response to luminal propionate in rat colon.

    PubMed

    Yajima, Takaji; Inoue, Ryo; Matsumoto, Megumi; Yajima, Masako

    2011-02-15

    Colonic chloride secretion is induced by chemical stimuli via the enteric nervous reflex. We have previously demonstrated that propionate stimulates chloride secretion via sensory and cholinergic systems of the mucosa in rat distal colon. In this study, we demonstrate non-neuronal release of ACh in the secretory response to propionate using an Ussing chamber. Mucosa preparations from the colon, not including the myenteric and submucosal plexuses, were used. Luminal addition of propionate and serosal addition of ACh caused biphasic changes in short-circuit current (Isc). TTX (1 μm) had no effects, while atropine (10 μm) significantly inhibited the Isc response to propionate and abolished that to ACh. In response to luminal propionate stimulation, ACh was released into the serosal fluid. A linear relationship was observed between the maximal increase in Isc and the amounts of ACh released 5 min after propionate stimulation. This ACh release induced by propionate was not affected by atropine and bumetanide, although both drugs significantly reduced the Isc responses to propionate. Luminal addition of 3-chloropropionate, an inactive analogue of propionate, abolished both ACh release and Isc response produced by propionate. RT-PCR analysis indicated that isolated crypt cells from the distal colon expressed an enzyme of ACh synthesis (ChAT) and transporters of organic cation (OCTs), but not neuronal CHT1 and VAChT. The isolated crypt cells contained comparable amounts of ACh to the residual muscle tissues including nerve plexuses. In conclusion, the non-neuronal release of ACh from colonocytes coupled with propionate stimulation plays a key role in chloride secretion, via the paracrine action of ACh on muscarinic receptors of colonocytes.

  7. Xanthenedione derivatives, new promising antioxidant and acetylcholinesterase inhibitor agents.

    PubMed

    Seca, Ana M L; Leal, Stephanie B; Pinto, Diana C G A; Barreto, Maria Carmo; Silva, Artur M S

    2014-01-01

    Natural and synthetic xanthone derivatives are well-known for their ability to act as antioxidants and/or enzyme inhibitors. This paper aims to present a successful synthetic methodology towards xanthenedione derivatives and the study of their aromatization to xanthones. Additionally their ability to reduce Fe(III), to scavenge DPPH radicals and to inhibit AChE was evaluated. The results demonstrated that xanthenedione derivative 5e, bearing a catechol unit, showed higher reduction capacity than BHT and similar to quercetin, strong DPPH scavenging activity (EC50 = 3.79 ± 0.06 µM) and it was also showed to be a potent AChEI (IC50 = 31.0 ± 0.09 µM) when compared to galantamine (IC50 = 211.8 ± 9.5 µM). PMID:24950437

  8. Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution

    PubMed Central

    CHEN, PO-YUAN; TSAI, CHING-TSAN; OU, CHE-YEN; HSU, WEI-TSE; JHUO, MIEN-DE; WU, CHIEH-HSI; SHIH, TZU-CHING; CHENG, TZU-HURNG; CHUNG, JING-GUNG

    2012-01-01

    Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907. AD is the most prevalent dementia- related disease, affecting over 20 million individuals worldwide. Currently, however, only a handful of drugs are available and they are at best only able to offer some relief of symptoms. Acetylcholinesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs and NMDA inhibitors are usually used to attempt to cure this disease. AChE inhibitors are the most effective therapy for AD at present. Researchers have found that histamine H3 receptor antagonists decrease re-uptake of acetylcholine and the nervous transmitter substance acetylcholine increases. In this study, we designed compounds by using docking, de novo evolution and adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to AChE inhibitors as well as histamine H3 receptor antagonists to forward drug research and investigate the potent compounds which can pass through the blood-brain barrier. The novel drugs may be useful for the treatment of AD, based on the results of this theoretical calculation study. We will subsequently examine them in future experiments. PMID:22267207

  9. Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution.

    PubMed

    Chen, Po-Yuan; Tsai, Ching-Tsan; Ou, Che-Yen; Hsu, Wei-Tse; Jhuo, Mien-De; Wu, Chieh-Hsi; Shih, Tzu-Ching; Cheng, Tzu-Hurng; Chung, Jing-Gung

    2012-04-01

    Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907. AD is the most prevalent dementia- related disease, affecting over 20 million individuals worldwide. Currently, however, only a handful of drugs are available and they are at best only able to offer some relief of symptoms. Acetylcholinesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs and NMDA inhibitors are usually used to attempt to cure this disease. AChE inhibitors are the most effective therapy for AD at present. Researchers have found that histamine H3 receptor antagonists decrease re-uptake of acetylcholine and the nervous transmitter substance acetylcholine increases. In this study, we designed compounds by using docking, de novo evolution and adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to AChE inhibitors as well as histamine H3 receptor antagonists to forward drug research and investigate the potent compounds which can pass through the blood-brain barrier. The novel drugs may be useful for the treatment of AD, based on the results of this theoretical calculation study. We will subsequently examine them in future experiments.

  10. Design, Synthesis and Structure-Activity Relationship (SAR) Studies of 2,4-Disubstituted Pyrimidine Derivatives: Dual Activity as Cholinesterase and Aβ-Aggregation Inhibitors

    PubMed Central

    Mohamed, Tarek; Zhao, Xiaobei; Habib, Lila K.; Yang, Jerry; Rao, Praveen P. N.

    2011-01-01

    A novel class of 2,4-disubstituted pyrimidines (7a–u, 8a–f, 9a–e) that possess substituents with varying steric and electronic properties at the C-2 and C-4 positions, were designed, synthesized and evaluated as dual cholinesterase and amyloid-β (Aβ)-aggregation inhibitors. In vitro screening identified N-(naphth-1-ylmethyl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (9a) as the most potent AChE inhibitor (IC50 = 5.5 μM). Among this class of compounds, 2-(4-methylpiperidin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine (9e) was identified as the most potent and selective BuChE inhibitor (IC50 = 2.2 μM, Selectivity Index = 11.7) and was about 5.7-fold more potent compared to the commercial, approved reference drug galanthamine (BuChE IC50 = 12.6 μM). In addition, the selective AChE inhibitor N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine (7d), exhibited good inhibition of hAChE-induced aggregation of Aβ1–40 fibrils (59% inhibition). Furthermore, molecular modeling studies indicate that a central pyrimidine ring serves as a suitable template to develop dual inhibitors of cholinesterase and AChE-induced Aβ aggregation thereby targeting multiple pathological routes in AD. PMID:21429752

  11. Wild Argentinian Amaryllidaceae, a new renewable source of the acetylcholinesterase inhibitor galanthamine and other alkaloids.

    PubMed

    Ortiz, Javier E; Berkov, Strahil; Pigni, Natalia B; Theoduloz, Cristina; Roitman, German; Tapia, Alejandro; Bastida, Jaume; Feresin, Gabriela E

    2012-11-13

    The Amaryllidaceae family is well known for its pharmacologically active alkaloids. An important approach to treat Alzheimer’s disease involves the inhibition of the enzyme acetylcholinesterase (AChE). Galanthamine, an Amaryllidaceae alkaloid, is an effective, selective, reversible, and competitive AchE inhibitor. This work was aimed at studying the alkaloid composition of four wild Argentinian Amarillydaceae species for the first time, as well as analyzing their inhibitory activity on acetylcholinesterase. Alkaloid content was characterized by means of GC-MS analysis. Chloroform basic extracts from Habranthus jamesonii, Phycella herbertiana, Rhodophiala mendocina and Zephyranthes filifolia collected in the Argentinian Andean region all contained galanthamine, and showed a strong AChE inhibitory activity (IC50 between 1.2 and 2 µg/mL). To our knowledge, no previous reports on alkaloid profiles and AChEIs activity of wild Argentinian Amarillydaceae species have been publisihed. The demand for renewable sources of industrial products like galanthamine and the need to protect plant biodiversity creates an opportunity for Argentinian farmers to produce such crops.

  12. Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation.

    PubMed

    Tripathi, Rati K P; Rai, Gopal K; Ayyannan, Senthil R

    2016-06-01

    A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032 μm), MAO-B (IC50 =0.059±0.002 μm), and AChE (IC50 =0.0087±0.0002 μm) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO-A and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics.

  13. Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation.

    PubMed

    Tripathi, Rati K P; Rai, Gopal K; Ayyannan, Senthil R

    2016-06-01

    A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032 μm), MAO-B (IC50 =0.059±0.002 μm), and AChE (IC50 =0.0087±0.0002 μm) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO-A and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics. PMID:27135466

  14. Acetylsalicylic acid and ascorbic acid combination improves cognition; via antioxidant effect or increased expression of NMDARs and nAChRs?

    PubMed

    Kara, Yusuf; Doguc, Duygu Kumbul; Kulac, Esin; Gultekin, Fatih

    2014-05-01

    Chronic inflammation occurs systematically in the central nervous system during ageing, it has been shown that neuroinflammation plays an important role in the pathogenesis of many neurodegenerative disorders. Aspirin, a nonselective COX inhibitor, as well as ascorbic acid, has been purported to protect cerebral tissue. We investigated the effects of subchronic aspirin and ascorbic acid usage on spatial learning, oxidative stress and expressions of NR2A, NR2B, nAChRα7, α4 and β2. Forty male rats (16-18 months) were divided into 4 groups, namely, control, aspirin-treated, ascorbic acid-treated, aspirin+ascorbic acid-treated groups. Following 10-weeks administration period, rats were trained and tested in the Morris water maze. 8-Hydroxy-2-deoxyguanosine and malondialdehyde were evaluated by ELISA and HPLC, respectively. Receptor expressions were assessed by western blotting of hippocampi. Spatial learning performance improved partially in the aspirin group, but significant improvement was seen in the aspirin+ascorbic acid group (p < 0.05). While 8-hydroxy-2-deoxyguanosine and malondialdehyde levels were significantly decreased, NR2B and nAChRα7 expressions were significantly increased in the aspirin+ascorbic acid group as compared to the control group (p < 0.05). Subchronic treatment with aspirin+ascorbic acid in aged rats was shown to enhance cognitive performance and increase the expressions of several receptors related to learning and memory process.

  15. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocenters

    PubMed Central

    Quasdorf, Kyle W.; Overman, Larry E.

    2015-01-01

    Preface Quaternary carbon stereocenters–carbon atoms to which four distinct carbon substituents are attached–are common features of molecules found in nature. However, prior to recent advances in chemical catalysis, there were few methods available for constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for synthesizing organic molecules containing such carbon atoms. This progress now makes it possible to selectively incorporate quaternary stereocenters in many high-value organic molecules for use in medicine, agriculture, and other areas. PMID:25503231

  16. 1H NMR Relaxation Investigation of Inhibitors Interacting with Torpedo californica Acetylcholinesterase

    NASA Astrophysics Data System (ADS)

    Delfini, Maurizio; Gianferri, Raffaella; Dubbini, Veronica; Manetti, Cesare; Gaggelli, Elena; Valensin, Gianni

    2000-05-01

    Two naphthyridines interacting with Torpedo californica acetylcholinesterase (AChE) were investigated. 1H NMR spectra were recorded and nonselective, selective, and double-selective spin-lattice relaxation rates were measured. The enhancement of selective relaxation rates could be titrated by different ligand concentrations at constant AChE (yielding 0.22 and 1.53 mM for the dissociation constants) and was providing evidence of a diverse mode of interaction. The double-selective relaxation rates were used to evaluate the motional correlation times of bound ligands at 34.9 and 36.5 ns at 300 K. Selective relaxation rates of bound inhibitors could be interpreted also in terms of dipole-dipole interactions with protons in the enzyme active site.

  17. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Ethoxylated alkyl quaternary ammonium... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  18. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Ethoxylated alkyl quaternary ammonium... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  19. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Ethoxylated alkyl quaternary ammonium... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  20. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Ethoxylated alkyl quaternary ammonium... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  1. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Ethoxylated alkyl quaternary ammonium... Specific Chemical Substances § 721.655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical... as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject to reporting...

  2. 40 CFR 721.10569 - Tricyclic quaternary amine salt (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Tricyclic quaternary amine salt... Specific Chemical Substances § 721.10569 Tricyclic quaternary amine salt (generic). (a) Chemical substance... tricyclic quaternary amine salt (PMN P-08-471) is subject to reporting under this section for...

  3. 40 CFR 721.10569 - Tricyclic quaternary amine salt (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Tricyclic quaternary amine salt... Specific Chemical Substances § 721.10569 Tricyclic quaternary amine salt (generic). (a) Chemical substance... tricyclic quaternary amine salt (PMN P-08-471) is subject to reporting under this section for...

  4. 40 CFR 721.4467 - Quaternary ammonium hydroxide.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Quaternary ammonium hydroxide. 721... Substances § 721.4467 Quaternary ammonium hydroxide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a quaternary ammonium...

  5. 40 CFR 721.4467 - Quaternary ammonium hydroxide.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Quaternary ammonium hydroxide. 721... Substances § 721.4467 Quaternary ammonium hydroxide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a quaternary ammonium...

  6. Synthesis, antioxidant and cathepsin D inhibition activity of quaternary ammonium chitosan derivatives.

    PubMed

    Li, Wenjuan; Duan, Yunfei; Huang, Jianying; Zheng, Qunxiong

    2016-01-20

    Two (2-hydroxypropyl) trimethyl ammonium and/or imidazole-based quaternary ammonium chitosan derivatives (NHT-chitosan and Im-OHT-chitosan) were synthesized by using nucleophilic substitution reaction. These two synthesized chitosan derivatives were characterized by Fourier transform infrared spectroscopy, NMR spectra, and UV-visible spectra. The applications as antioxidant agents and cathepsin D inhibitors were further investigated. Both of quaternary ammonium chitosan derivatives exhibited good antioxidant activity upon scavenging against hydroxyl radical and hydrogen peroxide as well as the lipid peroxidation inhibition in the linoleic acid emulsion system. They also exhibited good inhibition activity of cathepsin D protease. NHT-chitosan and Im-OHT-chitosan are potential the natural, healthy and safe preservatives in food industry.

  7. Flow-through enzyme immobilized amperometric detector for the rapid screening of acetylcholinesterase inhibitors by flow injection analysis.

    PubMed

    Vandeput, Marie; Parsajoo, Cobra; Vanheuverzwijn, Jérôme; Patris, Stéphanie; Yardim, Yavuz; le Jeune, Alexandre; Sarakbi, Ahmad; Mertens, Dominique; Kauffmann, Jean-Michel

    2015-01-01

    A commercially available thin-layer flow-through amperometric detector, with the sensing block customized in an original design, was applied to the screening of drug compounds known as acetylcholinesterase (AChE) inhibitors. AChE from electric eel was covalently immobilized onto a cysteamine modified gold disk adjacent to a silver disk working electrode. On-line studies were performed by flow injection analysis (FIA) in PBS buffer pH 7.4. Seven commercially available AChE inhibitors used in the medical field, namely neostigmine, eserine, tacrine, donepezil, rivastigmine, pyridostigmine and galantamine as well as two natural compounds, quercetin and berberine, were investigated. The same trend of inhibitory potency as described in the literature was observed. Of particular interest and in addition to the determination of the IC50 values, this flow-through system allowed the study of both, the stability of the enzyme-inhibitor complex and the kinetic of the enzyme activity recovery. PMID:25459923

  8. α5-nAChR modulates nicotine-induced cell migration and invasion in A549 lung cancer cells.

    PubMed

    Sun, Haiji; Ma, Xiaoli

    2015-09-01

    Cigarette smoking is the most important risk factor in the development of human lung cancer. Nicotine, the major component in tobacco, not only contributes to carcinogenesis but also promotes tumor metastasis. By binding to nicotinic acetylcholine receptors (nAChRs), nicotine induces the proliferation and migration of non-small cell lung cancer. Recently studies have indicated that α5-nAChR is highly associated with lung cancer risk and nicotine dependence. Nevertheless, it is unclear whether nicotine promotes the migration and invasion through activation of α5-nAChR in lung cancer. In the present study, A549 cell was exposed to 1μN nicotine for 8, 24 or 48h. Wound-healing assay and transwell assay were used to evaluate the capability of A549 cell migration and cell invasion, respectively. Silencing of α5-nAChR was done by siRNA. Western blotting and PCR were used to detect α5-nAChR expression. Nicotine can induce activation of α5-nAChR in association with increased migration and invasion of human lung cancer A549 cell. Treatment of cells with α5-nAChR specific siRNA blocks nicotine-stimulated activation of α5-nAChR and suppresses A549 cell migration and invasion. Reduction of α5-nAChR resulted in upregulation of E-cadherin, consistent with E-cadherin being inhibitive of cancer cell invasion. These findings suggest that nicotine-induced migration and invasion may occur in a mechanism through activation of α5-nAChR, which can contribute to metastasis or development of human lung cancer.

  9. Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.

    PubMed

    Zhang, Shuqun; Hou, Bo; Yang, Huaiyu; Zuo, Zhili

    2016-05-01

    Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.

  10. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates.

    PubMed

    Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína; Švarcová, Markéta; Vinšová, Jarmila

    2016-01-01

    Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization. PMID:26875979

  11. Deposition of a-C:H films on a nanotrench pattern by bipolar PBII&D

    NASA Astrophysics Data System (ADS)

    Hirata, Yuki; Nakahara, Yuya; Nagato, Keisuke; Choi, Junho

    2016-06-01

    In this study, hydrogenated amorphous carbon (a-C:H) films were deposited on a nanotrench pattern (300 nm pitch, aspect ratio: 2.0) by bipolar-type plasma based ion implantation and deposition technique (bipolar PBII&D), and the effects of bipolar pulse on the film properties were investigated. Moreover, the behaviour of ions and radicals surrounding the nanotrench was analyzed to clarify the coating mechanism and properties of the a-C:H films on the nanotrench. Further, thermal nanoimprint lithography was carried out using the nanotrench pattern coated with a-C:H films as the mold, and the mold release properties were evaluated. All nanotrench surfaces were successfully coated with the a-C:H films, but the film thickness on the top, sidewall, and bottom surfaces of the trench were not uniform. The surface roughness of the a-C:H films was found to decrease at a higher positive voltage; this happens due to the higher electron temperature around the nanotrench because of the surface migration of plasma particles arrived on the trench. The effects of the negative voltage on the behaviour of ions and radicals near the sidewall of the nanotrench are quite similar to those near the microtrench reported previously (Park et al 2014 J. Phys. D: Appl. Phys. 47 335306). However, the positive pulse voltage was also found to affect the behaviour of ions and radicals near the sidewall surface. The incident angles of ions on the sidewall surface increased with the positive pulse voltage because the energy of incoming ions on the trench decreases with increasing positive voltage. Moreover, the incident ion flux on the sidewall is affected by the positive voltage history. Further, the radical flux decreases with increasing positive voltage. It can be concluded that a higher positive voltage at a lower negative voltage condition is good to obtain better film properties and higher film thickness on the sidewall surface. Pattern transfer properties for the nanoimprint formed by

  12. Enantioselective Construction of Remote Quaternary Stereocenters

    PubMed Central

    Mei, Tian-Sheng; Patel, Harshkumar H.; Sigman, Matthew S.

    2014-01-01

    Summary Molecules containing all-carbon quaternary stereocenters – carbon atoms bonded to four distinct carbon substituents – are prevalent in Nature. However, the construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for forging quaternary stereocenters that are remote from other functional groups are underdeveloped. Herein we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. The reported method allows direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ aryl carbonyl compounds, as the unsaturation of the alkene is relayed to the alcohol resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocenters along the alkyl chain, which links the alkene and the alcohol, wherein the stereocenter is preserved. The described method is flexible, allowing access to diverse building blocks containing an enantiomerically enriched, quaternary center. PMID:24717439

  13. Extensive Quaternary glaciations in eastern Turkey

    NASA Astrophysics Data System (ADS)

    Yeşilyurt, Serdar; Akçar, Naki; Doǧan, Uǧur; Yavuz, Vural; Ivy-Ochs, Susan; Vockenhuber, Christof; Schlunegger, Fritz; Schlüchter, Christian

    2016-04-01

    During cold periods in the Quaternary, global ice volume increased and as a result valley glaciers advanced and the vice versa occurred during the warm periods. Quaternary glacier fluctuations had been also recorded in the Turkish mountains. Recently, the chronology of Late Quaternary advances in the northern and western Turkish mountains was reconstructed by surface exposure dating. However, these advances in the eastern Turkey are not dated yet. In this study, we investigated paleoglaciations in Kavuşşahap Mountains, which is located to the south of Lake Van in eastern Turkey. These mountains are one of the extensively glaciated areas in Turkey. Glacial activity is evidenced by more than 20 U-shaped valleys. For instance, one of the prominent and well-preserved glacial landscapes of Turkey is situated in the Narlıca valley system. Lateral and terminal moraines in the valley system indicate more than 10 glacial advances. To build their chronology, 39 erratic carbonaceous boulders were sampled for surface exposure dating with cosmogenic 36Cl. We also reconstructed the ice margin reconstruction of the Narlıca paleoglacier using the accumulation area ratio and area-altitude balance ratio approaches. We estimated an equilibrium line altitude (ELA) of ca. 2900 m above sea level based on the maximum ice extend, which implied ca. 800 m decrease in the ELA during the Late Quaternary in comparison to the lower bound of the modern ELA estimate. The first results of the surface exposure dating will be presented.

  14. A review on cholinesterase inhibitors for Alzheimer's disease.

    PubMed

    Anand, Preet; Singh, Baldev

    2013-04-01

    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

  15. Muscle aches

    MedlinePlus

    ... and fibromyalgia often respond well to massage. Gentle stretching exercises after a long rest period are also ... to try. A physical therapist can teach you stretching, toning, and aerobic exercises to help you feel ...

  16. Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer's disease- diabetes type 2 linkage via an enzoinformatics study.

    PubMed

    Rizvi, Syed M D; Shakil, Shahnawaz; Biswas, Deboshree; Shakil, Shazi; Shaikh, Sibhghatulla; Bagga, Paramdeep; Kamal, Mohammad A

    2014-04-01

    Acetylcholinesterase (AChE) is a primary target for Alzheimer's therapy while recently sodium glucose cotransporter 2 (SGLT2) has gained importance as a potential target for Type 2 Diabetes Mellitus (T2DM) therapy. The present study emphasizes the molecular interactions between a new Food and Drug Administration (FDA) approved antidiabetic drug 'Invokana' (chemically known as Canagliflozin) with AChE and SGLT2 to establish a link between the treatment of T2DM and Alzheimer's Disease (AD). Docking study was performed using 'Autodock4.2'. Both hydrophobic and π-π interactions play an important role in the correct positioning of Canagliflozin within SGLT2 and catalytic site (CAS) of AChE to permit docking. Free energy of binding (ΔG) for 'Canagliflozin-SGLT2' interaction and 'Canagliflozin - CAS domain of AChE' interaction were found to be -10.03 kcal/mol and -9.40 kcal/mol, respectively. During 'Canagliflozin-SGLT2' interaction, Canagliflozin was found to interact with the most important amino acid residue Q457 of SGLT2. This residue is known for its interaction with glucose during reabsorption in kidney. However, 'Canagliflozin-CAS domain of AChE' interaction revealed that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues (S203 and H447) interact with Canagliflozin. Hence, Invokana (Canagliflozin) might act as a potent dual inhibitor of AChE and SGLT2. However, scope still remains in the determination of the three-dimensional structure of SGLT2-Canagliflozin and AChE-Canagliflozin complexes by X-ray crystallography to validate the described data. Since the development of diabetes is associated with AD, the design of new AChE inhibitors based on antidiabetic drug scaffolds would be particularly beneficial. Moreover, the present computational study reveals that Invokana (Canagliflozin) is expected to form the basis of a future dual therapy against diabetes associated neurological disorders.

  17. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

    PubMed Central

    Bautista-Aguilera, Oscar M; Esteban, Gerard; Chioua, Mourad; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Soriano, Elena; Samadi, Abdelouahid; Unzeta, Mercedes; Marco-Contelles, José

    2014-01-01

    The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer’s disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13–15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hACh

  18. Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase.

    PubMed

    Camerino, Eugene; Wong, Dawn M; Tong, Fan; Körber, Florian; Gross, Aaron D; Islam, Rafique; Viayna, Elisabet; Mutunga, James M; Li, Jianyong; Totrov, Maxim M; Bloomquist, Jeffrey R; Carlier, Paul R

    2015-10-15

    Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored α-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 ± 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed. PMID:26386602

  19. Microdemographic Determinants of Population Recovery among the Northern Aché.

    PubMed

    Baker, Jack D; Hill, Kim; Hurtado, A Magdalena; Alcantara, Adelamar; Hunsinger, Eddie; Sprague, Webb

    2015-01-01

    A pattern of population crash and rapid recovery is a common feature of the pacification and settlement experience of the indigenous peoples of tropical South America. Despite the obvious importance of these events to the demographic and anthropological sciences as a whole, as well as their significant practical implications, little is known about the microdemographic determinants of these paired phenomena. Using methods of asymptotic and stochastic demographic analysis, we reconstructed the microdemographic drivers of this history among one indigenous population: the Northern Aché of eastern Paraguay. This article explores the implications of these relationships for understanding the overall demographic turnaround observed within similar groups, as well as for the future trajectory of the Northern Aché in particular.

  20. Sound localisation ability of soldiers wearing infantry ACH and PASGT helmets.

    PubMed

    Scharine, Angelique A; Binseel, Mary S; Mermagen, Timothy; Letowski, Tomasz R

    2014-01-01

    Helmets provide soldiers with ballistic and fragmentation protection but impair auditory spatial processing. Missed auditory information can be fatal for a soldier; therefore, helmet design requires compromise between protection and optimal acoustics. Twelve soldiers localised two sound signals presented from six azimuth angles and three levels of elevation presented at two intensity levels and with three background noises. Each participant completed the task while wearing no helmet and with two U.S. Army infantry helmets - the Personnel Armor System for Ground Troops (PASGT) helmet and the Advanced Combat Helmet (ACH). Results showed a significant effect of helmet type on the size of both azimuth and elevation error. The effects of level, background noise, azimuth and elevation were found to be significant. There was no effect of sound signal type. As hypothesised, localisation accuracy was greatest when soldiers did not wear helmet, followed by the ACH. Performance was worst with the PASGT helmet.

  1. Deposition of a-C:H films on UHMWPE substrate and its wear-resistance

    NASA Astrophysics Data System (ADS)

    Xie, Dong; Liu, Hengjun; Deng, Xingrui; Leng, Y. X.; Huang, Nan

    2009-10-01

    In prosthetic hip replacements, ultrahigh molecular weight polyethylene (UHMWPE) wear debris is identified as the main factor limiting the lifetime of the artificial joints. Especially UHMWPE debris from the joint can induce tissue reactions and bone resorption that may lead to the joint loosening. The diamond like carbon (DLC) film has attracted a great deal of interest in recent years mainly because of its excellent tribological property, biocompatibility and chemically inert property. In order to improve the wear-resistance of UHMWPE, a-C:H films were deposited on UHMWPE substrate by electron cyclotron resonance microwave plasma chemical vapor deposition (ECR-PECVD) technology. During deposition, the working gases were argon and acetylene, the microwave power was set to 800 W, the biased pulsed voltage was set to -200 V (frequency 15 kHz, duty ratio 20%), the pressure in vacuum chamber was set to 0.5 Pa, and the process time was 60 min. The films were analysed by X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, nano-indentation, anti-scratch and wear test. The results showed that a typical amorphous hydrogenated carbon (a-C:H) film was successfully deposited on UHMWPE with thickness up to 2 μm. The nano-hardness of the UHMWPE coated with a-C:H films, measured at an applied load of 200 μN, was increased from 10 MPa (untreated UHMWPE) to 139 MPa. The wear test was carried out using a ball (Ø 6 mm, SiC) on disk tribometer with an applied load of 1 N for 10000 cycles, and the results showed a reduction of worn cross-sectional area from 193 μm 2 of untreated UHMWPE to 26 μm 2 of DLC coated sample. In addition the influence of argon/acetylene gas flow ratio on the growth of a-C:H films was studied.

  2. Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates.

    PubMed

    Radić, Zoran; Sit, Rakesh K; Garcia, Edzna; Zhang, Limin; Berend, Suzana; Kovarik, Zrinka; Amitai, Gabriel; Fokin, Valery V; Barry Sharpless, K; Taylor, Palmer

    2013-03-25

    A library of more than 200 novel uncharged oxime reactivators was used to select and refine lead reactivators of human acetylcholinesterase (hAChE) covalently conjugated with sarin, cyclosarin, VX, paraoxon and tabun. N-substituted 2-hydroxyiminoacetamido alkylamines were identified as best reactivators and reactivation kinetics of the lead oximes, RS41A and RS194B, were analyzed in detail. Compared to reference pyridinium reactivators, 2PAM and MMB4, molecular recognition of RS41A reflected in its Kox constant was compromised by an order of magnitude on average for different OP-hAChE conjugates, without significant differences in the first order maximal phosphorylation rate constant k(2). Systematic structural modifications of the RS41A lead resulted in several-fold improvement with reactivator, RS194B. Kinetic analysis indicated K(ox) reduction for RS194B as the main kinetic constant leading to efficient reactivation. Subtle structural modifications of RS194B were used to identify essential determinants for efficient reactivation. Computational molecular modeling of RS41A and RS194B interactions with VX inhibited hAChE, bound reversibly in Michaelis type complex and covalently in the pentacoordinate reaction intermediate suggests that the faster reactivation reaction is a consequence of a tighter RS194B interactions with hAChE peripheral site (PAS) residues, in particular with D74, resulting in lower interaction energies for formation of both the binding and reactivation states. Desirable in vitro reactivation properties of RS194B, when coupled with its in vivo pharmacokinetics and disposition in the body, reveal the potential of this oxime design as promising centrally and peripherally active antidotes for OP toxicity.

  3. Evidence for aging theories from the study of a hunter-gatherer people (Ache of Paraguay).

    PubMed

    Libertini, G

    2013-09-01

    In the late seventies, a small tribal population of Paraguay, the Ache, living under natural conditions, was studied. Data from this population turn out to be useful for considerations about evolutionary hypotheses on the aging phenomenon. 1) Ache show an age-related increasing mortality, which strongly limits the mean duration of life, as observed in other studies on mammal and bird species. 2) According to current theories on aging, in the wild very few or no individual reach old age and, so, aging cannot be directly influenced by natural selection. However, data from our population show that a significant proportion of the population reaches in the wild 60 and 70 years of age. 3) Data from Ache are also in agreement with the observation about an inverse correlation between extrinsic mortality and deaths due to the age-related increasing mortality. 4) For many gerontologists, the age-related decline of vital functions is a consequence of the gradual decline of cell turnover, genetically determined and regulated by the declining duplication capacities of stem cells. The current interpretation is that these restrictions are a general defense against the proliferation of any tumoral mass. However, among wild Ache cancer is virtually unknown in non-elderly subjects, and only among older individuals are there deaths attributable to oncological diseases. Moreover, fitness decline begins long before oncological diseases have fatal effects in significant numbers. This completely disproves the current hypothesis, because a supposed defense against a deadly disease cannot exterminate a population before the disease begins to kill. These data are consistent with similar data from other species studied under natural conditions, and they bring new arguments against the non-adaptive interpretation of aging and in support of the adaptive interpretation.

  4. Circadian variation in salivary testosterone across age classes in Ache Amerindian males of Paraguay.

    PubMed

    Bribiescas, Richard G; Hill, Kim R

    2010-01-01

    Testosterone levels exhibit a circadian rhythm in healthy men, with morning levels tending to be higher compared to evening titers. However, circadian rhythms wane with age. Although this has been described in males living within industrialized settings, age-related changes have not received similar attention in populations outside these contexts. Because many nonindustrialized populations, such as Ache Amerindians of Paraguay, exhibit testosterone levels that are lower than what is commonly reported in the clinical literature and lack age-associated variation in testosterone, it was hypothesized that Ache men would not show age-related variation in testosterone circadian rhythms. Diurnal rhythmicity in testosterone within and between Ache men in association with age (n = 52; age range, 18-64) was therefore examined. A significant negative association was evident between the ratio of morning and evening salivary testosterone and age (r = -0.28, P = 0.04). Men in their third decade of life exhibited significant diurnal variation (P = 0.0003), whereas older and younger age classes did not. Men between the ages of 30 and 39 also exhibited a higher AM:PM testosterone ratio compared to 40-49 and 50< year old men (P = 0.002, 0.006). Overall, declines in testosterone with aging may not be universal among human males, however, within-individual analyses of diurnal variation capture age-related contrasts in daily testosterone fluctuations. Circadian rhythmicity differs with age among the Ache and may be a common aspect of reproductive senescence among men regardless of ecological context.

  5. Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor

    PubMed Central

    Schrage, R; Seemann, WK; Klöckner, J; Dallanoce, C; Racké, K; Kostenis, E; De Amici, M; Holzgrabe, U; Mohr, K

    2013-01-01

    Background and Purpose Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such ‘superagonism’ has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a ‘superagonist’. Experimental Approach Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. Key Results In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi/Gs signalling competence. In the orthosteric loss-of-function mutant M2-Y1043.33A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. ‘Superagonism’ is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure–signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that ‘superagonism’ of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. Conclusion and Implications Supraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR ‘superagonism’ is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators. Linked Article This article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12142 PMID:23062057

  6. The stabilization of Au NP-AChE nanocomposites by biosilica encapsulation for the development of a thiocholine biosensor.

    PubMed

    Buiculescu, Raluca; Chaniotakis, Nikos A

    2012-08-01

    We report on the construction of an amperometric biosensor based on the immobilization of the enzyme acetylcholinesterase (AChE) onto gold nanoparticles (Au NPs). The active enzyme is covalently bound directly onto the surface of the Au NPs via a thiol bond. This immobilization provides increased stability and high electron-transfer between the colloidal Au NPs, the catalyst and the transducer surface. To further increase the biosensor stability by protecting the enzyme from denaturation and protease attack, a layer of biosilica was grown around the Au NP enzyme nanocomposite. All steps, i.e., the conjugation of the enzyme to the gold nanoparticles and the encapsulation into biosilica, are monitored and confirmed by ATR-FT-IR spectroscopy. The stabilizing effect of the entrapment was evaluated amperometrically, while the operation of the biosensor was monitored over a period of 4 months. The initial sensitivity of the biosensor was calculated to be 27.58 nA mM(-1) with a linear response to the concentration of the substrate in the range from 0.04 to 0.4 mM. It is thus shown that the biosilica nanocomposites doped with Au NPs-AChE conjugates create a system that provides both signal mediation and significant enzyme stabilization over the existing AChE biosensor. The biosensor had retained all its activity at the end of the 4 months, compared with the normal AChE biosensor whose activity reached 50% after only 42 days of operation.

  7. Expression of human AChR extracellular domain mutants with improved characteristics.

    PubMed

    Lazaridis, Konstantinos; Zisimopoulou, Paraskevi; Giastas, Petros; Bitzopoulou, Kalliopi; Evangelakou, Panagiota; Sideri, Anastasia; Tzartos, Socrates J

    2014-02-01

    The muscle nicotinic acetylcholine receptor (AChR) has a central role in neuromuscular transmission, and is the major target in the autoimmune disease myasthenia gravis (MG). We created mutants of the extracellular domains (ECDs) of the human α1, β1, δ and ε AChR subunits, whereby their Cys-loop was exchanged for that of the acetylcholine binding protein. The mutants were expressed in Pichia pastoris and had improved solubility resulting in 2- to 43-fold higher expression yields compared to the wild type. An additional mutant was created for the α1 ECD restoring its glycosylation site within the Cys-loop and its α-bungarotoxin binding ability. Furthermore, we constructed dimeric and pentameric concatamers of the mutant ECDs. All concatamers were successfully expressed as soluble secreted proteins, although the pentamers had about 10-fold lower expression than the dimers and were more susceptible to fragmentation. Initial crystallizations with the mutant ECDs were promising, and we reproducibly obtained crystals of the β1 ECD, diffracting at ~12 Å. Further optimization is underway to obtain crystals suitable for high resolution crystallography. The proteins described herein are useful tools in structural studies of the human muscle AChR and can be used in applications requiring high yields such as therapeutic adsorbents for MG autoantibodies. PMID:24246999

  8. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    PubMed Central

    Schaal, Courtney; Padmanabhan, Jaya; Chellappan, Srikumar

    2015-01-01

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer. PMID:26264026

  9. Proteasome inhibitors.

    PubMed

    Teicher, Beverly A; Tomaszewski, Joseph E

    2015-07-01

    Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. PMID:25935605

  10. Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice.

    PubMed

    Leite, Paulo Emílio Correa; Gandía, Luís; de Pascual, Ricardo; Nanclares, Carmen; Colmena, Inés; Santos, Wilson C; Lagrota-Candido, Jussara; Quirico-Santos, Thereza

    2014-07-21

    Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChRα7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration. PMID:24833065

  11. The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies

    PubMed Central

    Muldoon, P P; Jackson, K J; Perez, E; Harenza, J L; Molas, S; Rais, B; Anwar, H; Zaveri, N T; Maldonado, R; Maskos, U; McIntosh, J M; Dierssen, M; Miles, M F; Chen, X; De Biasi, M; Damaj, M I

    2014-01-01

    BACKGROUND AND PURPOSE Recent data have indicated that α3β4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. EXPERIMENTAL APPROACHES To assess the role of α3β4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. KEY RESULTS BXD recombinant mouse lines demonstrated an increased expression of α3, β4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and β4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective α3β4* nACh receptor antagonists, α-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the α3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the α4β2* nACh receptor subtype is not involved in morphine somatic withdrawal signs. CONCLUSION AND IMPLICATIONS Overall, our findings suggest an important role for the α3β4* nACh receptor subtype in morphine physical dependence. PMID:24750073

  12. Silencing A7-nAChR levels increases the sensitivity of gastric cancer cells to ixabepilone treatment.

    PubMed

    Tu, Chao-Chiang; Huang, Chien-Yu; Cheng, Wan-Li; Hung, Chin-Sheng; Chang, Yu-Jia; Wei, Po-Li

    2016-07-01

    Gastric cancer is an important health issue worldwide. Currently, improving the therapeutic efficacy of chemotherapy drugs is an important goal of cancer research. Alpha-7 nicotine acetylcholine receptor (A7-nAChR) is the key molecule that mediates gastric cancer progression, metastasis, and therapy responses; however, the role of A7-nAChR in the therapeutic efficacy of ixabepilone remains unclear. A7-nAChR expression was silenced by small interfering RNA (siRNA) technology. The cytotoxicity of ixabepilone was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and ixabepilone-induced apoptosis was analyzed by flow cytometry and annexin V/propidium iodide (PI) apoptotic assay. The expression patterns of anti-apoptotic proteins (AKT, phospho-AKT, Mcl-1, and Bcl-2) and pro-apoptotic proteins (Bad and Bax) were determined by western blot. Our study found that A7-nAChR knockdown (A7-nAChR-KD) AGS cells were more sensitive to ixabepilone administration than scrambled control AGS cells. We found that A7-nAChR knockdown enhanced ixabepilone-induced cell death as evidenced by the increased number of annexin V-positive (apoptotic) cells. After scrambled control and A7-nAChR-KD cells were treated with ixabepilone, we found that pAKT and AKT levels were significantly reduced in both groups of cells. The levels of Bcl-2 and the anti-apoptotic Mcl-1 isoform increased dramatically after ixabepilone treatment in scrambled control cells but not in A7-nAChR-KD cells. Bad and Bax levels did not change between the treatment group and vehicle group in both A7-nAChR-KD and scrambled control cells, whereas cleaved PARP levels dramatically increased in ixabepilone-treated A7-nAChR-KD cells. Our results demonstrated that knockdown of A7-nAChR enhanced the sensitivity of gastric cancer cells to ixabepilone administration. Thus, the A7-nAChR expression level in patients with gastric cancer may be a good indicator of ixabepilone sensitivity.

  13. Otilonium: a potent blocker of neuronal nicotinic ACh receptors in bovine chromaffin cells.

    PubMed Central

    Gandía, L.; Villarroya, M.; Lara, B.; Olmos, V.; Gilabert, J. A.; López, M. G.; Martínez-Sierra, R.; Borges, R.; García, A. G.

    1996-01-01

    1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by

  14. Platelet Inhibitors.

    PubMed

    Shifrin, Megan M; Widmar, S Brian

    2016-03-01

    Antithrombotic medications have become standard of care for management of acute coronary syndrome. Platelet adhesion, activation, and aggregation are essential components of platelet function; platelet-inhibiting medications interfere with these components and reduce incidence of thrombosis. Active bleeding is a contraindication for administration of platelet inhibitors. There is currently no reversal agent for platelet inhibitors, although platelet transfusion may be used to correct active bleeding after administration of platelet inhibitors. PMID:26897422

  15. Conformational remodeling of femtomolar inhibitor-acetylcholinesterase complexes in the crystalline state

    PubMed Central

    Bourne, Yves; Radic, Zoran; Taylor, Palmer; Marchot, Pascale

    2010-01-01

    The active center of acetylcholinesterase (AChE), a target site for competitive inhibitors, resides centrosymmetric to the subunit at the base of a deep, narrow gorge lined by aromatic residues. At the gorge entry, a peripheral site encompasses overlapping binding loci for non-competitive inhibitors, which alter substrate access to the gorge. The click-chemistry inhibitor TZ2PA6 links the active center ligand, tacrine, to the peripheral site ligand, propidium, through a biorthogonal reaction of an acetylene and an azide that forms either a syn1 or an anti1 triazole. Compared with wild-type mouse AChE, a Tyr337Ala mutant displays full catalytic activity, albeit with two to three orders of magnitude higher affinities for the TZ2PA6 syn1 and anti1 regioisomers, reflected in low femtomolar Kd values, diffusion-limited association and dissociation half-times greater than one month and one week, respectively. Three structures of each of the co-crystallized syn1 and anti1 complexes of the Tyr337Ala mutant were solved at three distinct times of crystal maturation, consistent with or exceeding the half-lives of the complexes in solution, while crystalline complexes obtained from soaked Tyr337Ala crystals led to picturing “freshly formed” complexes. The structures, at 2.55-2.75Å resolution, reveal a range of unprecedented conformations of the bound regioisomers, not observed in the wild-type AChE complexes, associated with concerted positional rearrangements of side chains in the enzyme gorge. Moreover, time-dependent conformational remodeling of the crystalline complexes appears to correlate with the dissociation half-times of the solution complexes. Hence for the tight-binding TZ2PA6 inhibitors, the initial complexes kinetically driven in solution slowly form more stable complexes governed by thermodynamic equilibrium and observable in mature crystals. PMID:21090615

  16. 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer's disease treatment--synthesis, biological evaluation and molecular modeling studies.

    PubMed

    Spilovska, Katarina; Korabecny, Jan; Kral, Jan; Horova, Anna; Musilek, Kamil; Soukup, Ondrej; Drtinova, Lucie; Gazova, Zuzana; Siposova, Katarina; Kuca, Kamil

    2013-02-20

    A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.

  17. Quaternary Tipping Points in Tropical Northern Australia

    NASA Astrophysics Data System (ADS)

    Moss, Patrick; Dunbar, Gavin; Croke, Jacky; Katunar, Rosie

    2016-04-01

    Tropical northern Queensland, particularly the volcanic Atherton Tableland, contains some of the most detailed and longest terrestrial palaeoenvironmental archives in Australia and when combined with adjacent marine sediment records provides key insight into potential environmental 'tipping points' for the entire Quaternary period and beyond. This presentation will provide an overview of some of the key tipping points (i.e. significant landscape transformation) that have occurred within the tropical northern Australian region over the Quaternary, as well as discussing potential causes and subsequent impacts of these transformation episodes. These events include the development of the Great Barrier Reef, transition from obliquity to eccentricity dominated glacial-interglacial cycles, the Mid-Brunhes event, the Oxygen Isotope Stage 6 episode, the arrival of people into the region, Last Glacial-Interglacial Transition and European settlement.

  18. [Quaternary prevention: containment as an ethical necessity].

    PubMed

    Martínez González, C; Riaño Galán, I; Sánchez Jacob, M; González de Dios, J

    2014-12-01

    The growing capacity of medicine to generate more iatrogenic events than ever, and the risk of unsustainability of health systems have led to new prevention concept: quaternary prevention aimed at restraining medicalization. Quaternary prevention is essential in the phenomenon called disease mongering, which could be translated as commercialization of disease. Encouraging this sort of prevention and halting the consequences of disease mongering requires the development of all the institutional potential for prevention, as well as all the personal willingness for restraint; it involves separating us from the unnecessary auspices of industry, being critical of our work, not being maleficent, respecting the principle of justice as managers of the limited public resources and making ourselves feel responsible for the social cost resulting from medical decisions. From this point of view, this work analyses neonatal screening, developments in the area of neonatology and primary health care.

  19. [Quaternary prevention: containment as an ethical necessity].

    PubMed

    Martínez González, C; Riaño Galán, I; Sánchez Jacob, M; González de Dios, J

    2014-12-01

    The growing capacity of medicine to generate more iatrogenic events than ever, and the risk of unsustainability of health systems have led to new prevention concept: quaternary prevention aimed at restraining medicalization. Quaternary prevention is essential in the phenomenon called disease mongering, which could be translated as commercialization of disease. Encouraging this sort of prevention and halting the consequences of disease mongering requires the development of all the institutional potential for prevention, as well as all the personal willingness for restraint; it involves separating us from the unnecessary auspices of industry, being critical of our work, not being maleficent, respecting the principle of justice as managers of the limited public resources and making ourselves feel responsible for the social cost resulting from medical decisions. From this point of view, this work analyses neonatal screening, developments in the area of neonatology and primary health care. PMID:24907862

  20. Biochemical effects of glyphosate based herbicide, Excel Mera 71 on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content on teleostean fishes.

    PubMed

    Samanta, Palas; Pal, Sandipan; Mukherjee, Aloke Kumar; Ghosh, Apurba Ratan

    2014-09-01

    Effects of glyphosate based herbicide, Excel Mera 71 at a dose of 17.20mg/l on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content were measured in different tissues of two Indian air-breathing teleosts, Anabas testudineus (Bloch) and Heteropneustes fossilis (Bloch) during an exposure period of 30 days under laboratory condition. AChE activity was significantly increased in all the investigated tissues of both fish species and maximum elevation was observed in brain of H. fossilis, while spinal cord of A. testudineus showed minimum increment. Fishes showed significant increase LPO levels in all the tissues; highest was observed in gill of A. testudineus but lowest LPO level was observed in muscle of H. fossilis. CAT was also enhanced in both the fishes, while GST activity in liver diminished substantially and minimum was observed in liver of A. testudineus. Total protein content showed decreased value in all the tissues, maximum reduction was observed in liver and minimum in brain of A. testudineus and H. fossilis respectively. The results indicated that Excel Mera 71 caused serious alterations in the enzyme activities resulting into severe deterioration of fish health; so, AChE, LPO, CAT and GST can be used as suitable indicators of herbicidal toxicity. PMID:24927388

  1. Biochemical effects of glyphosate based herbicide, Excel Mera 71 on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content on teleostean fishes.

    PubMed

    Samanta, Palas; Pal, Sandipan; Mukherjee, Aloke Kumar; Ghosh, Apurba Ratan

    2014-09-01

    Effects of glyphosate based herbicide, Excel Mera 71 at a dose of 17.20mg/l on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content were measured in different tissues of two Indian air-breathing teleosts, Anabas testudineus (Bloch) and Heteropneustes fossilis (Bloch) during an exposure period of 30 days under laboratory condition. AChE activity was significantly increased in all the investigated tissues of both fish species and maximum elevation was observed in brain of H. fossilis, while spinal cord of A. testudineus showed minimum increment. Fishes showed significant increase LPO levels in all the tissues; highest was observed in gill of A. testudineus but lowest LPO level was observed in muscle of H. fossilis. CAT was also enhanced in both the fishes, while GST activity in liver diminished substantially and minimum was observed in liver of A. testudineus. Total protein content showed decreased value in all the tissues, maximum reduction was observed in liver and minimum in brain of A. testudineus and H. fossilis respectively. The results indicated that Excel Mera 71 caused serious alterations in the enzyme activities resulting into severe deterioration of fish health; so, AChE, LPO, CAT and GST can be used as suitable indicators of herbicidal toxicity.

  2. Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: 11C-Donepezil PET Study in the Normal Rat

    PubMed Central

    Watabe, Tadashi; Naka, Sadahiro; Ikeda, Hayato; Horitsugi, Genki; Kanai, Yasukazu; Isohashi, Kayako; Ishibashi, Mana; Kato, Hiroki; Shimosegawa, Eku; Watabe, Hiroshi; Hatazawa, Jun

    2014-01-01

    Purpose Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered 11C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. Methods The distribution of 11C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220±8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of 11C-DNP (45.0±10.7 MBq). The whole-body distribution of the 11C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. Results The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of 11C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm3, respectively), indicating that the distribution of 11C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9±1.6, 83.1±3.0, and 38.5±8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. Conclusions We demonstrated the whole-body distribution of 11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of 11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors. PMID:25225806

  3. Quaternary geology of the Amazonian Lowland

    NASA Astrophysics Data System (ADS)

    Irion, Georg; Müller, Jens; Nunes de Mello, Jose; Junk, Wolfgang J.

    1995-09-01

    The Quaternary history of the Amazon lowlands is characterized by deposition of sediments of Andean provenance and by the influences of changing sea levels. Areas well above the present water tables were not reached by Pleistocene high-water stages. These areas have been intensively weathered since the Tertiary, forming hard lateritic weathering horizons. These weathering horizons are best explained by the relatively constant, humid tropical climate throughout the Quaternary. In the western Amazonian Lowland, flood plains corresponding to the different Pleistocene sea-level heights were formed. During low sea level, erosion in the drainage areas increased and the water levels of the central Amazon River system were lowered. Valleys drowned and lakes formed in the lower reaches of rivers and creeks during high sea-level stages. These lakes (ria lakes) remained in the valleys with rivers having a low sediment load. Seismic profiling (3.5 kHz) in some of these lakes clearly showed deposits of the three last periods of Quaternary high sea-level stages.

  4. 3-Quaternary ammonium 1-carba-1-dethiacephems.

    PubMed

    Cook, G K; McDonald, J H; Alborn, W; Boyd, D B; Eudaly, J A; Indelicato, J M; Johnson, R; Kasher, J S; Pasini, C E; Preston, D A

    1989-11-01

    A series of structurally unique 1-carba-1-dethiacephems is described. The structural stability of the 1-carba-1-dethiacephem nucleus was essential for the preparation of this series of 3-quaternary ammonium carbacephems. The known p-nitrobenzyl 7 beta-(phenoxyacetamido)- 3-[(trifluoromethyl)sulfonyl]oxy]-1-carba-1-dethia-3-cephem- 4-carboxylate served as both a quaternization substrate as well as a precursor to derivatives such as allyl 7 beta-[[2-[allyloxy)carbonyl]amino-4- thiazoly] (methoxyimino)acetyl]amino]-3-[(trifluoromethyl) sulfonyl] oxy]-1-carba-1-dethia-3-cephem-4-carboxylate. Quaternization of these enol triflates was accomplished either by dissolution in acetonitrile containing the base or by dissolution in the base, with or without warning to 50 degrees C. Bases nucleophilic enough to displace the triflate include a variety of substituted pyridines and N-methylimidazole. Deprotection then produced a very active series of 1-[7 beta-[(2-amino- 4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo- 1-azabicyclo[4.2.0]oct-2-en-3-yl] quaternary ammonium hydroxide inner salts. These compounds were extremely potent antibacterials against a broad range of Gram-positive and -negative bacteria including constitutive cephalosporinase producers, such as Enterobacter cloacae. The compounds exhibit similar hydrolysis kinetics and pharmacokinetics to the analogous cephalosporin-3'-quaternary ammonium salts.

  5. Aleksis Dreimanis: a legacy in Quaternary science

    NASA Astrophysics Data System (ADS)

    Hicock, Stephen R.; Menzies, John

    2000-12-01

    Aleksis Dreimanis was born and raised in Latvia. His interest in Quaternary and glacial geology began early and developed into a career that has spanned 7 decades. At age 20 he published his first paper in glacial geology and soon after began teaching at the University of Latvia. Teaching and research were interrupted by World War II but resumed at the Baltic University (Pinneberg, Germany), then at the University of Western Ontario where he has been ever since. Throughout his career, Dreimanis has successfully balanced the twin disciplines of Quaternary history and glacial geology. He was among the first to study quantitatively the relationship between till lithology and till formation and to study how glacial transport and dynamics affect till texture and deformation. With co-workers he developed the well-known stratigraphic scheme of the last glaciation in the Great Lakes region of North America. Aleksis became world-renowned through his committee work, especially as President of the INQUA Commission on Genesis and Lithology of Glacial Quaternary Deposits. His diplomacy, enthusiasm, and passion for his subject have inspired students and colleagues around the globe and resulted in remarkable international dialogue, cooperation, and consensus. Professor Aleksis Dreimanis is an honest scientist, a gentleman, and a true scholar who has left a rich legacy for future Quaternarists.

  6. Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation.

    PubMed

    Zha, Gao-Feng; Zhang, Cheng-Pan; Qin, Hua-Li; Jantan, Ibrahim; Sher, Muhammad; Amjad, Muhammad Wahab; Hussain, Muhammad Ajaz; Hussain, Zahid; Bukhari, Syed Nasir Abbas

    2016-05-15

    A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1-42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.

  7. Sympathetic α₃β₂-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine.

    PubMed

    Lee, Reggie Hui-Chao; Liu, Yi-Qing; Chen, Po-Yi; Liu, Chin-Hung; Chen, Mei-Fang; Lin, Hung-Wen; Kuo, Jon-Son; Premkumar, Louis S; Lee, Tony Jer-Fu

    2011-08-01

    The α(7)-nicotinic ACh receptor (α(7)-nAChR) on sympathetic neurons innervating basilar arteries of pigs crossed bred between Landrace and Yorkshire (LY) is known to mediate nicotine-induced, β-amyloid (Aβ)-sensitive nitrergic neurogenic vasodilation. Preliminary studies, however, demonstrated that nicotine-induced cerebral vasodilation in pigs crossbred among Landrace, Yorkshire, and Duroc (LYD) was insensitive to Aβ and α-bungarotoxin (α-BGTX). We investigated nAChR subtype on sympathetic neurons innervating LYD basilar arteries. Nicotine-induced relaxation of porcine isolated basilar arteries was examined by tissue bath myography, inward currents on nAChR-expressing oocytes by two-electrode voltage recording, and mRNA and protein expression in the superior cervical ganglion (SCG) and middle cervical ganglion (MCG) by reverse transcription PCR and Western blotting. Nicotine-induced basilar arterial relaxation was not affected by Aβ, α-BGTX, and α-conotoxin IMI (α(7)-nAChR antagonists), or α-conotoxin AuIB (α(3)β(4)-nAChR antagonist) but was inhibited by tropinone and tropane (α(3)-containing nAChR antagonists) and α-conotoxin MII (selective α(3)β(2)-nAChR antagonist). Nicotine-induced inward currents in α(3)β(2)-nAChR-expressing oocytes were inhibited by α-conotoxin MII but not by α-BGTX, Aβ, or α-conotoxin AuIB. mRNAs of α(3)-, α(7)-, β(2)-, and β(4)-subunits were expressed in both SCGs and MCGs with significantly higher mRNAs of α(3)-, β(2)-, and β(4)-subunits than that of α(7)-subunit. The Aβ-insensitive sympathetic α(3)β(2)-nAChR mediates nicotine-induced cerebral nitrergic neurogenic vasodilation in LYD pigs. The different finding from Aβ-sensitive α(7)-nAChR in basilar arteries of LY pigs may offer a partial explanation for different sensitivities of individuals to Aβ in causing diminished cerebral nitrergic vasodilation in diseases involving Aβ.

  8. Corrosion inhibitor

    SciTech Connect

    Wisotsky, M.J.; Metro, S.J.

    1989-10-31

    A corrosion inhibitor for use in synthetic ester lubricating oils is disclosed. It comprises an effective amount of: at least one aromatic amide; and at least one hydroxy substituted aromatic compound. The corrosion inhibitor thus formed is particularly useful in synthetic ester turbo lubricating oils.

  9. Direct Proof of the In Vivo Pathogenic Role of the AChR Autoantibodies from Myasthenia Gravis Patients

    PubMed Central

    Kordas, Gregory; Lagoumintzis, George; Sideris, Sotirios; Poulas, Konstantinos; Tzartos, Socrates J.

    2014-01-01

    Several studies have suggested that the autoantibodies (autoAbs) against muscle acetylcholine receptor (AChR) of myasthenia gravis (MG) patients are the main pathogenic factor in MG; however, this belief has not yet been confirmed with direct observations. Although animals immunized with AChR or injected with anti-AChR monoclonal Abs, or with crude human MG Ig fractions exhibit MG symptoms, the pathogenic role of isolated anti-AChR autoAbs, and, more importantly, the absence of pathogenic factor(s) in the autoAb-depleted MG sera has not yet been shown by in vivo studies. Using recombinant extracellular domains of the human AChR α and β subunits, we have isolated autoAbs from the sera of four MG patients. The ability of these isolated anti-subunit Abs and of the Ab-depleted sera to passively transfer experimental autoimmune MG in Lewis rats was investigated. We found that the isolated anti-subunit Abs were at least as efficient as the corresponding whole sera or whole Ig in causing experimental MG. Abs to both α- and β-subunit were pathogenic although the anti-α-subunit were much more efficient than the anti-β-subunit ones. Interestingly, the autoAb-depleted sera were free of pathogenic activity. The later suggests that the myasthenogenic potency of the studied anti-AChR MG sera is totally due to their anti-AChR autoAbs, and therefore selective elimination of the anti-AChR autoAbs from MG patients may be an efficient therapy for MG. PMID:25259739

  10. Can quaternary ammonium methacrylates inhibit matrix MMPs and cathepsins?

    PubMed Central

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Mazzoni, Annalisa; Carvalho, Ricardo M.; Carrilho, Marcela; Tersariol, Ivarne L.; Nascimento, Fabio D.; Imazato, Satoshi; Tjäderhane, Leo; Breschi, Lorenzo; Tay, Franklin R; Pashley, David H.

    2014-01-01

    Objective Dentin matrices release ICTP and CTX fragments during collagen degradation. ICTP fragments are known to be produced by MMPs. CTX fragments are thought to come from cathepsin K activity. The purpose of this study was to determine if quaternary methacrylates (QAMs) can inhibit matrix MMPs and cathepsins. Methods Dentin beams were demineralizated, and dried to constant weight. Beams were incubated with rh-cathepsin B, K, L or S for 24 h at pH 7.4 to identify which cathepsins release CTX at neutral pH. Beams were dipped in ATA, an antimicrobial QAM to determine if it can inhibit dentin matrix proteases. Other beams were dipped in another QAM (MDPB) to determine if it produced similar inhibition of dentin proteases. Results Only beams incubated with cathepsin K lost more dry mass than the controls and released CTX. Dentin beams dipped in ATA and incubated for 1 week at pH 7.4, showed a concentration-dependent reduction in weight-loss. There was no change in ICTP release from control values, meaning that ATA did not inhibit MMPs. Media concentrations of CTX fell significantly at 15 wt% ATA indicating that ATA inhibits capthesins. Beams dipped in increasing concentrations of MDPB lost progressively less mass, showing that MDPB is a protease-inhibitor. ICTP released from controls or beams exposed to low concentrations were the same, while 5 or 10% MDPB significantly lowered ICTP production. CTX levels were strongly inhibited by 2.5–10% MDPB, indicating that MDPB is a potent inhibitor of both MMPs and cathepsin K. Significance CTX seems to be released from dentin matrix only by cathepsin K. MMPs and cathepsin K and B may all contribute to matrix degradation. PMID:25467953

  11. In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens▿

    PubMed Central

    Pucci, Michael J.; Podos, Steven D.; Thanassi, Jane A.; Leggio, Melissa J.; Bradbury, Barton J.; Deshpande, Milind

    2011-01-01

    ACH-702, a novel isothiazoloquinolone (ITQ), was assessed for antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and a Neisseria sp. but was less active against members of the Enterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well as Legionella pneumophila and Mycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10× MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple. In vivo efficacy was demonstrated against S. aureus with murine sepsis and thigh infection models, with decreases in the number of CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci, and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism of action include the following: low MIC values (≤0.25 μg/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of ≤0.5 μg/ml) against staphylococcal strains with two mutations in both gyrA and grlA, and low frequencies for the selection of higher-level resistance (<10−10). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates. PMID

  12. Isolation and characterization of pediocin AcH chimeric protein mutants with altered bactericidal activity.

    PubMed

    Miller, K W; Schamber, R; Osmanagaoglu, O; Ray, B

    1998-06-01

    A collection of pediocin AcH amino acid substitution mutants was generated by PCR random mutagenesis of DNA encoding the bacteriocin. Mutants were isolated by cloning mutagenized DNA into an Escherichia coli malE plasmid that directs the secretion of maltose binding protein-pediocin AcH chimeric proteins and by screening transformant colonies for bactericidal activity against Lactobacillus plantarum NCDO955 (K. W. Miller, R. Schamber, Y. Chen, and B. Ray, 1998. Appl. Environ. Microbiol. 64:14-20, 1998). In all, 17 substitution mutants were isolated at 14 of the 44 amino acids of pediocin AcH. Seven mutants (N5K, C9R, C14S, C14Y, G37E, G37R, and C44W) were completely inactive against the pediocin AcH-sensitive strains L. plantarum NCDO955, Listeria innocua Lin11, Enterococcus faecalis M1, Pediococcus acidilactici LB42, and Leuconostoc mesenteroides Ly. A C24S substitution mutant constructed by other means also was inactive against these bacteria. Nine other mutants (K1N, W18R, I26T, M31T, A34D, N41K, H42L, K43N, and K43E) retained from <1% to approximately 60% of wild-type activity when assayed against L. innocua Lin11. One mutant, K11E, displayed approximately 2. 8-fold-higher activity against this indicator. About one half of the mutations mapped to amino acids that are conserved in the pediocin-like family of bacteriocins. All four cysteines were found to be required for activity, although only C9 and C14 are conserved among pediocin-like bacteriocins. Several basic amino acids as well as nonpolar amino acids located within the hydrophobic C-terminal region also were found to be important. The mutations are discussed in the context of structural models that have been proposed for the bacteriocin.

  13. Isolation and characterisation of acetylcholinesterase inhibitors from Aquilaria subintegra for the treatment of Alzheimer's disease (AD).

    PubMed

    Bahrani, Hirbod; Mohamad, Jamaludin; Paydar, Mohammad Javad; Rothan, Hussin A

    2014-02-01

    Aquilaria subintegra, locally known as "Gaharu", belongs to the Thymelaeceae family. This plant's leaves have been claimed to be effective for the treatment of Alzheimer's disease (AD) by Malay traditional practitioner in Malaysia. In this research, the chloroform extracts of the leaves and stem of A. subintegra were tested for acetylcholinesterase (AChE) inhibitory activity. The Thin Layer Chromatography (TLC) results indicated the presence of phenols, flavonoids, terpenoids, and alkaloids compounds in the extracts. Analysis of the stem chloroform extracts with LCMS/MS displayed that it contains kaempferol 3,4,7-trimethyl ether. The AChE inhibitory activity of leaves and stem chloroform extracts and kaempferol were 80%, 93% and 85.8%, respectively. The Brine Shrimp Lethality Assay (BSLA) exhibited low to moderate toxicity of the chloroform extract from leaves (LC50=531.18 ± 49.53 μg/ml), the stem chloroform extract (LC50=407.34 ± 68.05 μg/ml) and kaempferol (LC50=762.41 ± 45.09 μg/ml). The extracts and kaempferol were not cytotoxic to human umbilical vein endothelial cells (HUVEC), human normal gastric epithelial cell line (GES-1) and human normal hepatic cell line (WRL-68). The effect of leaf and stem chloroform extracts and kaempferol were determined in the Radial Arm Maze (RAM) after administration by oral gavage to ICR male and female mice with valium-impaired memory. Administration of kaempferol to the mice significantly reduced the number of repeated entries into the arms of maze in males and females. In conclusion, the inhibition of AChE by leaf and stem chloroform extracts of A. subintegra could be due to the presence of kaempferol. This extract is safe for use as a natural AChE inhibitor as an alternative to berberine for the treatment of AD. PMID:24479629

  14. Isolation and characterisation of acetylcholinesterase inhibitors from Aquilaria subintegra for the treatment of Alzheimer's disease (AD).

    PubMed

    Bahrani, Hirbod; Mohamad, Jamaludin; Paydar, Mohammad Javad; Rothan, Hussin A

    2014-02-01

    Aquilaria subintegra, locally known as "Gaharu", belongs to the Thymelaeceae family. This plant's leaves have been claimed to be effective for the treatment of Alzheimer's disease (AD) by Malay traditional practitioner in Malaysia. In this research, the chloroform extracts of the leaves and stem of A. subintegra were tested for acetylcholinesterase (AChE) inhibitory activity. The Thin Layer Chromatography (TLC) results indicated the presence of phenols, flavonoids, terpenoids, and alkaloids compounds in the extracts. Analysis of the stem chloroform extracts with LCMS/MS displayed that it contains kaempferol 3,4,7-trimethyl ether. The AChE inhibitory activity of leaves and stem chloroform extracts and kaempferol were 80%, 93% and 85.8%, respectively. The Brine Shrimp Lethality Assay (BSLA) exhibited low to moderate toxicity of the chloroform extract from leaves (LC50=531.18 ± 49.53 μg/ml), the stem chloroform extract (LC50=407.34 ± 68.05 μg/ml) and kaempferol (LC50=762.41 ± 45.09 μg/ml). The extracts and kaempferol were not cytotoxic to human umbilical vein endothelial cells (HUVEC), human normal gastric epithelial cell line (GES-1) and human normal hepatic cell line (WRL-68). The effect of leaf and stem chloroform extracts and kaempferol were determined in the Radial Arm Maze (RAM) after administration by oral gavage to ICR male and female mice with valium-impaired memory. Administration of kaempferol to the mice significantly reduced the number of repeated entries into the arms of maze in males and females. In conclusion, the inhibition of AChE by leaf and stem chloroform extracts of A. subintegra could be due to the presence of kaempferol. This extract is safe for use as a natural AChE inhibitor as an alternative to berberine for the treatment of AD.

  15. Preliminary Geological Maps of the Ac-H-10 Rongo and Ac-H-15 Zadeni Quadrangles: An integrated Mapping Study Using Dawn Spacecraft Data

    NASA Astrophysics Data System (ADS)

    Platz, T.; Nathues, A.; Crown, D. A.; Mest, S. C.; Williams, D. A.; Hoffmann, M.; Schäfer, M.; Sizemore, H. G.; Yingst, R. A.; Ruesch, O.; Buczkowski, D.; Kneissl, T.; Schmedemann, N.; Hughson, K.; Preusker, F.; Russell, C. T.

    2015-12-01

    We used geologic mapping applied to Dawn spacecraft data as a tool to understand the geologic history of the Ac-H-10 Rongo and Ac-H-15 Zadeni quadrangles of dwarf planet Ceres. These regions, Rongo and Zadeni, are located between 22°S-22°N and 288°-360°E and 65-90°S and 0°-360°E, respectively. The Rongo Quadrangle hosts a number of features: 1) the southwest portion is dissected by curvilinear structures likely caused by Yalode basin formation; 2) the central part is marked by dome-like constructs up to 100 km across; 3) a peculiar bright, c.4 km tall, conical structure informally known as the 'pyramid'; 4) impact craters of various diameters appear moderately to highly degraded or are partially buried; and 5) bright material is primarily exposed in the central portion and often associated with craters. Rongo crater (68 km across) exhibits a central peak and scalloped walls indicative of its degraded appearance. The Zadeni Quadrangle is characterised by impact craters up to 130 km in diameter of which Zadeni crater is the largest. Impact craters across all sizes exhibit fresh to highly degraded morphologies or are partially buried. Many craters developed central peaks. Inter-crater plains are generally hummocky with isolated regions of smooth-textured surfaces. The south pole area (85-90°S) is poorly illuminated and may host a large impact structure. At the time of this writing geologic mapping was performed on Framing Camera (FC) mosaics from Approach (1.3 km/px) and Survey (415 m/px) orbits, including clear filter and colour images and digital terrain models derived from stereo images. In Fall 2015 images from the High Altitude Mapping Orbit (140 m/px) will be used to refine the mapping, followed by Low Altitude Mapping Orbit (35 m/px) starting in December 2015. Support of the Dawn Instrument, Operations, and Science Teams is acknowledged. This work is supported by grants from NASA through the Dawn project, and from the German and Italian Space Agencies.

  16. Age-dependency in hunting ability among the Ache of eastern Paraguay.

    PubMed

    Walker, Robert; Hill, Kim; Kaplan, Hillard; McMillan, Garnett

    2002-06-01

    This paper examines changes in hunting ability across the lifespan for the Ache of eastern Paraguay. Hunting ability is decomposed into two components-finding prey and probability of kill upon encounter- and analyzed for important prey species. Results support the argument that skill acquisition is an important aspect of the human foraging niche with hunting outcome variables reaching peaks surprisingly late in life, significantly after peaks in strength. The implications of this study are important for modeling the role of the human foraging niche in the co-evolution of various outstanding human life history characteristics such as large brains, long lifespans, and extended juvenile periods.

  17. Quaternary amines as nitrosamine precursors: a role for consumer products?

    PubMed

    Kemper, Jerome M; Walse, Spencer S; Mitch, William A

    2010-02-15

    Nitrosamine formation has been associated with wastewater-impacted waters, but specific precursors within wastewater effluents have not been identified. Experiments indicated that nitrosamines form in low yields from quaternary amines, and that the nitrosamines form from the quaternary amines themselves, not just lower order amine impurities. Polymeric and benzylated quaternary amines were more potent precursors than monomeric quaternary alkylamines. Pretreatment of quaternary amines with ozone or free chlorine, which deactivate lower order amine impurities, did not significantly reduce nitrosamine formation. The nitrosamine formation pathway is unclear but experiments indicated that transformation of quaternary amines to lower order amine precursors via Hofmann elimination was not involved. Experiments suggest that the pathway may involve quaternary amine degradation by amidogen or chloramino radicals formed from chloramines. Quaternary amines are significant constituents of consumer products, including shampoos, detergents, and fabric softeners. Although quaternary amines may be removed by sedimentation during wastewater treatment, their importance should be evaluated on a case-by-case basis. The high loadings from consumer products may enable the portion not removed to serve as precursors. PMID:20085252

  18. Quaternary Geologic Map of Connecticut and Long Island Sound Basin

    USGS Publications Warehouse

    Stone, Janet Radway; Schafer, John P.; London, Elizabeth Haley; DiGiacomo-Cohen, Mary L.; Lewis, Ralph S.; Thompson, Woodrow B.

    2005-01-01

    The Quaternary geologic map (sheet 1) and explanatory figures and cross sections (sheet 2) portray the geologic features formed in Connecticut during the Quaternary Period, which includes the Pleistocene (glacial) and Holocene (postglacial) Epochs. The Quaternary Period has been a time of development of many details of the landscape and of all the surficial deposits. At least twice in the late Pleistocene, continental ice sheets swept across Connecticut. Their effects are of pervasive importance to the present occupants of the land. The Quaternary geologic map illustrates the geologic history and the distribution of depositional environments during the emplacement of glacial and postglacial surficial deposits and the landforms resulting from those events.

  19. Muscle-specific kinase (MuSK) autoantibodies suppress the MuSK pathway and ACh receptor retention at the mouse neuromuscular junction

    PubMed Central

    Ghazanfari, Nazanin; Morsch, Marco; Reddel, Stephen W; Liang, Simon X; Phillips, William D

    2014-01-01

    Muscle-specific kinase (MuSK) autoantibodies from myasthenia gravis patients can block the activation of MuSK in vitro and/or reduce the postsynaptic localization of MuSK. Here we use a mouse model to examine the effects of MuSK autoantibodies upon some key components of the postsynaptic MuSK pathway and upon the regulation of junctional ACh receptor (AChR) numbers. Mice became weak after 14 daily injections of anti-MuSK-positive patient IgG. The intensity and area of AChR staining at the motor endplate was markedly reduced. Pulse-labelling of AChRs revealed an accelerated loss of pre-existing AChRs from postsynaptic AChR clusters without a compensatory increase in incorporation of (newly synthesized) replacement AChRs. Large, postsynaptic AChR clusters were replaced by a constellation of tiny AChR microaggregates. Puncta of AChR staining also appeared in the cytoplasm beneath the endplate. Endplate staining for MuSK, activated Src, rapsyn and AChR were all reduced in intensity. In the tibialis anterior muscle there was also evidence that phosphorylation of the AChR β-subunit-Y390 was reduced at endplates. In contrast, endplate staining for β-dystroglycan (through which rapsyn couples AChR to the synaptic basement membrane) remained intense. The results suggest that anti-MuSK IgG suppresses the endplate density of MuSK, thereby down-regulating MuSK signalling activity and the retention of junctional AChRs locally within the postsynaptic membrane scaffold. PMID:24860174

  20. Methadone's effect on nAChRs--a link between methadone use and smoking?

    PubMed

    Talka, Reeta; Tuominen, Raimo K; Salminen, Outi

    2015-10-15

    Methadone is a long-acting opioid agonist that is frequently prescribed as a treatment for opioid addiction. Almost all methadone maintenance patients are smokers, and there is a correlation between smoking habit and use of methadone. Methadone administration increases tobacco smoking, and heavy smokers use higher doses of methadone. Nevertheless, methadone maintenance patients are willing to quit smoking although their quit rates are low. Studies on nicotine-methadone interactions provide an example of the bedside-to-bench approach, i.e., observations in clinical settings have been studied experimentally in vivo and in vitro. In vivo studies have revealed the interplay between nicotine and the endogenous opioid system. At the receptor level, methadone has been shown to be an agonist of human α7 nAChRs and a non-competitive antagonist of human α4β2 and α3* nAChRs. These drugs do not have significant interactions at the level of drug metabolism, and thus the interaction is most likely pharmacodynamic. The net effect of the interaction may depend on individual characteristics because pharmacogenetic factors influence the disposition of both methadone and nicotine. PMID:26231941

  1. The significance of aches/pains among workers in an electronics factory.

    PubMed

    Ho, S F; Phoon, W H

    1997-06-01

    Three hundred and fifteen female workers with at least three months' employment history in a factory manufacturing disk drives were studied. Each worker completed a self-administered questionnaire on their personal particulars, hours of work, opinion on the work and the workplace and the presence and severity of aches/pains experienced over the past one month. One hundred and forty one (44.8%) of the workers had complaints of aches/pains. Of these, 81 (57.5%) reported an improvement in their symptoms during their off-days. 59 (41.8%) had symptoms affecting two or more sites. The most commonly affected sites were the hands and shoulders, followed by the head and back. There was no significant difference in the prevalence of symptoms between workers from the different work stations. Ninety four (66.7%) of these workers reported that the pains that were severe enough to affect their activities. 76 (53.9%) had to seek some form of medical treatment while 33 (23.4%) had to be on medical leave. However, the physical examinations of this group of workers were normal. The symptoms appeared to be influenced by their attitude towards work. A significantly higher number of workers with symptoms expressed dissatisfaction with work and had complaints of a noisy and cold environment. The study showed that workers' morale and the quality of the work environment may play an important role in improving their general well-being.

  2. Nicotinic Acetylcholine Receptor (nAChR) Dependent Chorda Tympani Taste Nerve Responses to Nicotine, Ethanol and Acetylcholine.

    PubMed

    Ren, Zuo Jun; Mummalaneni, Shobha; Qian, Jie; Baumgarten, Clive M; DeSimone, John A; Lyall, Vijay

    2015-01-01

    Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-β-erythroidine, and CP-601932 (a partial agonist of the α3β4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol.

  3. ACh and 5-HT stimulated thermogenesis at different core temperatures in the He-Cold hypothermic hamster.

    PubMed

    Simpson, C W; Resch, G E

    1985-08-01

    Hamsters in deep experimentally induced hypothermia, at body temperatures between 7 degrees C and 11.5 degrees C, were microinjected with 5-HT and ACh at brain sites in the anterior-preoptic area of the hypothalamus (AH/POA). ACh or 5-HT was injected into an AH/POA site at different starting core temperatures in different groups of hypothermic hamsters. Colonic temperatures (Tc) were maintained, following He-Cold induction, in a temperature controlled environmental chamber and measured with a YSI thermister probe and YSI telethermometer. Injections of either 5-HT or ACh at Tc's between 7.0 degrees C and 9.0 degrees C elicited only modest increases in Tc i.e., 0.3 degrees C--0.6 degrees C, respectively. As Tc increased, however, to ranges between 9.1 degrees C--10.0 degrees C and in different animals to greater than 10 degrees C both ACh and 5-HT at the same sites elicited significant increases in Tc, 1.5 degrees C for 5-HT and 2.2 degrees C for ACh compared to saline injections. These data suggest that at the lowest Tc's we are observing a "cold block" of temperature sensitive sites in the AH/POA. Increasing the starting Tc beyond 9.0 degrees C however, evokes significant increases in heat-gain following AH/POA injection of either ACh or 5-HT. These data are consistent with Myers' observations concerning the organization of heat-gain mechanisms at AH/POA sites. In addition, they suggest that both the afferent limb of the heat-gain circuit (5-HT) and the efferent limb of the circuit (ACh) are functionally impaired when Tc is close to the physiological limit in the He-Cold hypothermic hamster.

  4. Activity of nAChRs Containing α9 Subunits Modulates Synapse Stabilization via Bidirectional Signaling Programs

    PubMed Central

    Murthy, Vidya; Taranda, Julián; Elgoyhen, A. Belén; Vetter, Douglas E.

    2010-01-01

    Although the synaptogenic program for cholinergic synapses of the neuromuscular junction is well known, little is known of the identity or dynamic expression patterns of proteins involved in non-neuromuscular nicotinic synapse development. We have previously demonstrated abnormal presynaptic terminal morphology following loss of nicotinic acetylcholine receptor (nAChR) α9 subunit expression in adult cochleae. However, the molecular mechanisms underlying these changes have remained obscure. To better understand synapse formation and the role of cholinergic activity in the synaptogenesis of the inner ear, we exploit the nAChR α9 subunit null mouse. In this mouse, functional acetylcholine (ACh) neurotransmission to the hair cells is completely silenced. Results demonstrate a premature, effusive innervation to the synaptic pole of the outer hair cells in α9 null mice coinciding with delayed expression of cell adhesion proteins during the period of effusive contact. Collapse of the ectopic innervation coincides with an age-related hyperexpression pattern in the null mice. In addition, we document changes in expression of presynaptic vesicle recycling/trafficking machinery in the α9 null mice that suggests a bidirectional information flow between the target of the neural innervation (the hair cells) and the presynaptic terminal that is modified by hair cell nAChR activity. Loss of nAChR activity may alter transcriptional activity, as CREB binding protein expression is decreased coincident with the increased expression of N-Cadherin in the adult α9 null mice. Finally, by using mice expressing the nondesensitizing α9 L9′T point mutant nAChR subunit, we show that increased nAChR activity drives synaptic hyperinnervation. PMID:19790106

  5. Toluidine blue O is a potent inhibitor of human cholinesterases.

    PubMed

    Biberoglu, Kevser; Tek, Melike Yuksel; Ghasemi, Seyhan Turk; Tacal, Ozden

    2016-08-15

    In this study, the inhibitory effects of three phenothiazines [toluidine blue O (TBO), thionine (TH) and methylene violet (MV)] were tested on human plasma butyrylcholinesterase (BChE) and their inhibitory mechanisms were studied in detail. MV acted as a linear mixed type inhibitor of human BChE with Ki = 0.66 ± 0.06 μM and α = 13.6 ± 3.5. TBO and TH caused nonlinear inhibition of human BChE, compatible to double occupancy. Ki values estimated by nonlinear regression analysis for TBO and TH were 0.008 ± 0.003 μM and 2.1 ± 0.42 μM, respectively. The inhibitory potential of TBO was also tested on human erythrocyte AChE. TBO acted as a linear mixed type inhibitor of human AChE with Ki = 0.041 ± 0.005 μM and α = 1.6 ± 0.007. Using four site-directed BChE mutants, the role of peripheral anionic site residues of human BChE was also investigated in the binding of TBO to BChE. The peripheral anionic site mutants of BChE caused 16-69-fold increase in Ki value of TBO, compared to recombinant wild-type, suggesting that peripheral anionic site residues are involved in the binding of TBO to human BChE. In conclusion, TBO which is a potent inhibitor of human cholinesterases, may be a potential drug candidate for the treatment of Alzheimer's disease. PMID:27296777

  6. Shifting Sediment Sources in the Quaternary Nile

    NASA Astrophysics Data System (ADS)

    Woodward, Jamie; Macklin, Mark; Fielding, Laura; Millar, Ian; Williams, Martin

    2016-04-01

    Invited Paper The Nile basin contains the longest river channel system in the world and drains about one tenth of the African continent. A dominant characteristic of the modern Nile is the marked spatial and temporal variability in the flux of water and sediment. Because the major headwater basins of the Nile are linked to key elements of the global climate system, the sedimentary records in the basin have attracted good deal of attention from the Quaternary palaeoclimate and palaeohydrology communities. Various approaches (from heavy minerals to strontium isotopes) have been employed to examine present and past patterns of sediment yield in the basin. A good deal of work has been carried out on the long sediment records in the delta and offshore which provide high resolution archives of hydrological changes in the upstream basin as well fluctuations in the input of dust from the desert. The sediment load of the modern desert Nile (downstream of Khartoum) is dominated by sediment inputs from the Blue Nile (61 +/- 5%) and Atbara (35 +/- 4%), whilst the White Nile contribution is meagre (3 +/- 2%) (Padoan et al. 2011). Recent work has shown that these values were very different during humid phases of the Quaternary when stronger Northern Hemisphere summer insolation produced wetter conditions across North Africa. In the early Holocene, for example, the Nile floodplain in Northern Sudan shows a tributary wadi input of 40-50%. This paper will review three decades of work on the sediment delivery dynamics of the Quaternary Nile and explore their palaeoclimatic implications. Padoan, M., Garzanti, E., Harlavan, Y., Villa, I.M. (2011) Tracing Nile sediment sources by Sr and Nd isotope signatures (Uganda, Ethiopia, Sudan). Geochim. Cosmochim. Acta 75 (12), 3627-3644.

  7. Late Quaternary history of southern Chesapeake Bay

    SciTech Connect

    Colman, S.M.; Hobbs, C.H. III; Halka, J.P.

    1985-01-01

    More than 700 km of high-resolution, seismic-reflection profiles and sidescan-sonar images provide new information about the late Quaternary history of southern Chesapeake Bay. Sidescan-sonar images show that, excluding the nearshore zone, most of the bay bottom has a monotonously smooth surface, except that sand waves, ripples, and other bedforms occur in local areas affected by tidal currents. Seismic-reflection data show that the Quaternary stratigraphy of the southern part of the Bay is related primarily to the last cycle of sea-level change. The Quaternary section overlies an erosion surface cut deeply into gently seaward-dipping marine beds of Neogene age. Fluvial paleochannels, related to the last major low sea-level stand, are characterized by as much as 55 m of incision and by thin, irregular, terrace and channel-bottom deposits. Marine and estuarine deposits related to the Holocene transgression partially or fully bury the fluvial valleys and overlie the interfluves. A prominent feature of the Bay-mouth area is a wedge of sediment that has prograded into the Bay from the inner shelf. The common assumption--that the Chesapeake Bay is the drowned valley of the Pleistocene Susquehanna River--is only partially valid for the southern part of the Bay. The Bay mouth area, in general, is relatively young. The axial channel of the Bay is a modern tidal channel that is actively eroding Tertiary deposits and migrating toward the south and west; it is unrelated to older fluvial channels. Also, the positions of the modern axial channel and the last two fluvial paleochannels indicate long-term southward migration of the Bay mouth.

  8. Quaternary vertebrates from Greenland: A review

    NASA Astrophysics Data System (ADS)

    Bennike, Ole

    Remains of fishes, birds and mammals are rarely reported from Quaternary deposits in Greenland. The oldest remains come from Late Pliocene and Early Pleistocene deposits and comprise Atlantic cod, hare, rabbit and ringed seal. Interglacial and interstadial deposits have yielded remains of cod, little auk, collared lemming, ringed seal, reindeer and bowhead whale. Early and Mid-Holocene finds include capelin, polar cod, red fish, sculpin, three-spined stickleback, Lapland longspur, Arctic hare, collared lemming, wolf, walrus, ringed seal, reindeer and bowhead whale. It is considered unlikely that vertebrates could survive in Greenland during the peak of the last glaciation, but many species had probably already immigrated in the Early Holocene.

  9. Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice.

    PubMed

    Somm, Emmanuel; Guérardel, Audrey; Maouche, Kamel; Toulotte, Audrey; Veyrat-Durebex, Christelle; Rohner-Jeanrenaud, Françoise; Maskos, Uwe; Hüppi, Petra S; Schwitzgebel, Valérie M

    2014-05-01

    Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of α7 and β2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in α7β2nAChR(-/-) mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. α7β2nAChR(-/-) mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in α7β2nAChR(-/-) mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to α7nAChR(-/-) mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of α7β2nAChR(-/-) mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central β2nAChR deficiency.

  10. Development of 3D-QSAR Model for Acetylcholinesterase Inhibitors Using a Combination of Fingerprint, Molecular Docking, and Structure-Based Pharmacophore Approaches.

    PubMed

    Lee, Sehan; Barron, Mace G

    2015-11-01

    Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based approaches have been successfully applied to AChE inhibitors (AChEIs). The major limitation of these approaches has been the small applicability domain due to the lack of structural diversity in the training set. In this study, we developed a 3 dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitory activity of 89 reversible and irreversible AChEIs including drugs and insecticides. A 3D-fingerprint descriptor encoding protein-ligand interactions was developed using molecular docking and structure-based pharmacophore to rationalize the structural requirements responsible for the activity of these compounds. The obtained 3D-QSAR model exhibited high correlation value (R(2) = 0.93) and low mean absolute error (MAE = 0.32 log units) for the training set (n = 63). The model was predictive across a range of structures as shown by the leave-one-out cross-validated correlation coefficient (Q(2) = 0.89) and external validation results (n = 26, R(2) = 0.89, and MAE = 0.38 log units). The model revealed that the compounds with high inhibition potency had proper conformation in the active site gorge and interacted with key amino acid residues, in particular Trp84 and Phe330 at the catalytic anionic site, Trp279 at the peripheral anionic site, and Gly118, Gly119, and Ala201 at the oxyanion hole. The resulting universal 3D-QSAR model provides insight into the multiple molecular interactions determining AChEI potency that may guide future chemical design and regulation of toxic AChEIs.

  11. Development of 3D-QSAR Model for Acetylcholinesterase Inhibitors Using a Combination of Fingerprint, Molecular Docking, and Structure-Based Pharmacophore Approaches.

    PubMed

    Lee, Sehan; Barron, Mace G

    2015-11-01

    Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based approaches have been successfully applied to AChE inhibitors (AChEIs). The major limitation of these approaches has been the small applicability domain due to the lack of structural diversity in the training set. In this study, we developed a 3 dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitory activity of 89 reversible and irreversible AChEIs including drugs and insecticides. A 3D-fingerprint descriptor encoding protein-ligand interactions was developed using molecular docking and structure-based pharmacophore to rationalize the structural requirements responsible for the activity of these compounds. The obtained 3D-QSAR model exhibited high correlation value (R(2) = 0.93) and low mean absolute error (MAE = 0.32 log units) for the training set (n = 63). The model was predictive across a range of structures as shown by the leave-one-out cross-validated correlation coefficient (Q(2) = 0.89) and external validation results (n = 26, R(2) = 0.89, and MAE = 0.38 log units). The model revealed that the compounds with high inhibition potency had proper conformation in the active site gorge and interacted with key amino acid residues, in particular Trp84 and Phe330 at the catalytic anionic site, Trp279 at the peripheral anionic site, and Gly118, Gly119, and Ala201 at the oxyanion hole. The resulting universal 3D-QSAR model provides insight into the multiple molecular interactions determining AChEI potency that may guide future chemical design and regulation of toxic AChEIs. PMID:26202430

  12. Evidence for the exclusive expression of functional homomeric α7 nAChRs in hypothalamic histaminergic tuberomammillary neurons in rats.

    PubMed

    Tischkau, Shelley; Mhaskar, Yashanad; Uteshev, Victor V

    2014-03-20

    Hypothalamic histaminergic tuberomammillary (TM) neurons in rats express high densities of nicotinic acetylcholine receptors (nAChRs) whose Ca(2+) permeability, kinetic and pharmacological properties are similar to those of heterologous homomeric α7 nAChRs. However, native α7 nAChR subunits can co-assemble with β or α5 nAChR subunits to form functional heteromeric α7-containing α7β or α7α5 nAChRs with kinetics and pharmacology similar to those of α7 homomers. Therefore, although TM nAChRs have been used as an ex vivo model of functional α7 homomers, the molecular makeup of TM nAChRs has not been determined and the expression of functional α7-containing heteromers in TM neurons has not been excluded. To determine the profile of TM nAChR subunit transcripts, we have conducted single-cell qRT-PCR experiments using acutely dissociated TM neurons in rats. TM neurons were found to express transcripts of only principal α3, α6 and α7 nAChR subunits. Transcripts of other known mammalian neuronal subunits (α2, α4-5, α9-10, β2-4) were not detected. In the absence of β and α5 subunits, the expression of functional α7-containing heteromers in TM neurons is highly unlikely because principal α3, α6 and α7 nAChR subunits alone are not known to form functional heteromeric nAChRs. These results support the exclusive expression of native functional α7 homomers in rat TM neurons and introduce these neurons as a unique reliable source of native functional homomeric α7 nAChRs suitable for ex vivo and in vitro pharmacological assays in developing selective α7 nAChR agents.

  13. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Quaternary ammonium chloride combination. 172.165 Section 172.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  14. 40 CFR 721.10582 - Quaternary ammonium compound (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Quaternary ammonium compound (generic... Specific Chemical Substances § 721.10582 Quaternary ammonium compound (generic). (a) Chemical substance and... ammonium compound (PMN P-10-571) is subject to reporting under this section for the significant new...

  15. 40 CFR 721.10582 - Quaternary ammonium compound (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Quaternary ammonium compound (generic... Specific Chemical Substances § 721.10582 Quaternary ammonium compound (generic). (a) Chemical substance and... ammonium compound (PMN P-10-571) is subject to reporting under this section for the significant new...

  16. 40 CFR 721.10511 - Quaternary ammonium salts (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Quaternary ammonium salts (generic... Specific Chemical Substances § 721.10511 Quaternary ammonium salts (generic). (a) Chemical substance and... ammonium salts (PMNs P-07-320, P-07-321, P-07-322, P-07-323, and P-07-324) are subject to reporting...

  17. 40 CFR 721.10511 - Quaternary ammonium salts (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Quaternary ammonium salts (generic... Specific Chemical Substances § 721.10511 Quaternary ammonium salts (generic). (a) Chemical substance and... ammonium salts (PMNs P-07-320, P-07-321, P-07-322, P-07-323, and P-07-324) are subject to reporting...

  18. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Quaternary ammonium chloride combination. 172.165 Section 172.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  19. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Quaternary ammonium chloride combination. 172.165 Section 172.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  20. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Quaternary ammonium chloride combination. 172.165 Section 172.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  1. Going up in Smoke? A Review of nAChRs-based Treatment Strategies for Improving Cognition in Schizophrenia

    PubMed Central

    Boggs, Douglas L.; Carlson, Jon; Cortes-Briones, Jose; Krystal, John H.; D’Souza, D. Cyril

    2015-01-01

    Cognitive impairment is known to be a core deficit in schizophrenia. Existing treatments for schizophrenia have limited efficacy against cognitive impairment. The ubiquitous use of nicotine in this population is thought to reflect an attempt by patients to self-medicate certain symptoms associated with the illness. Concurrently there is evidence that nicotinic receptors that have lower affinity for nicotine are more important in cognition. Therefore, a number of medications that target nicotinic acetylcholine receptors (nAChRs) have been tested or are in development. In this article we summarize the clinical evidence of nAChRs dysfunction in schizophrenia and review clinical studies testing either nicotine or nicotinic medications for the treatment of cognitive impairment in schizophrenia. Some evidence suggests beneficial effects of nAChRs based treatments for the attentional deficits associated with schizophrenia. Standardized cognitive test batteries have failed to capture consistent improvements from drugs acting at nAChRs. However, more proximal measures of brain function, such as ERPs relevant to information processing impairments in schizophrenia, have shown some benefit. Further work is necessary to conclude that nAChRs based treatments are of clinical utility in the treatment of cognitive deficits of schizophrenia. PMID:24345265

  2. Nicotinic acetylcholine receptors: a comparison of the nAChRs of Caenorhabditis elegans and parasitic nematodes.

    PubMed

    Holden-Dye, Lindy; Joyner, Michelle; O'Connor, Vincent; Walker, Robert J

    2013-12-01

    Nicotinic acetylcholine receptors (nAChRs) play a key role in the normal physiology of nematodes and provide an established target site for anthelmintics. The free-living nematode, Caenorhabditis elegans, has a large number of nAChR subunit genes in its genome and so provides an experimental model for testing novel anthelmintics which act at these sites. However, many parasitic nematodes lack specific genes present in C. elegans, and so care is required in extrapolating from studies using C. elegans to the situation in other nematodes. In this review the properties of C. elegans nAChRs are reviewed and compared to those of parasitic nematodes. This forms the basis for a discussion of the possible subunit composition of nAChRs from different species of parasitic nematodes. Currently our knowledge on this is largely based on studies using heterologous expression and pharmacological analysis of receptor subunits in Xenopus laevis oocytes. It is concluded that more information is required regarding the subunit composition and pharmacology of endogenous nAChRs in parasitic nematodes. PMID:23500392

  3. Geological Mapping of the Ac-H-10 Rongo and Ac-H-15 Zadeni quadrangles of Ceres from NASA's Dawn Mission.

    NASA Astrophysics Data System (ADS)

    Platz, Thomas; Nathues, Andreas; Sizemore, Hanna; Ruesch, Ottaviano; Hoffmann, Martin; Schaefer, Michael; Crown, David; Mest, Scott; Aileen Yingst, R.; Williams, David; Buczkowski, Debra; Hughson, Kynan; Kneissl, Thomas; Schmedemann, Nico; Schorghofer, Norbert; Nass, Andrea; Preusker, Frank; Russell, Christopher

    2016-04-01

    On March 6, 2015 NASA's Dawn spacecraft arrived at (1) Ceres, the largest object in the main asteroid belt. Dawn is studying the dwarf planet more than one year through successively lower orbits at increasing resolution. Main orbital phases include Survey Orbit, High Altitude Mapping Orbit (HAMO), and Low Altitude Mapping Orbit (LAMO) where Framing Camera (FC) [1] resolution increased from c.400 m/px to c.140 m/px and c.35 m/px, respectively. The Dawn Science Team is conducting geological mapping campaigns for Ceres (as done before for Vesta [2,3]) and includes the production of a Survey/HAMO-based global geological map and a series of 15 LAMO-based geological quadrangle maps. This abstract presents HAMO-based geological maps of Ac-H-10 Rongo (22°N-22°S, 288-360°E) and Ac-H-15 Zadeni (65°-90°S, 0°-360°E) quadrangles. The Rongo Quadrangle is located at the equatorial region and comprises the unique isolated mountain Ahuna Mons (10.5°S/316.0°E; formerly known as the pyramid), abundant impact craters spanning a range in diameters and states of preservation - from fresh to highly degraded - , and a number of tholi, which may represent surface expressions of sub-surface diapir intrusions. The SW portion of the quandrangle is characterised by Yalode (D=260 km) sourced ejecta. The Zadeni Quadrangle is dominated by the 122-km-diameter crater Zadeni located at 70.2°S/37.4°E) and a suite of mid-sized craters whose morphologies range from fresh to highly degraded. Portions of the quadrangle are covered by Urvara [4] and Yalode [5] ejecta materials. The South Polar Region is poorly illuminated and the South Pole itself is likely located within a larger impact structure. Future work of this mapping campaign includes revision of HAMO-based line work (e.g., contacts) with higher resolution LAMO data. Final interpretations regarding the geological histories of these two quadrangles will also be based on FC colour and stereo-derived topography data, VIR spectra as well

  4. Late Quaternary climate change shapes island biodiversity.

    PubMed

    Weigelt, Patrick; Steinbauer, Manuel Jonas; Cabral, Juliano Sarmento; Kreft, Holger

    2016-04-01

    Island biogeographical models consider islands either as geologically static with biodiversity resulting from ecologically neutral immigration-extinction dynamics, or as geologically dynamic with biodiversity resulting from immigration-speciation-extinction dynamics influenced by changes in island characteristics over millions of years. Present climate and spatial arrangement of islands, however, are rather exceptional compared to most of the Late Quaternary, which is characterized by recurrent cooler and drier glacial periods. These climatic oscillations over short geological timescales strongly affected sea levels and caused massive changes in island area, isolation and connectivity, orders of magnitude faster than the geological processes of island formation, subsidence and erosion considered in island theory. Consequences of these oscillations for present biodiversity remain unassessed. Here we analyse the effects of present and Last Glacial Maximum (LGM) island area, isolation, elevation and climate on key components of angiosperm diversity on islands worldwide. We find that post-LGM changes in island characteristics, especially in area, have left a strong imprint on present diversity of endemic species. Specifically, the number and proportion of endemic species today is significantly higher on islands that were larger during the LGM. Native species richness, in turn, is mostly determined by present island characteristics. We conclude that an appreciation of Late Quaternary environmental change is essential to understand patterns of island endemism and its underlying evolutionary dynamics. PMID:27027291

  5. Late Quaternary climate change shapes island biodiversity.

    PubMed

    Weigelt, Patrick; Steinbauer, Manuel Jonas; Cabral, Juliano Sarmento; Kreft, Holger

    2016-04-01

    Island biogeographical models consider islands either as geologically static with biodiversity resulting from ecologically neutral immigration-extinction dynamics, or as geologically dynamic with biodiversity resulting from immigration-speciation-extinction dynamics influenced by changes in island characteristics over millions of years. Present climate and spatial arrangement of islands, however, are rather exceptional compared to most of the Late Quaternary, which is characterized by recurrent cooler and drier glacial periods. These climatic oscillations over short geological timescales strongly affected sea levels and caused massive changes in island area, isolation and connectivity, orders of magnitude faster than the geological processes of island formation, subsidence and erosion considered in island theory. Consequences of these oscillations for present biodiversity remain unassessed. Here we analyse the effects of present and Last Glacial Maximum (LGM) island area, isolation, elevation and climate on key components of angiosperm diversity on islands worldwide. We find that post-LGM changes in island characteristics, especially in area, have left a strong imprint on present diversity of endemic species. Specifically, the number and proportion of endemic species today is significantly higher on islands that were larger during the LGM. Native species richness, in turn, is mostly determined by present island characteristics. We conclude that an appreciation of Late Quaternary environmental change is essential to understand patterns of island endemism and its underlying evolutionary dynamics.

  6. Geologic Mapping of the Ac-H-1 quadrangle of Ceres from NASA's Dawn mission

    NASA Astrophysics Data System (ADS)

    Rüsch, Ottaviano; McFadden, Lucy A.; Hiesinger, Harald; Scully, Jennifer; Kneissl, Thomas; Hughson, Kynan; Williams, David A.; Roatsch, Thomas; Platz, Thomas; Preusker, Frank; Schmedemann, Nico; Marchi, Simone; Jaumann, Ralf; Nathues, Andreas; Raymond, Carol A.; Russell, Christopher T.

    2016-04-01

    The Dawn Science Team is conducting a geologic mapping campaign for Ceres similar to that done for Vesta (1, 2), including production of a Survey- and High Altitude Mapping Orbit (HAMO)-based global map, and a series of 15 Low Altitude Mapping Orbit (LAMO)-based quadrangle maps. In this abstract, we present the geologic map and geologic evolution of the Ac-H-1 Asari Quadrangle. At the time of writing, LAMO images (35 m/pixel) are just becoming available. Thus, our geologic maps are based on HAMO images (140 m/pixel) and HAMO and Survey (400 m/pixel) digital terrain models (for topographic information) (3). Dawn Framing Camera (FC) color images are also used to provide context for map unit identification. The maps to be presented as posters will be updated from analyses of LAMO images. Ac-H-1 quadrangle covers the North Pole area: 65°N-90°N. Key characteristics of the study area are: (i) a high density of impact craters and (ii) only moderate topographic variations across the quadrangle. We measured a crater density of 9.8E-04 km-2 for crater diameters >10 km, the highest on Ceres measured so far. Topographic lows, reaching -4 km, correspond to the floors of impact craters with diameters up to 64 km. A few isolated topographic highs (plateaus), reaching ~5 km in altitude relative to the ellipsoid are present. Their irregular shape is often sculpted by impacts. A peculiar topographic rise is represented by Ysolo Mons: a ~5 km high and ~20 km wide mountain. No downslope striations are preserved on the Mons flanks, indicating an older surface relative to Ahuna Mons, a similar but morphologically fresh appearing mountain at the equator (quadrangle Ac-H-10, (4)). Several impact craters show central peaks and/or mass wasting deposits on their floor. Crater rims often display terraces. These morphologies show varying degrees of degradation. Uncommon crater morphologies are a smooth crater floor (crater located at 79°N-170°E) and a large mass wasting landform inside

  7. Functionality and stability data of detergent purified nAChR from Torpedo using lipidic matrixes and macroscopic electrophysiology.

    PubMed

    Padilla-Morales, Luis F; Colón-Sáez, José O; González-Nieves, Joel E; Quesada-González, Orestes; Lasalde-Dominicci, José A

    2016-03-01

    The presented data provides additional information about the assessment of affinity purified nicotinic acetylcholine receptor (nAChR) rich membrane solubilized with long chain (16 saturated carbons) lysophospholipid with glycerol headgroup (LFG-16). The assessment of stability and functionality of solubilized membrane protein is a critical step prior to further crystallization trails. One of the key factors for this task is the appropriate choice of a detergent that can support nAChR activity and stability comparable to the crude membranes. The stability of the nAChR-LFG-16 complex incorporated into lipid cubic phase (LCP) was monitored for a period of 30 days by means of fluorescence recovery after photobleaching (FRAP) and the functionality was evaluated after its incorporation into Xenopus oocyte by means of the two electrode voltage clamp technique. PMID:26870753

  8. Auger electron spectroscopy, secondary ion mass spectroscopy and optical characterization of a-C-H and BN films

    NASA Technical Reports Server (NTRS)

    Pouch, J. J.; Alterovitz, S. A.; Warner, J. D.

    1986-01-01

    The amorphous dielectrics a-C:H and BN were deposited on III-V semiconductors. Optical band gaps as high as 3 eV were measured for a-C:H generated by C4H10 plasmas; a comparison was made with bad gaps obtained from films prepared by CH4 glow discharges. The ion beam deposited BN films exhibited amorphous behavior with band gaps on the order of 5 eV. Film compositions were studied by Auger electron spectroscopy (AES), x-ray photoelectron spectroscopy (XPS) and secondary ion mass spectrometry (SIMS). The optical properties were characterized by ellipsometry, UV/VIS absorption, and IR reflection and transmission. Etching rates of a-C:H subjected to O2 dicharges were determined.

  9. Electron cyclotron resonance deposition and plasma diagnostics of a-Si:H and a-C:H films

    NASA Technical Reports Server (NTRS)

    Shing, Y. H.

    1989-01-01

    Amorphous silicon (a-Si:H) and amorphous carbon (a-C:H) films deposited by electron cyclotron resonance (ECR) microwave plasma-enhanced chemical vapor deposition are discussed. It is shown that the ECR microwave plasma deposition technique can produce a-Si:H films with material qualities similar to and with a deposition rate one order of magnitude higher than for films deposited by radio-frequency glow discharge. The ECR-deposited a-C:H films are characterized by fluorescence, IR, and Raman spectroscopy. In situ optical emission spectroscopy plasma diagnostics indicates that ECR plasmas have a strong emission at 434 nm, which indicates a higher chemical reactivity than radio-frequency glow discharge plasmas. The radio frequency bias to the substrate is found to play a critical role in determining the film structure and the carbon bonding configuration of ECR-deposited a-C:H films.

  10. Erosion of a-C:H in the afterglow of ammonia plasma

    NASA Astrophysics Data System (ADS)

    Drenik, Aleksander; Mourkas, Angelos; Zaplotnik, Rok; Primc, Gregor; Mozetič, Miran; Panjan, Peter; Alegre, Daniel; Tabarés, Francisco L.

    2016-07-01

    Amorphous hydrogenated carbon (a-C:H) deposits were eroded in the afterglow of a NH3 plasma, created with an inductively coupled RF generator in pure NH3 at the gas pressure of 50 Pa. The plasma system was characterised by optical emission spectroscopy and mass spectrometry, and the erosion process was monitored in-situ with a laser interferometry system. Based on the mass spectrometry measurements, the degree of dissociation of the NH3 molecules was estimated at 90% at the highest generator forward power in the discharge region, however the densities of N and H atoms were significantly smaller at the location of the sample holder. The erosion rates were found to increase with surface temperature and forward generator power. In the high dissociation regime, the composition of the afterglow and the reaction products highlight the role of N atoms in the erosion process.

  11. Rapid thermal annealing of Amorphous Hydrogenated Carbon (a-C:H) films

    NASA Technical Reports Server (NTRS)

    Alterovitz, Samuel A.; Pouch, John J.; Warner, Joseph D.

    1987-01-01

    Amorphous hydrogenated carbon (a-C:H) films were deposited on silicon and quartz substrates by a 30 kHz plasma discharge technique using methane. Rapid thermal processing of the films was accomplished in nitrogen gas using tungsten halogen light. The rapid thermal processing was done at several fixed temperatures (up to 600 C), as a function of time (up to 1800 sec). The films were characterized by optical absorption and by ellipsometry in the near UV and the visible. The bandgap, estimated from extrapolation of the linear part of a Tauc plot, decreases both with the annealing temperature and the annealing time, with the temperature dependence being the dominating factor. The density of states parameter increases up to 25 percent and the refractive index changes up to 20 percent with temperature increase. Possible explanations of the mechanisms involved in these processes are discussed.

  12. Deposition of a-C:H films on inner surface of high-aspect-ratio microchannel

    NASA Astrophysics Data System (ADS)

    Hirata, Yuki; Choi, Junho

    2016-08-01

    Hydrogenated amorphous carbon (a-C:H) films were prepared on inner surface of 100-μm-width microchannel by using a bipolar-type plasma based ion implantation and deposition. The microchannel was fabricated using a silicon plate, and two kinds of microchannels were prepared, namely, with a bottom layer (open at one end) and without a bottom layer (open at both ends). The distribution of thickness and hardness of films was evaluated by SEM and nanoindentation measurements, respectively, and the microstructures of films were evaluated by Raman spectroscopy. Furthermore, the behavior of ions and radicals was analyzed simultaneously by combining the calculation methods of Particle-In-Cell/Monte Carlo Collision and Direct Simulation Monte Carlo to investigate the coating mechanism for the microchannel. It was found that the film thickness decreased as the depth of the coating position increased in the microchannels where it is open at one end. The uniformity of the film thickness improved by increasing the negative pulse voltage because ions can arrive at the deeper part of the microchannel. In addition, the hardness increased as the depth of the coating position increased. This is because the radicals do not arrive at the deeper part of the microchannel, and the incident proportion of ions relative to that of radicals increases, resulting in a high hardness due to the amorphization of the film. The opening area of the microchannel where the aspect ratio is very small, radicals dominate the incident flux, whereas ions prevail over radicals above an aspect ratio of about 7.5. On the other hand, in the microchannels that are open at both ends, there were great improvements in uniformity of the film thickness, hardness, and the film structure. The a-C:H films were successfully deposited on the entire inner surface of a microchannel with an aspect ratio of 20.

  13. Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs

    PubMed Central

    Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon; Grady, Sharon R.; McIntosh, J. Michael; Brunzell, Darlene H.; Cannon, Jason R.; Drenan, Ryan M.

    2014-01-01

    α6β2* nAChRs in the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6β2* nAChRs (α6L9’S mice) that are hypersensitive to nicotine and endogenous acetylcholine (ACh). Evoked extracellular dopamine (DA) levels were enhanced in α6L9’S NAc slices compared to control, non-transgenic (nonTg) slices. Extracellular DA levels in both nonTg and α6L9’S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6β2* nAChR activation by ACh plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9’S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9’S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) compared to nonTg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE) were unchanged in α6L9’S compared to nonTg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9’S NAc. Overall, these results show that enhanced α6β2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels. PMID:24266758

  14. α7nAChR is expressed in satellite cells at different myogenic status during skeletal muscle wound healing in rats.

    PubMed

    Tian, Zhi-Ling; Jiang, Shu-Kun; Zhang, Miao; Wang, Meng; Li, Jiao-Yong; Zhao, Rui; Wang, Lin-Lin; Liu, Min; Li, Shan-Shan; Zhang, Meng-Zhou; Guan, Da-Wei

    2015-12-01

    Recent study has reported that α7 nicotine acetylcholine receptor (α7nAChR) is expressed in regenerated multinucleated myotubes. But the distribution of α7nAChR in satellite cells in different myogenic status is unknown. A preliminary study on the dynamic distribution of α7nAChR in satellite cells was performed by double indirect immunofluorescent procedures during skeletal muscle wound healing in rats. An animal model of skeletal muscle contusion was established in 40 Sprague-Dawley male rats. Samples were taken at 1, 3, 5, 7, 9, 13, 17 and 21 days after injury, respectively (five rats in each posttraumatic interval). Five rats were employed as control. In normal muscle specimens, weak immunoreactivity for α7nAChR was detected in a few satellite cells (considered as quiescent). α7nAChR-positive signals were observed in proliferated and differentiated satellite cells and regenerated multinucleated myotubes in the wounded areas. By morphometric analysis, the average number of α7nAChR+/Pax7+ and α7nAChR+/MyoD+ cells climaxed at 5 days post-injury. The average number of α7nAChR+/myogenin+ cells was significantly increased from 3 to 9 days post-injury as compared with other posttraumatic intervals. The protein level of α7nAChR maximized at 9 days post-injury, which implies that α7nAChR was associated with the satellite cells status. Our observations on expression of α7nAChR in satellite cells from quiescence to myotube formation suggest that α7nAChR may be involved in muscle regeneration by regulating satellite cell status.

  15. Association between Anti-Ganglionic Nicotinic Acetylcholine Receptor (gAChR) Antibodies and HLA-DRB1 Alleles in the Japanese Population

    PubMed Central

    Maeda, Yasuhiro; Migita, Kiyoshi; Higuchi, Osamu; Mukaino, Akihiro; Furukawa, Hiroshi; Komori, Atsumasa; Nakamura, Minoru; Hashimoto, Satoru; Nagaoka, Shinya; Abiru, Seigo; Yatsuhashi, Hiroshi; Matsuo, Hidenori; Kawakami, Atsushi; Yasunami, Michio; Nakane, Shunya

    2016-01-01

    Background/Aims Anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies are observed in autoimmune diseases, as well as in patients with autoimmune autonomic ganglionopathy. However, the genetic background of anti-gAChR antibodies is unclear. Here, we investigated HLA alleles in autoimmune hepatitis (AIH) patients with or without anti-gAChR antibodies. Methodology/Principal Findings Genomic DNA from 260 patients with type-1 autoimmune hepatitis (AIH) were genotyped for HLA-A, B, DRB1, and DQB1 loci. Anti-gAChR antibodies in the sera form AIH patients were measured using the luciferase immunoprecipitation system, and examined allelic association in patients with or without anti-gAChR antibodies. Methodology/ Methods We detected anti-α3 or -β4 gAChR antibodies in 11.5% (30/260) of patients with AIH. Among AIH patients there was no significant association between HLA-A, B DQB1 alleles and the positivity for anti-gAChR antibodies. Whereas the HLA-DRB1*0403 allele showed a significantly increased frequency in AIH patients with anti-gAChR antibodies compared with those without anti-gAChR antibodies. Conclusions/Significance The frequency of the HLA-DRB1*0403 allele differed among Japanese patients with AIH according to the presence or absence of anti-gAChR antibodies. Our findings suggest that particular HLA class II molecules might control the development of anti-gAChR antibodies in the autoimmune response to gAChR. PMID:26807576

  16. Differential Cytokine Changes in Patients with Myasthenia Gravis with Antibodies against AChR and MuSK

    PubMed Central

    Yilmaz, Vuslat; Oflazer, Piraye; Aysal, Fikret; Durmus, Hacer; Poulas, Kostas; Yentur, Sibel P.; Gulsen-Parman, Yesim; Tzartos, Socrates; Marx, Alexander; Tuzun, Erdem; Deymeer, Feza; Saruhan-Direskeneli, Güher

    2015-01-01

    Neuromuscular transmission failure in myasthenia gravis (MG) is most commonly elicited by autoantibodies (ab) to the acetylcholine receptor or the muscle-specific kinase, constituting AChR-MG and MuSK-MG. It is controversial whether these MG subtypes arise through different T helper (Th) 1, Th2 or Th17 polarized immune reactions and how these reactions are blunted by immunosuppression. To address these questions, plasma levels of cytokines related to various Th subtypes were determined in patients with AChR-MG, MuSK-MG and healthy controls (CON). Peripheral blood mononuclear cells (PBMC) were activated in vitro by anti-CD3, and cytokines were quantified in supernatants. In purified blood CD4+ T cells, RNA of various cytokines, Th subtype specific transcription factors and the co-stimulatory molecule, CD40L, were quantified by qRT-PCR. Plasma levels of Th1, Th2 and Th17 related cytokines were overall not significantly different between MG subtypes and CON. By contrast, in vitro stimulated PBMC from MuSK-MG but not AChR-MG patients showed significantly increased secretion of the Th1, Th17 and T follicular helper cell related cytokines, IFN-γ, IL-17A and IL-21. Stimulated expression of IL-4, IL-6, IL-10 and IL-13 was not significantly different. At the RNA level, expression of CD40L by CD4+ T cells was reduced in both AChR-MG and MuSK-MG patients while expression of Th subset related cytokines and transcription factors were normal. Immunosuppression treatment had two effects: First, it reduced levels of IL12p40 in the plasma of AChR-MG and MuSK-MG patients, leaving other cytokine levels unchanged; second, it reduced spontaneous secretion of IFN-γ and increased secretion of IL-6 and IL-10 by cultured PBMC from AChR-MG, but not MuSK-MG patients. We conclude that Th1 and Th17 immune reactions play a role in MuSK-MG. Immunosuppression attenuates the Th1 response in AChR-MG and MuSK-MG, but otherwise modulates immune responses in AChR-MG and MuSK-MG patients

  17. Acetaldehyde metabolism by liver mitochondrial ALDH from UChA and UChB rats: effect of inhibitors.

    PubMed

    Tampier, L; Sánchez, E; Quintanilla, M E

    1996-01-01

    We have observed that blood acetaldehyde (AcH) levels after an ethanol dose were significantly higher in disulfiram-pre-treated UChA (low ethanol consumer) than in UChB (high ethanol consumer) rats. In order to explore these results further, we studied the effect of disulfiram (300 mg/kg i.p.) and chlorpropamide (80) mg/kg i.p.) pre-treatment on blood AcH levels after oral ethanol (60 mmol/kg) and on AcH metabolism by liver mitochondrial aldehyde(s) dehydrogenase(s) from UChA and UChB rats. AcH metabolism by liver mitochondrial aldehyde dehydrogenase (ALDH) was studied by following AcH disappearance rate and the formation of NADH at 340 nm in the incubation medium. The results showed that chlorpropamide, like disulfiram, produced a higher blood AcH level consistent with a greater inhibition of the low-Km mitochondrial ALDH in the UChA rats than in the UChB rats. These drugs did not inhibit the high Km mitochondrial ALDH. Kinetic studies of mitochondrial ALDH show that low-Km mitochondrial ALDH from UChB rats exhibits a higher affinity for NAD than UChA rats. This observation could explain the different inhibition of ALDH by both drugs, assuming that the inhibitors reduce NAD availability, the rate limiting step in the mitochondrial ALDH oxidation.

  18. Converting maslinic acid into an effective inhibitor of acylcholinesterases.

    PubMed

    Schwarz, Stefan; Loesche, Anne; Lucas, Susana Dias; Sommerwerk, Sven; Serbian, Immo; Siewert, Bianka; Pianowski, Elke; Csuk, René

    2015-10-20

    During the last decade, maslinic acid has been evaluated for many biological properties, e.g. as an anti-tumor or an anti-viral agent but also as a nutraceutical. The potential of maslinic acid and related derivatives to act as inhibitors of acetyl- or butyryl-cholinesterase was examined in this communication in more detail. Cholinesterases do still represent an interesting group of target enzymes with respect to the investigation and treatment of the Alzheimer's disease and other dementia illnesses as well. Although other triterpenoic acids have successfully been tested for their ability to act as inhibitors of cholinesterases, up to now maslinic acid has not been part of such studies. For this reason, three series of maslinic acid derivatives possessing modifications at different centers were synthesized and subjected to Ellman's assay to determine their inhibitory strength and type of inhibitory action. While parent compound maslinic acid was no inhibitor in these assays, some of the compounds exhibited an inhibition of acetylcholinesterase in the single-digit micro-molar range. Two compounds were identified as inhibitors of butyrylcholinesterase showing inhibition constants comparable to those of galantamine, a drug often used in the treatment of Alzheimer's disease. Furthermore, additional selectivity as well as cytotoxicity studies were performed underlining the potential of several derivatives and qualifying them for further investigations. Docking studies revealed that the different kinetic behavior within the same compound series may be explained by the ability of the compounds to enter the active site gorge of AChE. PMID:26383128

  19. Quaternary coral reef refugia preserved fish diversity.

    PubMed

    Pellissier, Loïc; Leprieur, Fabien; Parravicini, Valeriano; Cowman, Peter F; Kulbicki, Michel; Litsios, Glenn; Olsen, Steffen M; Wisz, Mary S; Bellwood, David R; Mouillot, David

    2014-05-30

    The most prominent pattern in global marine biogeography is the biodiversity peak in the Indo-Australian Archipelago. Yet the processes that underpin this pattern are still actively debated. By reconstructing global marine paleoenvironments over the past 3 million years on the basis of sediment cores, we assessed the extent to which Quaternary climate fluctuations can explain global variation in current reef fish richness. Comparing global historical coral reef habitat availability with the present-day distribution of 6316 reef fish species, we find that distance from stable coral reef habitats during historical periods of habitat loss explains 62% of the variation in fish richness, outweighing present-day environmental factors. Our results highlight the importance of habitat persistence during periods of climate change for preserving marine biodiversity. PMID:24876495

  20. [Quaternary ammonium compounds--new occupational hazards].

    PubMed

    Lipińska-Ojrzanowska, Agnieszka; Walusiak-Skorupa, Jolanta

    2014-01-01

    Quaternary ammonium compounds (QACs, quats) belong to organic ionic chemical agents which display unique properties of both surfactants and disinfectants. Their wide distribution in the work environment and also in private households brings about new occupational hazards. This paper reviews reports about the health effects of QACs. QACs could play a role of sensitizers and irritants to the skin and mucous membranes. It is suspected that particular QACs can display an immunologic cross-reactivity between each other and with other chemical compounds containing ammonium ion, such as muscle relaxants widely used in anesthesia. They may promote the development of airway allergy, however, the background mechanisms are still unclear and need to be further investigated. Until now, a few cases of occupational asthma induced by QACs have been described and their involvement in contact dermatitis has been documented. The possibility of anaphylaxis due to QACs cannot be excluded as well. PMID:25812396

  1. Suggested terminology for Quaternary dating methods

    USGS Publications Warehouse

    Colman, Steven M.; Pierce, K.L.; Birkeland, P.W.

    1987-01-01

    Classification of Quaternary dating methods should be based on the level of quantitative information and the degree of confidence contained in the age estimates produced by the dating methods. We recommend the use of the terms numerical-age, calibrated-age, relative-age, and correlated-age to describe these levels. We also classify dating methods by type into sideral, isotopic, radiogenic, chemical and biological, geomorphic, and correlation methods. The use of "absolute" is inappropriate for most dating methods, and should be replaced by "numerical." The use of "date" should be minimized in favor of "age" or "age estimate." We recommend use of the abbreviations ka and Ma for most ages; calender dates can be used where appropriate and yr B.P. can be used for radiocarbon ages. ?? 1987.

  2. Quaternary geology of Avery Island, Louisiana

    SciTech Connect

    Autin, W.J.; McCulloh, R.P.; Davison, A.T.

    1986-09-01

    Avery Island, one of the Five Islands salt domes of south-central Louisiana, is a piercement-type dome that has been uplifted from several kilometers' depth. It is nearly circular in plan with a maximum elevation approximately 50 m above the surrounding coastal marsh. Dissection has produced a terrain of gullies and steep slopes. The features identified indicate a complex geologic history for Avery Island. Deposition of late Pleistocene sediments in a low-relief alluvial plain and subsequent soil development predate domal uplift. The stratigraphy of loess and colluvial silts indicates the island was emergent during loess depositions. The degree of dissection, distribution of colluvium, and shearing of Quaternary sediments reflects continual uplift after loess deposition.

  3. Association between acetylcholinesterase inhibitors and risk of stroke in patients with dementia

    PubMed Central

    Lin, Yi-Ting; Wu, Ping-Hsun; Chen, Cheng-Sheng; Yang, Yi-Hsin; Yang, Yuan-Han

    2016-01-01

    Patients with dementia are at increased risk of stroke. Acetylcholinesterase inhibitors (AChEIs) have endothelial function protection effects and anti-inflammatory properties. We investigated the ischemic stroke risk in AChEIs use in dementia patients without stroke history. Using Taiwan National Health Insurance Database from 1999 to 2008, 37,352 dementia patients over 50 years old without stroke history were eligible. The results were analyzed by propensity score–matched Cox proportional hazard models with competing risk adjustment. AChEIs users had lower incidence of ischemic stroke (160.3/10,000 person-years), compared to the propensity score–matched reference (240.8/10,000 person-years). The adjusted hazard ratio for ischemic stroke based on propensity score–matched Cox proportional hazard model was 0.508 (95% confidence interval, 0.434–0.594; P < 0.001). There was no significant difference in all-cause mortality between AChEIs users and nonusers. In conclusion, among dementia patients without previous ischemic stroke history, AChEIs treatment was associated with a decreased risk of ischemic stroke but not greater survival. PMID:27377212

  4. Antimicrobial Polymeric Materials with Quaternary Ammonium and Phosphonium Salts

    PubMed Central

    Xue, Yan; Xiao, Huining; Zhang, Yi

    2015-01-01

    Polymeric materials containing quaternary ammonium and/or phosphonium salts have been extensively studied and applied to a variety of antimicrobial-relevant areas. With various architectures, polymeric quaternary ammonium/phosphonium salts were prepared using different approaches, exhibiting different antimicrobial activities and potential applications. This review focuses on the state of the art of antimicrobial polymers with quaternary ammonium/phosphonium salts. In particular, it discusses the structure and synthesis method, mechanisms of antimicrobial action, and the comparison of antimicrobial performance between these two kinds of polymers. PMID:25667977

  5. Resistance to Inhibitors of Cholinesterase 3 (Ric-3) Expression Promotes Selective Protein Associations with the Human α7-Nicotinic Acetylcholine Receptor Interactome

    PubMed Central

    Mulcahy, Matthew J.; Blattman, Sydney B.; Barrantes, Francisco J.; Lukas, Ronald J.; Hawrot, Edward

    2015-01-01

    The α7-nicotinic acetylcholine receptor (α7-nAChR) is a ligand-gated ion channel widely expressed in vertebrates and is associated with numerous physiological functions. As transmembrane ion channels, α7-nAChRs need to be expressed on the surface of the plasma membrane to function. The receptor has been reported to associate with proteins involved with receptor biogenesis, modulation of receptor properties, as well as intracellular signaling cascades and some of these associated proteins may affect surface expression of α7-nAChRs. The putative chaperone resistance to inhibitors of cholinesterase 3 (Ric-3) has been reported to interact with, and enhance the surface expression of, α7-nAChRs. In this study, we identified proteins that associate with α7-nAChRs when Ric-3 is expressed. Using α-bungarotoxin (α-bgtx), we isolated and compared α7-nAChR-associated proteins from two stably transfected, human tumor-derived cell lines: SH-EP1-hα7 expressing human α7-nAChRs and the same cell line further transfected to express Ric-3, SH-EP1-hα7-Ric-3. Mass spectrometric analysis of peptides identified thirty-nine proteins that are associated with α7-nAChRs only when Ric-3 was expressed. Significantly, and consistent with reports of Ric-3 function in the literature, several of the identified proteins are involved in biological processes that may affect nAChR surface expression such as post-translational processing of proteins, protein trafficking, and protein transport. Additionally, proteins affecting the cell cycle, the cytoskeleton, stress responses, as well as cyclic AMP- and inositol triphosphate-dependent signaling cascades were identified. These results illuminate how α-bgtx may be used to isolate and identify α7-nAChRs as well as how the expression of chaperones such as Ric-3 can influence proteins associating with α7-nAChRs. These associating proteins may alter activities of α7-nAChRs to expand their functionally-relevant repertoire as well as to affect

  6. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

    PubMed Central

    Inoue, Tsuyoshi; Abe, Chikara; Sung, Sun-sang J.; Moscalu, Stefan; Jankowski, Jakub; Huang, Liping; Ye, Hong; Guyenet, Patrice G.

    2016-01-01

    The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The inflammatory reflex referred to as the cholinergic antiinflammatory pathway regulates innate and adaptive immunity, and modulation of this reflex by vagus nerve stimulation (VNS) is effective in various inflammatory disease models, such as rheumatoid arthritis and inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates kidney ischemia-reperfusion injury (IRI), which promotes the release of proinflammatory molecules. Stimulation of vagal afferents or efferents in mice 24 hours before IRI markedly attenuated acute kidney injury (AKI) and decreased plasma TNF. Furthermore, this protection was abolished in animals in which splenectomy was performed 7 days before VNS and IRI. In mice lacking α7nAChR, prior VNS did not prevent IRI. Conversely, adoptive transfer of VNS-conditioned α7nAChR splenocytes conferred protection to recipient mice subjected to IRI. Together, these results demonstrate that VNS-mediated attenuation of AKI and systemic inflammation depends on α7nAChR-positive splenocytes. PMID:27088805

  7. Effect of nicotinic acetylcholine receptor alpha 1 (nAChRα1) peptides on rabies virus infection in neuronal cells.

    PubMed

    Sajjanar, Basavaraj; Saxena, Shikha; Bisht, Deepika; Singh, Arvind Kumar; Manjunatha Reddy, G B; Singh, Rajendra; Singh, R P; Kumar, Satish

    2016-06-01

    Rabies virus (RABV) is neurotropic and causes acute progressive encephalitis. Herein, we report the interaction of nAChRα1-subunit peptides with RABV and the effect of these peptides on RABV infection in cultured neuronal cells. Peptide sequences derived from torpedo, bovine, human and rats were synthesized and studied for their interactions with RABV using virus capture ELISA and peptide immunofluorescence. The results showed specific binding of the nAChRα1-subunit peptides to the RABV. In the virus adsorption assay, these peptides were found to inhibit the attachment of the RABV to the neuronal cells. The nAChRα1-subunit peptides inhibited the RABV infection and reduced viral gene expression in the cultured neuroblastoma (N2A) cells. Torpedo peptide sequence (T-32) had highest antiviral effect (IC50=14±3.01μM) compared to the other peptides studied. The results of the study indicated that nAChRα1-subunit peptides may act as receptor decoy molecules and inhibit the binding of virus to the native host cell receptors and hence may reduce viral infection. PMID:26656837

  8. R86Q, a mutation in BmAChE3 yielding a Rhipicephalus microplus organophosphate-insensitive acetylcholinesterase

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations were identified in the sequence encoding the acetylcholinesterase, BmAChE3, in strains of Rhipicephalus (Boophilus) microplus (Canestrini) resistant or susceptible to orgaonphosphorus acaricide. The mutation which appeared most frequently in the organophosphorus-resistant San Román strain...

  9. Myopathic changes detected by quantitative electromyography in patients with MuSK and AChR positive myasthenia gravis.

    PubMed

    Nikolic, Ana; Basta, Ivana; Stojanovic, Vidosava Rakocevic; Stevic, Zorica; Peric, Stojan; Lavrnic, Dragana

    2016-05-01

    Myopathic changes are frequent a electrophysiological finding in patients with muscle specific tyrosine kinase (MuSK) positive myasthenia gravis (MG). The aim of this study was to explore the importance of quantitative electromyography (EMG) in the detection of myopathic changes in MuSK MG patients. Classical and quantitative EMG were performed in 31 MuSK and 28 acetylcholine receptor (AChR) positive MG patients, matched by sex, age, disease duration and severity. Classical EMG revealed the presence of myopathic changes more frequently in MuSK MG compared to AChR MG patients, especially in the facial muscles. Quantitative EMG registered myopathic lesions more frequently than classical EMG, but the frequency was similar between MuSK and AChR MG patients. Quantitative EMG revealed myopathic changes in the majority of both MuSK and AChR positive MG patients. This examination is sensitive, but it cannot be used to differentiate between MG patients belonging to the different disease groups. It should not be used in isolation. Rather, it should complement classical EMG in the detection of myopathic changes.

  10. Geological Mapping of the Ac-H-9 Occator Quadrangle of Ceres from NASA Dawn Mission

    NASA Astrophysics Data System (ADS)

    Buczkowski, Debra; Williams, David; Scully, Jennifer; Mest, Scott; Crown, David; Aileen Yingst, R.; Schenk, Paul; Jaumann, Ralf; Roatsch, Thomas; Preusker, Frank; Platz, Thomas; Nathues, Andreas; Hoffmann, Martin; Schaefer, Michael; Marchi, Simone; De Sanctis, M. Cristina; Raymond, Carol; Russell, Chris

    2016-04-01

    As was done at Vesta [1], the Dawn Science Team is conducting a geological mapping cam-paign at Ceres during the nominal mission, including iterative mapping using data obtained dur-ing each orbital phase. We are using geological mapping as a method to identify the geologic processes that have modified the surface of dwarf planet Ceres. We here present the geology of the Ac-H-9 Occator quadrangle, located between 22°S-22°N and 216-288°E. The Ac-H-9 map area is completely within the topographically high region on Ceres named Erntedank Planum. It is one of two longitudinally distinct regions where ESA Herschel space telescope data suggested a release of water vapor [2]. The quadrangle includes several other notable features, including those discussed below. Occator is the 92 km diameter crater that hosts the "Bright Spot 5" that was identified in Hubble Space Telescope data [3], which is actually comprised of multiple bright spots on the crater floor. The floor of Occator is cut by linear fractures, while circumferential fractures are found in the ejecta and on the crater walls. The bright spots are noticeably associated with the floor fractures, although the brightest spot is associated with a central pit [4]. Multiple lobate flows are observed on the crater floor; these appear to be sourced from the center of the crater. The crater has a scalloped rim that is cut by regional linear structures, displaying a cross-section of one structure in the crater wall. Color data show that the Occator ejecta have multiple colors, generally related to changes in morphology. Azacca is a 50 km diameter crater that has a central peak and bright spots on its floor and within its ejecta. Like Occator, Azacca has both floor fractures and circumferential fractures in its ejecta and crater walls. Also like Occator, the Azacca ejecta is multi-colored with variable morphology. Linear structures - including grooves, pit crater chains, fractures and troughs - cross much of the eastern

  11. Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers.

    PubMed

    Hamulakova, Slavka; Imrich, Jan; Janovec, Ladislav; Kristian, Pavol; Danihel, Ivan; Holas, Ondrej; Pohanka, Miroslav; Böhm, Stanislav; Kozurkova, Maria; Kuca, Kamil

    2014-09-01

    A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.

  12. Development of radiohalogenated muscarinic ligands for the in vivo imaging of m-AChR by nuclear medicine techniques

    SciTech Connect

    McPherson, D.W.; Luo, H.; Knapp, F.F. Jr.

    1994-06-01

    Alterations in the density of acetylcholinergic muscarinic receptors (m-AChR) have been observed in various dementias. This has spurred interest in the development of radiohalogenated ligands which can be used for the non-invasive in vivo detection of m-AChR by nuclear medicine techniques. We have developed a new ligand 1-azabicyclo[2.2.2]oct-3-yl ({alpha}-hydroxy-{alpha}-(1-iodo-1-propen-3-yl)-{alpha}-phenylacetate (IQNP,12) which demonstrates high affinity for the muscarinic receptor. When labeled with radioiodine it has been shown to be selective and specific for m-ACHR. Initial studies on the separation and in vivo evaluation of the various isomers of IQNP have shown that the stereochemistry of the chiral centers and the configuration around the double bond play an important role in m-AChR subtype specificity. In vivo evaluation of these stereoisomers demonstrate that E-(R,R)-IQNP has a high affinity for the M{sub 1} muscarinic subtype while Z-(R,R)-IQNP demonstrate a high affinity for M{sub 1} and M{sub 2} receptor subtypes. These data demonstrate IQNP (12) has potential for use in the non-evasive in vivo detection of m-AChR by single photon emission computed tomography (SPECT). A brominated analogue, ``BrQNP,`` in which the iodine has been replaced by a bromine atom, has also been prepared and was shown to block the in vivo uptake of IQNP in the brain and heart and therefore has potential for positron emission tomographic (PET) studies of m-AChR.

  13. Inhibition of ACh release at an Aplysia synapse by neurotoxic phospholipases A2: specific receptors and mechanisms of action.

    PubMed Central

    Fossier, P; Lambeau, G; Lazdunski, M; Baux, G

    1995-01-01

    1. Monochain (OS2) and multichain (taipoxin) neurotoxic phospholipases A2 (PLA2), purified from taipan snake venom, both inhibited ACh release at a concentration of 20 nM (90% inhibition in 2 h) at an identified synapse from buccal ganglion of Aplysia californica. 2. The Na+ current was unchanged upon application of either OS2 or taipoxin. Conversely, presynaptic K+ currents (IA and IK) were increased by taipoxin but not by OS2. In addition, OS2 induced a significant decrease of the presynaptic Ca2+ current (30%) while taipoxin increased this latter current by 20-30%. 3. Bee venom PLA2, another monochain neurotoxic PLA2, also inhibited ACh release while non-toxic enzymatically active PLA2s like OS1 (also purified from taipan snake venom) or porcine pancreatic PLA2 elicited a much weaker inhibition of ACh release, suggesting a specific action of neurotoxic PLA2s versus non-toxic PLA2s on ACh release. 4. Using iodinated OS2, specific high affinity binding sites with molecular masses of 140 and 18 kDa have been identified on Aplysia ganglia. The maximal binding capacities were 55 and 300-400 fmol (mg protein)-1 for membrane preparations from whole and buccal ganglia, respectively. These binding sites are of high affinity for neurotoxic PLA2s (Kd values, 100-800 pM) and of very low affinity for non-toxic PLA2s (Kd values in the micromolar range), thus indicating that these binding sites are presumably involved in the blockade of ACh release by neurotoxic PLA2s. Images Figure 8 Figure 9 PMID:8583413

  14. A Quaternary Geomagnetic Instability Time Scale

    NASA Astrophysics Data System (ADS)

    Singer, B. S.

    2013-12-01

    Reversals and excursions of Earth's geomagnetic field create marker horizons that are readily detected in sedimentary and volcanic rocks worldwide. An accurate and precise chronology of these geomagnetic field instabilities is fundamental to understanding several aspects of Quaternary climate, dynamo processes, and surface processes. For example, stratigraphic correlation between marine sediment and polar ice records of climate change across the cryospheres benefits from a highly resolved record of reversals and excursions. The temporal patterns of dynamo behavior may reflect physical interactions between the molten outer core and the solid inner core or lowermost mantle. These interactions may control reversal frequency and shape the weak magnetic fields that arise during successive dynamo instabilities. Moreover, weakening of the axial dipole during reversals and excursions enhances the production of cosmogenic isotopes that are used in sediment and ice core stratigraphy and surface exposure dating. The Geomagnetic Instability Time Scale (GITS) is based on the direct dating of transitional polarity states recorded by lava flows using the 40Ar/39Ar method, in parallel with astrochronologic age models of marine sediments in which O isotope and magnetic records have been obtained. A review of data from Quaternary lava flows and sediments yields a GITS comprising 10 polarity reversals and 27 excursions during the past 2.6 million years. Nine of the ten reversals bounding chrons and subchrons are associated with 40Ar/39Ar ages of transitionally-magnetized lava flows. The tenth, the Guass-Matuyama chron boundary, is tightly bracketed by 40Ar/39Ar dated ash deposits. Of the 27 well-documented excursions, 14 occurred during the Matuyama chron and 13 during the Brunhes chron; 19 have been dated directly using the 40Ar/39Ar method on transitionally-magnetized volcanic rocks and form the backbone of the GITS. Excursions are clearly not the rare phenomena once thought

  15. Continuing Education in the Era of Quantum Change. 2003 ACHE Proceedings. (65th Annual Meeting, Charlottesville, VA, November 8-12, 2003)

    ERIC Educational Resources Information Center

    Barrineau, Irene T., Ed.

    2003-01-01

    This document presents the proceedings of the 2003 annual meeting of the Association for Continuing Higher Education (ACHE). These proceedings record the 65th Annual Meeting of ACHE held in Charlottesville, Virginia. President Allen Varner's theme for this annual meeting was, "Continuing Education in the Era of Quantum Change." The theme was…

  16. Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer.

    PubMed

    Kouvatsos, Nikolaos; Giastas, Petros; Chroni-Tzartou, Dafni; Poulopoulou, Cornelia; Tzartos, Socrates J

    2016-08-23

    In this study we report the X-ray crystal structure of the extracellular domain (ECD) of the human neuronal α2 nicotinic acetylcholine receptor (nAChR) subunit in complex with the agonist epibatidine at 3.2 Å. Interestingly, α2 was crystallized as a pentamer, revealing the intersubunit interactions in a wild type neuronal nAChR ECD and the full ligand binding pocket conferred by two adjacent α subunits. The pentameric assembly presents the conserved structural scaffold observed in homologous proteins, as well as distinctive features, providing unique structural information of the binding site between principal and complementary faces. Structure-guided mutagenesis and electrophysiological data confirmed the presence of the α2(+)/α2(-) binding site on the heteromeric low sensitivity α2β2 nAChR and validated the functional importance of specific residues in α2 and β2 nAChR subunits. Given the pathological importance of the α2 nAChR subunit and the high sequence identity with α4 (78%) and other neuronal nAChR subunits, our findings offer valuable information for modeling several nAChRs and ultimately for structure-based design of subtype specific drugs against the nAChR associated diseases. PMID:27493220

  17. Experimental investigation into Quaternary badland geomorphic development

    NASA Astrophysics Data System (ADS)

    Kasanin-Grubin, Milica; Kuhn, Nikolaus; Yair, Aaron; Bryan, Rorke; Schwanghart, Wolfgang

    2010-05-01

    Badland morphology is commonly linked to lithological properties of the bedrock. However, recent investigations indicate that the geomorphic development is sensitive to climate and in particular to precipitation characteristics. In this study, the precipitation characteristics that are critical for the Quaternary landscape development in the Dinosaur Badlands in Alberta, Canada, and Zin Valley Badlands, Negev Desert, Israel are investigated. Runoff, erosion and weathering were simulated in the field and the laboratory to determine rates for modeling different precipitation regimes. Currently, the geomorphic development in the Dinosaur badlands is characterized by weathering/supply limited conditions, leading to slope retreat independent of lithology. In the Negev, transport limited conditions cause frequent runoff discontinuity, creating a pattern of areas dominated by erosion or deposition. The results of the weathering and erosion experiments show that the balance between snowmelt induced weathering in the spring and summer rainfall and erosion determine the rate of slope retreat in the Dinosaur Badlands. In the Zin Valley, on the other hand, the magnitude of the individual rainstorms determines whether a slope section is eroded or acts as a sediment sink. The experiments illustrate that the badland slopes experienced an auto-stabilization during the Quaternary in the Zin Valley. In the Dinosaur Badlands Holocene climatic variations have not caused a permanent differentiation of patterns of erosion and deposition. Based on these results the reaction of badland slopes to changing precipitation characteristics was modeled. In their current state, both badland slope systems appear to be fairly stable against climate change in the range of those occurring during the Holocene. However, the stability is achieved in different ways. In the Dinosaur Badlands, weathering rates are low compared to erosion capacity, maintaining continuous evacuation of sediment from slopes

  18. Known and suggested quaternary faulting in the midcontinent United States

    USGS Publications Warehouse

    Wheeler, R.L.; Crone, A.J.

    2001-01-01

    The midcontinent United States between the Appalachian and Rocky Mountains contains 40 known faults or other potentially tectonic features for which published geologic information shows or suggests Quaternary tectonic faulting. We report results of a systematic evaluation of published and other publicly available geologic evidence of Quaternary faulting. These results benefit seismic-hazard assessments by (1) providing some constraints on the recurrence intervals and magnitudes of large, prehistoric earthquakes, and (2) identifying features that warrant additional study. For some features, suggested Quaternary tectonic faulting has been disproved, whereas, for others, the suggested faulting remains questionable. Of the 40 features, nine have clear geologic evidence of Quaternary tectonic faulting associated with prehistoric earthquakes, and another six features have evidence of nontectonic origins. An additional 12 faults, uplifts, or historical seismic zones lack reported paleoseismological evidence of large. Quaternary earthquakes. The remaining 13 features require further paleoseismological study to determine if they have had Quaternary earthquakes that were larger than any known from local historical records; seven of these 13 features are in or near urbanized areas where their study could affect urban hazard estimates. These seven are: (1) the belt of normal faults that rings the Gulf of Mexico from Florida to Texas. (2) the Northeast Ohio seismic zone, (3) the Valmont and (4) Goodpasture faults of Colorado. (5) the Champlain lowlands normal faults of New York State and Vermont, and (6) the Lexington and (7) Kentucky River fault systems of eastern Kentucky. Published by Elsevier Science B.V.

  19. Surface-Wave Plasma Deposition of a-C:H Films for Field Emission

    NASA Astrophysics Data System (ADS)

    Sano, Toru; Nagatsu, Masaaki; Takada, Noriharu; Toyoda, Hirotaka; Sugai, Hideo; Guang, W. X.; Hirao, Takashi; Toyoda, Naoki

    2000-10-01

    Recently crystalline diamond or diamondlike carbon (DLC) thin films prepared by the plasma enhanced CVD techniques have been widely studied as a new material of electron emitter for the next generation large-area field emission display. Among them, DLC films grown at low temperature are more attractive from an aspect of industrial manufacturing. In this study, we have carried out the deposition of hydrogenated amorphous carbon(a-C:H) films using a high density, low pressure surface-wave plasma (SWP). The SWP was produced in a 40cm-diameter vacuum chamber by introducing 2.45 GHz microwave through a quartz window via slot antennas. The a-C:H films were deposited on a silicon substrate immersed in He/CH4 plasma, under discharge conditions of 700 W microwave power and 200 mTorr total pressure. Excellent field emission characteristics were obtained: the threshold electric field defined at an emission current density of 1 μA/cm^2 was obtained to be 4 V/μm. Other film characteristics measured with the XPS and FT-IR are also presented. This work was supported by a Grant-in-Aid for Science Research from the Ministry of Education, Science, Sports and Culture in Japan.

  20. Biocompatible Silver-containing a-C:H and a-C coatings: AComparative Study

    SciTech Connect

    Endrino, Jose Luis; Allen, Matthew; Escobar Galindo, Ramon; Zhang, Hanshen; Anders, Andre; Albella, Jose Maria

    2007-04-01

    Hydrogenated diamond-like-carbon (a-C:H) and hydrogen-free amorphous carbon (a-C) coatings are known to be biocompatible and have good chemical inertness. For this reason, both of these materials are strong candidates to be used as a matrix that embeds metallic elements with antimicrobial effect. In this comparative study, we have incorporated silver into diamond-like carbon (DLC) coatings by plasma based ion implantation and deposition (PBII&D) using methane (CH4) plasma and simultaneously depositing Ag from a pulsed cathodic arc source. In addition, we have grown amorphous carbon - silver composite coatings using a dual-cathode pulsed filtered cathodic-arc (FCA) source. The silver atomic content of the deposited samples was analyzed using glow discharge optical spectroscopy (GDOES). In both cases, the arc pulse frequency of the silver cathode was adjusted in order to obtain samples with approximately 5 at.% of Ag. Surface hardness of the deposited films was analyzed using the nanoindentation technique. Cell viability for both a-C:H/Ag and a-C:/Ag samples deposited on 24-well tissue culture plates has been evaluated.

  1. Adsorption of alcohols and fatty acids onto hydrogenated (a-C:H) DLC coatings

    NASA Astrophysics Data System (ADS)

    Simič, R.; Kalin, M.; Kovač, J.; Jakša, G.

    2016-02-01

    Information about the interactions between lubricants and DLC coatings is scarce, despite there having been many studies over the years. In this investigation we used ToF-SIMS, XPS and contact-angle analyses to examine the adsorption ability and mechanisms with respect to two oiliness additives, i.e., hexadecanol and hexadecanoic acid, on an a-C:H coating. In addition, we analyzed the resistance of the adsorbed films to external influences like solvent cleaning. The results show that both molecules adsorb onto surface oxides and hydroxides present on the initial DLC surface and shield these structures with their hydrocarbon tails. This makes the surfaces less polar, which is manifested in a smaller polar component of the surface energy. We also showed that ultrasonic cleaning in heptane has no significant effect on the quantity of adsorbed molecules or on their chemical state. This not only shows the relatively strong adsorption of these molecules, but also provides useful information for future experimental work. Of the two examined molecules, the acid showed a greater adsorption ability than the alcohol, which explains some of the previously reported better tribological properties in the case of the acid with respect to the alcohol.

  2. Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management?

    PubMed Central

    Mohammadi, Sarasa A.; Christie, MacDonald J.

    2015-01-01

    The α9α10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the α9α10-nAChR in pain is conflicted. This receptor was first implicated in pain with the characterisation of conotoxin Vc1.1, which is highly selective for α9α10-nAChRs and is an efficacious analgesic in chronic pain models with restorative capacities and no reported side effects. Numerous other analgesic conotoxin and non-conotoxin molecules have been subsequently characterised that also inhibit α9α10-nAChRs. However, there is evidence that α9α10-nAChR inhibition is neither necessary nor sufficient for analgesia. α9α10-nAChR-inhibiting analogues of Vc1.1 have no analgesic effects. Genetically-modified α9-nAChR knockout mice have a phenotype that is markedly different from the analgesic profile of Vc1.1 and similar conotoxins, suggesting that the conotoxin effects are largely independent of α9α10-nAChRs. Furthermore, an alternative mechanism of analgesia by Vc1.1 and other similar conotoxins involving non-canonical coupling of GABAB receptors to voltage-gated calcium channels is known. Additional incongruities regarding α9α10-nAChRs in analgesia are discussed. A more comprehensive characterisation of the role of α9α10-nAChRs in pain is crucial for understanding the analgesic action of conotoxins and for improved drug design. PMID:26426047

  3. A Quaternary Fault Database for Central Asia

    NASA Astrophysics Data System (ADS)

    Mohadjer, S.; Ehlers, T. A.; Bendick, R.; Stübner, K.; Strube, T.

    2015-09-01

    Earthquakes represent the highest risk in terms of potential loss of lives and economic damage for Central Asian countries. Knowledge of fault location and behavior is essential in calculating and mapping seismic hazard. Previous efforts in compiling fault information for Central Asia have generated a large amount of data that are published in limited-access journals with no digital maps publicly available, or are limited in their description of important fault parameters such as slip rates. This study builds on previous work by improving access to fault information through a web-based interactive map and an online database with search capabilities that allow users to organize data by different fields. The data presented in this compilation include fault location, its geographic, seismic and structural characteristics, short descriptions, narrative comments and references to peer-reviewed publications. The interactive map displays 1196 fault segments and 34 000 earthquake locations on a shaded-relief map. The online database contains attributes for 122 faults mentioned in the literature, with Quaternary and geodetic slip rates reported for 38 and 26 faults respectively, and earthquake history reported for 39 faults. This work has implications for seismic hazard studies in Central Asia as it summarizes important fault parameters, and can reduce earthquake risk by enhancing public access to information. It also allows scientists and hazard assessment teams to identify structures and regions where data gaps exist and future investigations are needed.

  4. (Model) Peatlands in late Quaternary interglacials

    NASA Astrophysics Data System (ADS)

    Kleinen, Thomas; Brovkin, Victor

    2016-04-01

    Peatlands have accumulated a substantial amount of carbon, roughly 600 PgC, during the Holocene. Prior to the Holocene, there is relatively little direct evidence of peatlands, though coal deposits bear witness to a long history of peat-forming ecosystems going back to the Carboniferous. We therefore need to rely on models to investigate peatlands in times prior to the Holocene. We have developed a dynamical model of wetland extent and peat accumulation, integrated in the coupled climate carbon cycle model of intermediate complexity CLIMBER2-LPJ, in order to mechanistically model interglacial carbon cycle dynamics. This model consists of the climate model of intermediate complexity CLIMBER2 and the dynamic global vegetation model LPJ, which we have extended with modules to determine peatland extent and carbon accumulation. The model compares reasonably well to Holocene peat data. We have used this model to investigate the dynamics of atmospheric CO2 in the Holocene and two other late Quaternary interglacials, namely the Eemian, which is interesting due to its warmth, and Marine Isotope Stage 11 (MIS11), which is the longest interglacial during the last 500ka. We will also present model results of peatland extent and carbon accumulation for these interglacials. We will discuss model shortcomings and knowledge gaps currently preventing an application of the model to full glacial-interglacial cycles.

  5. Late Quaternary mammalian zoogeography of eastern Washington

    NASA Astrophysics Data System (ADS)

    Lyman, R. Lee; Livingston, Stephanie D.

    1983-11-01

    The late Quaternary mammalian zoogeographic history of eastern Washington as revealed by archaeological and paleontological research conforms to a set of past environmental conditions inferred from botanical data. During the relatively cool and moist late Pleistocene and early Holocene, Cervus cf. elaphus, Ovis canadensis, Vulpes vulpes, Martes americana, Alopex lagopus, and perhaps Rangifer sp., taxa with ecological preferences for mesic steppe habitats, were present in the now xeric Columbia Basin. As the climate became progressively warmer and drier during the late Pleistocene and early Holocene, Antilocapra americana, Onychomys leucogaster, Spermophilus townsendii, and Neotoma cinerea, taxa with ecological preferences for xeric steppe habitats, appear in the Columbia Basin. Bison sp. and Taxidea taxus may have been present in eastern Washington for the last 20,000 yr. Middle and late Holocene records for Oreamnos americanus, Spermophilus columbianus, S. townsendii, Lagurus curtatus, and Urocyon cinereoargenteus in central eastern Washington suggest fluctuations in the ranges of these taxa that conform to a middle Holocene period of less effective precipitation and a ca. 3500-yr-old period of more effective precipitation before essentially modern environmental conditions prevailed.

  6. Late Quaternary history of the Atacama Desert

    USGS Publications Warehouse

    Latorre, Claudio; Betancourt, Julio L.; Rech, Jason A.; Quade, Jay; Holmgren, Camille; Placzek, Christa; Maldonado, Antonio; Vuille, Mathias; Rylander, Kate A.; Smith, Mike; Hesse, Paul

    2005-01-01

    Of the major subtropical deserts found in the Southern Hemisphere, the Atacama Desert is the driest. Throughout the Quaternary, the most pervasive climatic influence on the desert has been millennial-scale changes in the frequency and seasonality of the scant rainfall, and associated shifts in plant and animal distributions with elevation along the eastern margin of the desert. Over the past six years, we have mapped modern vegetation gradients and developed a number of palaeoenvironmental records, including vegetation histories from fossil rodent middens, groundwater levels from wetland (spring) deposits, and lake levels from shoreline evidence, along a 1200-kilometre transect (16–26°S) in the Atacama Desert. A strength of this palaeoclimate transect has been the ability to apply the same methodologies across broad elevational, latitudinal, climatic, vegetation and hydrological gradients. We are using this transect to reconstruct the histories of key components of the South American tropical (summer) and extratropical (winter) rainfall belts, precisely at those elevations where average annual rainfall wanes to zero. The focus has been on the transition from sparse, shrubby vegetation (known as the prepuna) into absolute desert, an expansive hyperarid terrain that extends from just above the coastal fog zone (approximately 800 metres) to more than 3500 metres in the most arid sectors in the southern Atacama.

  7. Quaternary Ammonium Biocides: Efficacy in Application

    PubMed Central

    2014-01-01

    Quaternary ammonium compounds (QACs) are among the most commonly used disinfectants. There has been concern that their widespread use will lead to the development of resistant organisms, and it has been suggested that limits should be place on their use. While increases in tolerance to QACs have been observed, there is no clear evidence to support the development of resistance to QACs. Since efflux pumps are believe to account for at least some of the increased tolerance found in bacteria, there has been concern that this will enhance the resistance of bacteria to certain antibiotics. QACs are membrane-active agents interacting with the cytoplasmic membrane of bacteria and lipids of viruses. The wide variety of chemical structures possible has seen an evolution in their effectiveness and expansion of applications over the last century, including non-lipid-containing viruses (i.e., noroviruses). Selection of formulations and methods of application have been shown to affect the efficacy of QACs. While numerous laboratory studies on the efficacy of QACs are available, relatively few studies have been conducted to assess their efficacy in practice. Better standardized tests for assessing and defining the differences between increases in tolerance versus resistance are needed. The ecological dynamics of microbial communities where QACs are a main line of defense against exposure to pathogens need to be better understood in terms of sublethal doses and antibiotic resistance. PMID:25362069

  8. A Quaternary fault database for central Asia

    NASA Astrophysics Data System (ADS)

    Mohadjer, Solmaz; Ehlers, Todd Alan; Bendick, Rebecca; Stübner, Konstanze; Strube, Timo

    2016-02-01

    Earthquakes represent the highest risk in terms of potential loss of lives and economic damage for central Asian countries. Knowledge of fault location and behavior is essential in calculating and mapping seismic hazard. Previous efforts in compiling fault information for central Asia have generated a large amount of data that are published in limited-access journals with no digital maps publicly available, or are limited in their description of important fault parameters such as slip rates. This study builds on previous work by improving access to fault information through a web-based interactive map and an online database with search capabilities that allow users to organize data by different fields. The data presented in this compilation include fault location, its geographic, seismic, and structural characteristics, short descriptions, narrative comments, and references to peer-reviewed publications. The interactive map displays 1196 fault traces and 34 000 earthquake locations on a shaded-relief map. The online database contains attributes for 123 faults mentioned in the literature, with Quaternary and geodetic slip rates reported for 38 and 26 faults respectively, and earthquake history reported for 39 faults. All data are accessible for viewing and download via http://www.geo.uni-tuebingen.de/faults/. This work has implications for seismic hazard studies in central Asia as it summarizes important fault parameters, and can reduce earthquake risk by enhancing public access to information. It also allows scientists and hazard assessment teams to identify structures and regions where data gaps exist and future investigations are needed.

  9. Quaternary glaciation of the Bale Mountains, Ethiopia

    NASA Astrophysics Data System (ADS)

    Osmaston, Henry A.; Mitchell, Wishart A.; Osmaston, J. A. Nigel

    2005-09-01

    Central Ethiopia comprises a high plateau at 2000-3000 m, formed from Tertiary lava flows and bisected by the Eastern African Rift. Ten volcanic mountains rise to altitudes of just over 4000 m, but on only three has Quaternary glaciation been substantiated by published field observations. On the Bale Mountains (4400 m), a previous report based on limited evidence proposed an ice-cap extending to 600 km2. Based on aerial photographs and ground surveys, this paper reports evidence of a more complex situation. A wide spread of large erratic boulders on the plateau records a central ice cap of 30 km2, though ice probably extended for a further 40 km2. Further north two groups of deeply incised and clearly glaciated valleys contain moraines and roches moutonnées (60 km2). On interfluves between them and on the open north slopes are moraines from an earlier stage of the same glaciation or from a distinct older event. Altogether about 180 km2 may have been glaciated. Cores dated by 14C from inside and outside the glaciated area suggest that at least the northern valley glaciers may date from the Last Glacial Maximum. Estimated equilibrium line altitudes for these glaciers and the ice-cap are 3750-4230 m. Copyright

  10. Luminescence dating of quaternary sediments: recent advances

    NASA Astrophysics Data System (ADS)

    Duller, G. A. T.

    2004-02-01

    Luminescence dating is unique amongst geochronological methods in dating the deposition of sediments based upon the properties of the constituent minerals. For Quaternary sediments the event being dated is the last exposure of the grains to daylight, and an implicit assumption is that this exposure was sufficient to remove any pre-existing signal. Until recently it has been difficult to test this assumption, other than by dating samples from a given depositional context with an age that is known from independent methods. There have been a series of technological and methodological developments in the past 5-10 yr that make it possible to undertake many replicate measurements of the luminescence from a single sample and hence to explicitly test whether for a specific sample all the grains had their luminescence signal reset at deposition. This allows the reliability of the luminescence age to be assessed. Where all the grains in a sample were not exposed to sufficient daylight to reset their luminescence signal, the apparent age will be an average value of the luminescence from all the grains measured at one time. Where many grains are measured simultaneously, this will overestimate the depositional age. The distribution of apparent age can be made clear by reducing the number of grains being measured in a given experiment, ultimately to the point of measuring individual sand-sized mineral grains. Copyright

  11. Microstructure of a-C:H films prepared on a microtrench and analysis of ions and radicals behavior

    NASA Astrophysics Data System (ADS)

    Hirata, Yuki; Choi, Junho

    2015-08-01

    Amorphous carbon films (a-C:H) were prepared on a microtrench (4-μm pitch and 4-μm depth), and the uniformity of film thickness and microstructure of the films on the top, sidewall, and bottom surfaces of the microtrench were evaluated by scanning electron microscopy and Raman spectroscopy. The a-C:H films were prepared by bipolar-type plasma based ion implantation and deposition (bipolar PBII&D), and the negative pulse voltage, which is the main parameter dominating the film structure, was changed from -1.0 to -15 kV. Moreover, the behavior of ions and radicals was analyzed simultaneously by combining the calculation methods of Particle-In-Cell/Monte Carlo Collision (PIC-MCC) and Direct Simulation Monte Carlo (DSMC) to investigate the coating mechanism for the microtrench. The results reveal that the thickness uniformity of a-C:H films improves with decreasing negative pulse voltage due to the decreasing inertia of incoming ions from the trench mouth, although the film thickness on the sidewall tends to be much smaller than that on the top and bottom surfaces of the trench. The normalized flux and the film thickness show similar behavior, i.e., the normalized flux or thickness at the bottom surface increases at low negative pulse voltages and then saturates at a certain value, whereas at the sidewall it monotonically decreases with increasing negative voltage. The microstructure of a-C:H films on the sidewall surface is very different from that on the top and bottom surfaces. The film structure at a low negative pulse voltage shifts to more of a polymer-like carbon (PLC) structure due to the lower incident energy of ions. Although the radical flux on the sidewall increases slightly, the overall film structure is not significantly changed because this film formation at a low negative voltage is originally dominated by radicals. On the other hand, the flux of radicals is dominant on the sidewall in the case of high negative pulse voltage, resulting in a deviation

  12. Microstructure of a-C:H films prepared on a microtrench and analysis of ions and radicals behavior

    SciTech Connect

    Hirata, Yuki; Choi, Junho

    2015-08-28

    Amorphous carbon films (a-C:H) were prepared on a microtrench (4-μm pitch and 4-μm depth), and the uniformity of film thickness and microstructure of the films on the top, sidewall, and bottom surfaces of the microtrench were evaluated by scanning electron microscopy and Raman spectroscopy. The a-C:H films were prepared by bipolar-type plasma based ion implantation and deposition (bipolar PBII&D), and the negative pulse voltage, which is the main parameter dominating the film structure, was changed from −1.0 to −15 kV. Moreover, the behavior of ions and radicals was analyzed simultaneously by combining the calculation methods of Particle-In-Cell/Monte Carlo Collision (PIC-MCC) and Direct Simulation Monte Carlo (DSMC) to investigate the coating mechanism for the microtrench. The results reveal that the thickness uniformity of a-C:H films improves with decreasing negative pulse voltage due to the decreasing inertia of incoming ions from the trench mouth, although the film thickness on the sidewall tends to be much smaller than that on the top and bottom surfaces of the trench. The normalized flux and the film thickness show similar behavior, i.e., the normalized flux or thickness at the bottom surface increases at low negative pulse voltages and then saturates at a certain value, whereas at the sidewall it monotonically decreases with increasing negative voltage. The microstructure of a-C:H films on the sidewall surface is very different from that on the top and bottom surfaces. The film structure at a low negative pulse voltage shifts to more of a polymer-like carbon (PLC) structure due to the lower incident energy of ions. Although the radical flux on the sidewall increases slightly, the overall film structure is not significantly changed because this film formation at a low negative voltage is originally dominated by radicals. On the other hand, the flux of radicals is dominant on the sidewall in the case of high negative pulse voltage, resulting in a

  13. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and {beta}-adrenergic receptor signaling pathways

    SciTech Connect

    Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K.; Cho, C.H.; Sung, J.J.Y.

    2008-12-01

    Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor ({alpha}7 nAChR) and {beta}-adrenergic receptors. Treatment of cells with {alpha}-bungarotoxin ({alpha}-BTX, {alpha}7nAChR antagonist) or propranolol ({beta}-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE{sub 2} and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE{sub 2} induction can only be suppressed by propranolol, but not {alpha}-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis.

  14. Geological Mapping of the Ac-H-12 Toharu Quadrangle of Ceres from NASA Dawn Mission

    NASA Astrophysics Data System (ADS)

    Mest, Scott; Williams, David; Crown, David; Yingst, Aileen; Buczkowski, Debra; Scully, Jennifer; Jaumann, Ralf; Roatsch, Thomas; Preusker, Frank; Nathues, Andres; Hoffmann, Martin; Schaefer, Michael; Raymond, Carol; Russell, Christopher

    2016-04-01

    The Dawn Science Team is conducting a geologic mapping campaign for Ceres similar to that done for Vesta [1,2], including production of a Survey- and High Altitude Mapping Orbit (HAMO)-based global map and a series of 15 Low Altitude Mapping Orbit (LAMO)-based quadrangle maps. In this abstract we discuss the surface geology and geologic evolution of the Ac-H-12 Toharu Quadrangle (21-66°S, 90-180°E). At the time of this writing LAMO images (35 m/pixel) are just becoming available. The current geologic map of Ac-H-12 was produced using ArcGIS software, and is based on HAMO images (140 m/pixel) and Survey (400 m/pixel) digital terrain models (for topographic information). Dawn Framing Camera (FC) color images were also used to provide context for map unit identification. The map (to be presented as a poster) will be updated from analyses of LAMO images. The Toharu Quadrangle is named after crater Toharu (86 km diameter; 48.3°S, 156°E), and is dominated by smooth terrain in the north, and more heavily cratered terrain in the south. The quad exhibits ~9 km of relief, with the highest elevations (~3.5-4.6 km) found among the western plateau and eastern crater rims, and the lowest elevation found on the floor of crater Chaminuka. Preliminary geologic mapping has defined three regional units (smooth material, smooth Kerwan floor material, and cratered terrain) that dominate the quadrangle, as well as a series of impact crater material units. Smooth materials form nearly flat-lying plains in the northwest part of the quad, and overlies hummocky materials in some areas. These smooth materials extend over a much broader area outside of the quad, and appear to contain some of the lowest crater densities on Ceres. Cratered terrain forms much of the map area and contains rugged surfaces formed largely by the structures and deposits of impact features. In addition to geologic units, a number of geologic features - including crater rims, furrows, scarps, troughs, and impact

  15. Toxicity and mAChRs binding activity of Cassiopea xamachana venom from Puerto Rican coasts.

    PubMed

    Radwan, Faisal F Y; Román, Laura G; Baksi, Krishna; Burnett, Joseph W

    2005-01-01

    A separation of toxic components from the upside down jellyfish Cassiopea xamachana (Cx) was carried out to study their cytotoxic effects and examine whether these effects are combined with a binding activity to cell membrane receptors. Nematocysts containing toxins were isolated from the autolysed tentacles, ruptured by sonication, and the crude venom (CxTX) was separated from the pellets by ultracentrifugation. For identifying its bioactive components, CxTX was fractionated by gel filtration chromatography into six fractions (named fraction I-VI). The toxicity of CxTX and fractions was tested on mice; however, the hemolytic activity was tested on saline washed human erythrocytes. The LD50 of CxTX was 0.75 microg/g of mouse body and for fraction III, IV and VI were 0.28, 0.25 and 0.12 microg/g, respectively. Fractions I, II and V were not lethal at doses equivalent to LD50 1 microg/g. The hemolytic and phospholipase A2 (PLA2) activities of most fractions were well correlated with their mice toxicity. However, fraction VI, which contains the low molecular mass protein components (< or =10 kDa), has shown no PLA2 activity but highest toxicity to mice, highest hemolytic activity, and bound significantly to the acetylcholine muscarinic receptors (mAChRs) isolated from rat brain. The results suggested that fraction VI contains proteinaceous components contributing to most of cytolysis as well as membrane binding events. Meanwhile, fraction IV has shown high PLA2 that may contribute to the venom lethality and paralytic effects. PMID:15581689

  16. Heritability and Fitness Correlates of Personality in the Ache, a Natural-Fertility Population in Paraguay

    PubMed Central

    Bailey, Drew H.; Walker, Robert S.; Blomquist, Gregory E.; Hill, Kim R.; Hurtado, A. Magdalena; Geary, David C.

    2013-01-01

    The current study assessed the heritability of personality in a traditional natural-fertility population, the Ache of eastern Paraguay. Self-reports (n = 110) and other-reports (n = 66) on the commonly used Big Five Personality Inventory (i.e., extraversion, agreeableness, conscientiousness, neuroticism, openness) were collected. Self-reports did not support the Five Factor Model developed with Western samples, and did not correlate with other-reports for three of the five measured personality factors. Heritability was assessed using factors that were consistent across self- and other-reports and factors assessed using other-reports that showed reliabilities similar to those found in Western samples. Analyses of these items in combination with a multi-generation pedigree (n = 2,132) revealed heritability estimates similar to those found in most Western samples, although we were not able to separately estimate the influence of the common environment on these traits. We also assessed relations between personality and reproductive success (RS), allowing for a test of several mechanisms that might be maintaining heritable variation in personality. Phenotypic analyses, based largely on other-reports, revealed that extraverted men had higher RS than other men, but no other dimensions of personality predicted RS in either sex. Mothers with more agreeable children had more children, and parents mated assortatively on personality. Of the evolutionary processes proposed to maintain variation in personality, assortative mating, selective neutrality, and temporal variation in selection pressures received the most support. However, the current study does not rule out other processes affecting the evolution and maintenance of individual differences in human personality. PMID:23527163

  17. Heritability and fitness correlates of personality in the Ache, a natural-fertility population in Paraguay.

    PubMed

    Bailey, Drew H; Walker, Robert S; Blomquist, Gregory E; Hill, Kim R; Hurtado, A Magdalena; Geary, David C

    2013-01-01

    The current study assessed the heritability of personality in a traditional natural-fertility population, the Ache of eastern Paraguay. Self-reports (n = 110) and other-reports (n = 66) on the commonly used Big Five Personality Inventory (i.e., extraversion, agreeableness, conscientiousness, neuroticism, openness) were collected. Self-reports did not support the Five Factor Model developed with Western samples, and did not correlate with other-reports for three of the five measured personality factors. Heritability was assessed using factors that were consistent across self- and other-reports and factors assessed using other-reports that showed reliabilities similar to those found in Western samples. Analyses of these items in combination with a multi-generation pedigree (n = 2,132) revealed heritability estimates similar to those found in most Western samples, although we were not able to separately estimate the influence of the common environment on these traits. We also assessed relations between personality and reproductive success (RS), allowing for a test of several mechanisms that might be maintaining heritable variation in personality. Phenotypic analyses, based largely on other-reports, revealed that extraverted men had higher RS than other men, but no other dimensions of personality predicted RS in either sex. Mothers with more agreeable children had more children, and parents mated assortatively on personality. Of the evolutionary processes proposed to maintain variation in personality, assortative mating, selective neutrality, and temporal variation in selection pressures received the most support. However, the current study does not rule out other processes affecting the evolution and maintenance of individual differences in human personality.

  18. Haemocompatibility of hydrogenated amorphous carbon (a-C:H) films synthesized by plasma immersion ion implantation-deposition

    NASA Astrophysics Data System (ADS)

    Yang, P.; Kwok, S. C. H.; Chu, P. K.; Leng, Y. X.; Chen, J. Y.; Wang, J.; Huang, N.

    2003-05-01

    Diamond-like-carbon has attracted much attention recently as a potential biomaterial in blood contacting biomedical devices. However, previous reports in this area have not adequately addressed the biocompatibility and acceptability of the materials in blood contacting applications. In this study, hydrogenated amorphous carbon (a-C:H) films were fabricated on silicon wafers (1 0 0) using plasma immersion ion implantation-deposition. A series of a-C:H films with different structures and chemical bonds were fabricated under different substrate voltages. The results indicate that film graphitization is promoted at higher substrate bias. The film deposited at a lower substrate bias of -75 V possesses better blood compatibility than the films at higher bias and stainless steel. Our results suggest two possible paths to improve the blood compatibility, suppression of the endogenic clotting system and reduction of platelet activation.

  19. Automated Patch Clamp Analysis of nAChα7 and Na(V)1.7 Channels.

    PubMed

    Obergrussberger, Alison; Haarmann, Claudia; Rinke, Ilka; Becker, Nadine; Guinot, David; Brueggemann, Andrea; Stoelzle-Feix, Sonja; George, Michael; Fertig, Niels

    2014-01-01

    Automated patch clamp devices are now commonly used for studying ion channels. A useful modification of this approach is the replacement of the glass pipet with a thin planar glass layer with a small hole in the middle. Planar patch clamp devices, such as the three described in this unit, are overtaking glass pipets in popularity because they increase throughput, are easier to use, provide for the acquisition of high-quality and information-rich data, and allow for rapid perfusion and temperature control. Covered in this unit are two challenging targets in drug discovery: voltage-gated sodium subtype 1.7 (Na(V)1.7) and nicotinic acetylcholine α7 receptors (nAChα7R). Provided herein are protocols for recording activation and inactivation kinetics of Na(V)1.7, and activation and allosteric modulation of nAChα7R. PMID:24934604

  20. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model.

    PubMed

    Komla-Ebri, Davide; Dambroise, Emilie; Kramer, Ina; Benoist-Lasselin, Catherine; Kaci, Nabil; Le Gall, Cindy; Martin, Ludovic; Busca, Patricia; Barbault, Florent; Graus-Porta, Diana; Munnich, Arnold; Kneissel, Michaela; Di Rocco, Federico; Biosse-Duplan, Martin; Legeai-Mallet, Laurence

    2016-05-01

    Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH. PMID:27064282

  1. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

    PubMed Central

    Dambroise, Emilie; Kramer, Ina; Benoist-Lasselin, Catherine; Kaci, Nabil; Le Gall, Cindy; Martin, Ludovic; Busca, Patricia; Barbault, Florent; Graus-Porta, Diana; Munnich, Arnold; Kneissel, Michaela; Di Rocco, Federico; Biosse-Duplan, Martin

    2016-01-01

    Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3–encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH. PMID:27064282

  2. Quaternary Magmatism in the Cascades - Geologic Perspectives

    USGS Publications Warehouse

    Hildreth, Wes

    2007-01-01

    Foreward The Cascade magmatic arc is a belt of Quaternary volcanoes that extends 1,250 km from Lassen Peak in northern California to Meager Mountain in Canada, above the subduction zone where the Juan de Fuca Plate plunges beneath the North American Plate. This Professional Paper presents a synthesis of the entire volcanic arc, addressing all 2,300 known Quaternary volcanoes, not just the 30 or so visually prominent peaks that comprise the volcanic skyline. Study of Cascade volcanoes goes back to the geological explorers of the late 19th century and the seminal investigations of Howel Williams in the 1920s and 1930s. However, major progress and application of modern scientific methods and instrumentation began only in the 1970s with the advent of systematic geological, geophysical, and geochemical studies of the entire arc. Initial stimulus from the USGS Geothermal Research Program was enhanced by the USGS Volcano Hazards Program following the 1980 eruption of Mount St. Helens. Together, these two USGS Programs have provided more than three decades of stable funding, staffing, and analytical support. This Professional Paper summarizes the resultant USGS data sets and integrates them with the parallel contributions of other investigators. The product is based upon an all-encompassing and definitive geological database, including chemical and isotopic analyses to characterize the rocks and geochronology to provide the critical time constraints. Until now, this massive amount of data has not been summarized, and a systematic and uniform interpretation firmly grounded in geological fact has been lacking. Herein lies the primary utility of this Cascade volume. It not only will be the mandatory starting point for new workers, but also will provide essential geological context to broaden the perspectives of current investigators of specific Cascade volcanoes. Wes Hildreth's insightful understanding of volcanic processes and his uncompromising scientific integrity make him

  3. The isotope hydrology of Quaternary climate change.

    PubMed

    Darling, W G

    2011-04-01

    Understanding the links between climate change and human migration and culture is an important theme in Quaternary archaeology. While oxygen and hydrogen stable isotopes in high-latitude ice cores provide the ultimate detailed record of palaeoclimate extending back to the Middle Pleistocene, groundwater can act as a climate archive for areas at lower latitudes, permitting a degree of calibration for proxy records such as lake sediments, bones, and organic matter. Not only can oxygen and hydrogen stable isotopes be measured on waters, but the temperature of recharge can be calculated from the amount of the atmospheric noble gases neon, argon, krypton, and xenon in solution, while residence time can be estimated from the decay of the radioisotopes carbon-14, chlorine-36, and krypton-81 over timescales comparable to the ice core record. The Pleistocene-Holocene transition is well characterised in aquifers worldwide, and it is apparent that isotope-temperature relationships of the present day are not necessarily transferable to past climatic regimes, with important implications for the interpretation of proxy isotope data. Groundwaters dating back to one million years, i.e., to beyond the Middle Pleistocene, are only found in major aquifer basins and information is relatively sparse and of low resolution. Speleothem fluid inclusions offer a way of considerably increasing this resolution, but both speleothem formation and large-scale groundwater recharge requires humid conditions, which may be relatively infrequent for areas currently experiencing arid climates. Both types of record therefore require caution in their interpretation when considering a particular archaeological context.

  4. Landward-advancing Quaternary eolianites of Bermuda

    NASA Astrophysics Data System (ADS)

    Rowe, Mark P.; Bristow, Charlie S.

    2015-12-01

    The landscape of Bermuda is dominated by Quaternary carbonate cemented dunes, or "eolianites", which form the islands' topography. Sections through the dunes are revealed in extensive natural and man-made rock faces, which expose the dune stratigraphy as well as the preserved morphology. An analysis of 3751 foreset measurements confirms the conclusion reached by earlier researchers that Bermuda's dunes advanced sub-perpendicularly to the coast in a landward direction away from source beaches. Dune orientation, being multi-directional, is not consistent with northeast net sand transportation predicted by a drift potential analysis of modern wind data. The putative predisposition of Bermuda's carbonate dunes to rapid cementation is supposed to have curtailed their landward advance such that younger dunes developed as static ridges at the seaward margin of their lithified predecessors. Geological mapping has revealed, however, that in many cases young dunes did advance inland onto interior terrain, overstepping older dune ridges. Molds of large trees, preserved within the dunes, and a sharp contact of steep slip-face dune foresets on palaeosols evoke the encroachment of landward-advancing precipitation ridges into a forested landscape. The internal structure of the dunes, featuring thick sets of slip-face foresets truncated by sub-horizontal planar bounding surfaces, uphold the ascendancy of sand transportation processes over those of sand retention and vertical accretion. Although meteoric cementation was responsible for the ultimate preservation of eolianite ridges which dominate Bermuda's landscape, it took effect too slowly to influence the behaviour of the carbonate dunes at the time of their emplacement.

  5. Late Quaternary fire regimes of Australasia

    NASA Astrophysics Data System (ADS)

    Mooney, S. D.; Harrison, S. P.; Bartlein, P. J.; Daniau, A.-L.; Stevenson, J.; Brownlie, K. C.; Buckman, S.; Cupper, M.; Luly, J.; Black, M.; Colhoun, E.; D'Costa, D.; Dodson, J.; Haberle, S.; Hope, G. S.; Kershaw, P.; Kenyon, C.; McKenzie, M.; Williams, N.

    2011-01-01

    We have compiled 223 sedimentary charcoal records from Australasia in order to examine the temporal and spatial variability of fire regimes during the Late Quaternary. While some of these records cover more than a full glacial cycle, here we focus on the last 70,000 years when the number of individual records in the compilation allows more robust conclusions. On orbital time scales, fire in Australasia predominantly reflects climate, with colder periods characterized by less and warmer intervals by more biomass burning. The composite record for the region also shows considerable millennial-scale variability during the last glacial interval (73.5-14.7 ka). Within the limits of the dating uncertainties of individual records, the variability shown by the composite charcoal record is more similar to the form, number and timing of Dansgaard-Oeschger cycles as observed in Greenland ice cores than to the variability expressed in the Antarctic ice-core record. The composite charcoal record suggests increased biomass burning in the Australasian region during Greenland Interstadials and reduced burning during Greenland Stadials. Millennial-scale variability is characteristic of the composite record of the sub-tropical high pressure belt during the past 21 ka, but the tropics show a somewhat simpler pattern of variability with major peaks in biomass burning around 15 ka and 8 ka. There is no distinct change in fire regime corresponding to the arrival of humans in Australia at 50 ± 10 ka and no correlation between archaeological evidence of increased human activity during the past 40 ka and the history of biomass burning. However, changes in biomass burning in the last 200 years may have been exacerbated or influenced by humans.

  6. Effect of calcium on nicotine-induced current expressed by an atypical alpha-bungarotoxin-insensitive nAChR2.

    PubMed

    Thany, Steeve H; Courjaret, Raphael; Lapied, Bruno

    2008-06-27

    Two distinct native alpha-bungarotoxin (alpha-Bgt)-insensitive nicotinic acetylcholine receptors (nAChRs), named nAChR1 and nAChR2, were identified in the cockroach Periplaneta americana dorsal unpaired median (DUM) neurons. They differed in their electrophysiological, pharmacological properties and intracellular regulation pathways. nAChR2 being an atypical nicotinic receptor closed upon agonist application and its current-voltage relationship resulted from a reduction in potassium conductance. In this study, using whole-cell patch-clamp technique, we demonstrated that calcium modulated nAChR2-mediated nicotine response. Under 0.5 microM alpha-Bgt and 20 mM d-tubocurarine, the nicotine-induced inward current amplitude was strongly reduced in the presence of intracellularly applied BAPTA or bath application of calcium-free solution. In addition, using cadmium chloride, we showed that nicotine response was modulated by extracellular calcium through plasma membrane calcium channels. Moreover, extracellular application of caffeine and thapsigargin reduced nAChR2-mediated response. Together these experiments revealed a complex calcium-dependent regulation of nAChR2. PMID:18485593

  7. Effects of a7nAChR agonist on the tissue estrogen receptor expression of castrated rats

    PubMed Central

    Ma, Feng; Gong, Fan; Lv, Jinhan; Gao, Jun; Ma, Jingzu

    2015-01-01

    Osteoporosis is one common disease in postmenopausal women due to depressed estrogen level. It has been known that inflammatory factors are involved in osteoporosis pathogenesis. One regulator of inflammatory cascade reaction, a7-nicotinic acetylcholine receptor (a7nAChR), therefore, may exert certain role in osteoporosis. This study thus investigated this question on an osteoporosis rat model after castration. Rats were firstly castrated to induce osteoporosis, and then received a7nAChR agonist (PNU-282987), diethylstilbestrol or saline via intraperitoneal injection. After 6 or 12 weeks, bone samples were collected for counting osteoblast number, bone density and estrogen receptor (ERα and ERβ) expression, in addition to the serum laboratory of inflammatory factors. Bone density, osteoclast number, ERα and ERβ expression level were significantly depressed in model group, and were remarkable potentiated in the drug treatment group (P<0.05). The levels of BGP and PTH in drug treatment group were decreased compared to diethylstilbestrol group, while E2 and IGF-1 showed up-regulation. Agonist of a7nAChR can up-regulate estrogen receptor expression and may prevent the occurrence and development of osteoporosis. PMID:26722551

  8. The novel Na+/Ca2+ exchange inhibitor KB-R7943 also blocks native and expressed neuronal nicotinic receptors

    PubMed Central

    Pintado, Antonio J; Herrero, Carlos J; García, Antonio G; Montiel, Carmen

    2000-01-01

    We studied the effects of the novel Na+/Ca2+ exchange inhibitor KB-R7943, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulphonate, on the native nicotinic receptors present at the bovine adrenal chromaffin cells, as well as on rat brain α3β4 and α7 nicotinic acetylcholine receptors (AChRs) expressed in Xenopus oocytes.As expected, KB-R7943 blocked the Na+-gradient dependent 45Ca2+ uptake into chromaffin cells (IC50 of 5.5 μM); but in addition, the compound also inhibited the 45Ca2+ entry and the increase of cytosolic Ca2+ concentration, [Ca2+]c, stimulated by 5 s pulses of ACh (IC50 of 6.5 and 1.7 μM, respectively).In oocytes expressing α3β4 and α7 nicotinic AChRs, voltage-clamped at −60 mV, inward currents elicited by 1 s pulses of 100 μM ACh (IACh) were blocked by KB-R7943 with an IC50 of 0.4 μM and a Hill coefficient of 0.9.Blockade of α3β4 currents by KB-R7943 was noncompetitive; moreover, the blocker (0.3 μM) became more active as the ACh concentration increased (34 versus 66% blockade at 30 μM and 1 mM ACh, respectively).Inhibition of α3β4 currents by 0.3 μM KB-R7943 was more pronounced at hyperpolarized potentials. If given within the ACh pulse (10 μM), the inhibition amounted to 33, 64 and 80% in oocytes voltage-clamped at −40, −60 and −100 mV, respectively. The onset of blockade was faster and the recovery slower at −100 mV; the reverse was true at −40 mV.In conclusion, KB-R7943 is a potent blocker of nicotinic AChRs; moreover, it displays many features of an open-channel blocker at the rat brain α3β4 AChR. These results should be considered when KB-R7943 is to be used to study Ca2+ homeostasis in cells expressing nicotinic AChRs and the Na+/Ca2+ exchanger. PMID:10952680

  9. Endogenously released ACh and exogenous nicotine differentially facilitate long-term potentiation induction in the hippocampal CA1 region of mice.

    PubMed

    Nakauchi, Sakura; Sumikawa, Katumi

    2012-05-01

    We examined the role of α7- and β2-containing nicotinic acetylcholine receptors (nAChRs) in the induction of long-term potentiation (LTP). Theta-burst stimulation (TBS), mimicking the brain's naturally occurring theta rhythm, induced robust LTP in hippocampal slices from α7 and β2 knockout mice. This suggests TBS is capable of inducing LTP without activation of α7- or β2-containing nAChRs. However, when weak TBS was applied, the modulatory effects of nicotinic receptors on LTP induction became visible. We showed that during weak TBS, activation of α7 nAChRs occurs by the release of ACh, contributing to LTP induction. Additionally, bath-application of nicotine activated β2-containing nAChRs to promote LTP induction. Despite predicted nicotine-induced desensitization, synaptically mediated activation of α7 nAChRs still occurs in the presence of nicotine and contributed to LTP induction. Optical recording of single-stimulation-evoked excitatory activity with a voltage-sensitive dye revealed enhanced excitatory activity in the presence of nicotine. This effect of nicotine was robust during high-frequency stimulation, and was accompanied by enhanced burst excitatory postsynaptic potentials. Nicotine-induced enhancement of excitatory activity was observed in slices from α7 knockout mice, but was absent in β2 knockout mice. These results suggest that the nicotine-induced enhancement of excitatory activity is mediated by β2-containing nAChRs, and is related to the nicotine-induced facilitation of LTP induction. Thus, our study demonstrates that the activation of α7- and β2-containing nAChRs differentially facilitates LTP induction via endogenously released ACh and exogenous nicotine, respectively, in the hippocampal CA1 region of mice.

  10. Contribution of α4β2 nAChR in nicotine-induced intracellular calcium response and excitability of MSDB neurons.

    PubMed

    Wang, Jiangang; Wang, Yali; Wang, Yang; Wang, Ran; Zhang, Yunpeng; Zhang, Qian; Lu, Chengbiao

    2014-12-10

    The neurons of medial septal diagonal band of broca (MSDB) project to hippocampus and play an important role in MSDB-hippocampal synaptic transmission, plasticity and network oscillation. Nicotinic acetylcholine receptor (nAChR) subunits, α4β2 and α7 nAChRs, are expressed in MSDB neurons and permeable to calcium ions, which may modulate the function of MSDB neurons. The aims of this study are to determine the roles of selective nAChR activation on the calcium responses and membrane currents in MSDB neurons. Our results showed that nicotine increased calcium responses in the majority of MSDB neurons, pre-treatment of MSDB slices with a α4β2 nAChR antagonist, DhβE but not a α7 nAChR antagonist, MLA prevented nicotine-induced calcium responses. The whole cell patch clamp recordings showed that nicotine-induced inward current and acetylcholine (ACh) induced-firing activity can be largely reduced or prevented by DhβE in MSDB neurons. Surprisingly, post-treatment of α4β2 or α7 nAChR antagonists failed to block nicotine׳s role, they increased calcium responses instead. Application of calcium chelator EGTA reduced calcium responses in all neurons tested. These results suggest that there was a subtype specific modulation of nAChRs on calcium signaling and membrane currents in MSDB neurons and nAChR antagonists were also able to induce calcium responses involving a distinct mechanism.

  11. Neuroprotective effect of cellular prion protein (PrPC) is related with activation of alpha7 nicotinic acetylcholine receptor (α7nAchR)-mediated autophagy flux.

    PubMed

    Jeong, Jae-Kyo; Park, Sang-Youel

    2015-09-22

    Activation of the alpha7 nicotinic acetylcholine receptor (α7nAchR) is regulated by prion protein (PrPC) expression and has a neuroprotective effect by modulating autophagic flux. In this study, we hypothesized that PrPC may regulate α7nAchR activation and that may prevent prion-related neurodegenerative diseases by regulating autophagic flux. PrP(106-126) treatment decreased α7nAchR expression and activation of autophagic flux. In addition, the α7nAchR activator PNU-282987 enhanced autophagic flux and protected neuron cells against PrP(106-126)-induced apoptosis. However, activation of autophagy and the protective effects of PNU-282987 were inhibited in PrPC knockout hippocampal neuron cells. In addition, PrPC knockout hippocampal neuron cells showed decreased α7nAchR expression levels. Adenoviral overexpression of PrPC in PrPC knockout hippocampal neuron cells resulted in activation of autophagic flux and inhibition of prion peptide-mediated cell death via α7nAchR activation. This is the first report demonstrating that activation of α7nAchR-mediated autophagic flux is regulated by PrPC, and that activation of α7nAchR regulated by PrPC expression may play a pivotal role in protection of neuron cells against prion peptide-induced neuron cell death by autophagy. These results suggest that α7nAchR-mediated autophagic flux may be involved in the pathogenesis of prion-related diseases and may be a therapeutic target for prion-related neurodegenerative diseases.

  12. Neuroprotective effect of cellular prion protein (PrPC) is related with activation of alpha7 nicotinic acetylcholine receptor (α7nAchR)-mediated autophagy flux.

    PubMed

    Jeong, Jae-Kyo; Park, Sang-Youel

    2015-09-22

    Activation of the alpha7 nicotinic acetylcholine receptor (α7nAchR) is regulated by prion protein (PrPC) expression and has a neuroprotective effect by modulating autophagic flux. In this study, we hypothesized that PrPC may regulate α7nAchR activation and that may prevent prion-related neurodegenerative diseases by regulating autophagic flux. PrP(106-126) treatment decreased α7nAchR expression and activation of autophagic flux. In addition, the α7nAchR activator PNU-282987 enhanced autophagic flux and protected neuron cells against PrP(106-126)-induced apoptosis. However, activation of autophagy and the protective effects of PNU-282987 were inhibited in PrPC knockout hippocampal neuron cells. In addition, PrPC knockout hippocampal neuron cells showed decreased α7nAchR expression levels. Adenoviral overexpression of PrPC in PrPC knockout hippocampal neuron cells resulted in activation of autophagic flux and inhibition of prion peptide-mediated cell death via α7nAchR activation. This is the first report demonstrating that activation of α7nAchR-mediated autophagic flux is regulated by PrPC, and that activation of α7nAchR regulated by PrPC expression may play a pivotal role in protection of neuron cells against prion peptide-induced neuron cell death by autophagy. These results suggest that α7nAchR-mediated autophagic flux may be involved in the pathogenesis of prion-related diseases and may be a therapeutic target for prion-related neurodegenerative diseases. PMID:26295309

  13. The inhibitive effect of some quaternary ammonium salts towards corrosion of aluminium in hydrochloric acid solution

    NASA Astrophysics Data System (ADS)

    Mohamed, A.-M. K.; Al-Nadjm, A.; Fouda, A.-A. S.

    1998-10-01

    The inhibitive action of some quaternary ammonium salts towards the corrosion of aluminium in hydrochloric acid was tested by thermometric, mass loss and polarization measurements. Parallelism between the different methods was established. It is suggested that the tested compounds act as cathodic inhibitors. The inhibitors appear to function through adsorption, following the Temkin adsorption isotherm. The values of free energy of adsorption have been calculated and discussed. The inhibitor character of the additives depends upon the concentration as well as the composition of the inhibitor. Within the given homolegous series the contribution of the functional group to adsorption increases with the length of the chain. The aim of this article is to throw some light on the mechanism of inhibition of these bulky molecules on the corrosion of aluminium in hydrochloric acid. L'action inhibitrice de certains sels d'ammonium quaternaires vis-à-vis de la corrosion de l'aluminium dans l'acide chlorhydrique en solution a été testée par des mesures thermiques de perte de matière et de polarisation. Il est suggéré que les composés testés agissent comme des inhibiteurs cathodiques, fonctionnant par adsorption suivant l'isotherme de Temkin. Les énergies libres d'adsorption ont été calculées et discutées. Le caractère inhibiteur des additifs dépend aussi bien de leur concentration que de leur composition. Pour une série d'inhibiteurs homologues, la contribution à l'adsorption du groupe fonctionnel augmente avec la longueur de la chaîne. Le but de cet article est de mieux comprendre le mécanisme d'inhibition de ces grosses molécules sur la corrosion de l'aluminium dans l'acide chlorhydrique.

  14. Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases.

    PubMed

    Farina, Roberta; Pisani, Leonardo; Catto, Marco; Nicolotti, Orazio; Gadaleta, Domenico; Denora, Nunzio; Soto-Otero, Ramon; Mendez-Alvarez, Estefania; Passos, Carolina S; Muncipinto, Giovanni; Altomare, Cosimo D; Nurisso, Alessandra; Carrupt, Pierre-Alain; Carotti, Angelo

    2015-07-23

    The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.

  15. Carbon dots-assisted colorimetric and fluorometric dual-mode protocol for acetylcholinesterase activity and inhibitors screening based on the inner filter effect of silver nanoparticles.

    PubMed

    Zhao, Dan; Chen, Chuanxia; Sun, Jian; Yang, Xiurong

    2016-06-01

    In this work, we proposed an original and versatile dual-readout (colorimetric and fluorometric) protocol by means of silver nanoparticles (AgNPs) and fluorescent carbon dots (CDs), which was amenable to rapid, ultrasensitive assay of acetylcholinesterase (AChE) activity and its inhibitors. The sensing mechanism was based on the non-fluorescence state of CDs resulting from the inner filter effect (IFE) of AgNPs and the specific AChE-catalyzed hydrolysis of acetylthiocholine (ATCh) into thiocholine (TCh). Herein, the generated positively-charged and thiol-bearing TCh at trace concentration levels could trigger the aggregation of AgNPs through the well-known electrostatic and Ag-SH interactions, thereby turning the sensing solutions grey and recovering the IFE-quenched fluorescence simultaneously. Furthermore, the existence of IFE mechanism was conceivably confirmed by combining the zeta potentials, fluorescence spectra, UV-vis spectra, fluorescence lifetime and TEM measurements. As far as we know, the present study has reported the first dual-mode proposal for assessing AChE activity by using a CDs-based IFE sensing strategy, where the detection limit was as low as 0.021 mU mL(-1) and 0.016 mU mL(-1) by colorimetric and fluorometric measurements, respectively. On the other hand, the proposed assay was feasible to screen AChE inhibitors such as tacrine and carbaryl. Meanwhile, this rationally designed dual-mode sensing platform featured simplicity, rapidity, flexibility and diversity, which was demonstrated by the quantitative detection of spiked carbaryl in apple juice samples with satisfactory results. PMID:27099097

  16. Expression and function of striatal nAChRs differ in the flinders sensitive (FSL) and resistant (FRL) rat lines.

    PubMed

    Auta, J; Lecca, D; Nelson, M; Guidotti, A; Overstreet, D H; Costa, E; Javaid, J I

    2000-10-01

    Rats of Flinders Sensitive (FSL) and Flinders Resistant lines (FRL) differ in their susceptibility to physiological and associated behavioral responses elicited by nicotine. In the present study, we measured dopamine (DA) content in striatal dialysates to investigate the sensitivity of FSL and FRL rats to nicotine delivered locally through a microdialysis probe placed in the striatum. We also measured the expression density of striatal high-affinity nicotinic acetylcholine receptors (nAChRs), and that of mRNAs encoding for alpha3, alpha4, alpha7 and beta2 nAChR subunits in both lines. The DA content of dialysates was measured before and after a 1-min perfusion of nicotine (6, 10 or 20 nmoles/min) and the resulting DA increase was taken as a measure of the alkaloid's intrinsic activity for nAChRs involved in the release of DA. The nicotine-induced increase of striatal DA release was greater in FSL than in FRL rats for all concentrations of nicotine, suggesting that the intrinsic activity of nicotine was greater in the FSL than in the FRL rats. This was further supported by our finding that the density of high-affinity nAChRs in the striatum of FSL rats was 44% greater than in the FRL rats, whereas affinity (K(D)) was virtually the same in the two lines of rats. Also the expression of mRNAs encoding for alpha(4), alpha(7), and beta(2) subunits in the striatum was greater in FSL than in FRL rats (attomol/microg total RNA, alpha(4):98+/-10 vs. 77+/-7; alpha(7):279+/-16 vs. 184+/-16; beta(2):310+/-19 vs. 201+/-12). We hypothesize that the difference in nicotine-induced DA release in the striatum of FSL and FRL rats depends on the difference in nAChR subunit expression in the striatum between the two lines. The Flinders rats could be used as a model for nicotine self-administration studies to evaluate the susceptibilities of FSL and FRL rats to nicotine dependence.

  17. Tertiary and Quaternary Research with Remote Sensing Methods

    NASA Technical Reports Server (NTRS)

    Conel, J. E.

    1985-01-01

    Problems encountered in mapping the Quaternary section of the Wind River Region using remote sensing methods are discussed. Analysis of the stratigraphic section is a fundamental aspect of the geologic study of sedimentary basins. Stratigraphic analysis of post-Cretaceous rocks in the Wind River Basin encounters problems of a distinctly different character from those involved in studying the pre-Cretaceous section. The interior of the basin is predominantly covered by Tertiary and Quaternary sediments. These rocks, except on the basin margin to the north, are mostly flat lying or gently dipping. The Tertiary section consists of sandstones, siltstones, and tuffaceous sediments, some variegated, but in general poorly bedded and of great lithologic similarity. The Quaternary sediments consist of terrace, fan, and debris tongue deposits, unconsolidated alluvium occupying the bottoms of modern watercourses, deposits of eolian origin and tufa. Terrace and fan deposits are compositionally diverse and reflect the lithologic diversity of the source terranes.

  18. Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity

    SciTech Connect

    Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

    1984-04-01

    The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

  19. Atmospheric effects on Quaternary polarization encoding for free space communication

    NASA Astrophysics Data System (ADS)

    Soorat, Ram; Vudayagiri, Ashok

    2016-10-01

    We have simulated atmospheric effects such as fog and smoke in laboratory environment to simulate depolarisation due to atmospheric effects during a free space optical communi- cation. This has been used to study noise in two components of quaternary encoding for polarization shift keying. Individual components of a Quaternary encoding, such as vertical and horizontal as well as 45$^\\circ$ and 135$^\\circ$ , are tested separately and indicates that the depo- larization effects are different for these two situation. However, due to a differential method used to extract information bits, the protocol shows extremely low bit error rates. The information obtained is useful during deployment of a fully functional Quaternary encoded PolSK scheme in free space.

  20. Characterization of Quaternary and suspected Quaternary faults, Amargosa area, Nevada and California

    SciTech Connect

    Anderson, R.E.; Crone, A.J.; Machette, M.N.; Bradley, L.A.; Diehl, S.F.

    1995-12-31

    This report presents the results of geologic studies that help define the Quaternary history of selected faults in the region around Yucca Mountain, Nevada. These results are relevant to the seismic-design basis of a potential nuclear waste repository at Yucca Mountain. The relevancy is based, in part, on a need for additional geologic data that became apparent in ongoing studies by S. Pezzopane (written commun., 1995) that resulted in the identification of 51 relevant and potentially relevant (see appendix A for definitions) individual and compound faults and fault zones in the 100-km-radius region around the Yucca Mountain site. These structures were divided into local and regional categories by Pezzopane (1995); this report deals with selected regional structures. In this introduction, the authors outline the scope and strategy of the studies and the tectonic environment of the studied structures.

  1. Geological Mapping of the Ac-H-13 Urvara Quadrangle of Ceres from NASA's Dawn Mission

    NASA Astrophysics Data System (ADS)

    Sizemore, Hanna; Williams, David; Platz, Thomas; Mest, Scott; Yingst, Aileen; Crown, David; O'Brien, David; Buczkowski, Debra; Schenk, Paul; Scully, Jennifer; Jaumann, Ralf; Roatsch, Thomas; Preusker, Frank; Nathues, Andreas; De Sanctis, Maria Cristina; Russell, Christopher; Raymond, Carol

    2016-04-01

    The Dawn Science Team is conducting a geologic mapping campaign for Ceres similar to that done for Vesta [1,2], including production of a Survey- and High Altitude Mapping Orbit (HAMO)-based global map, and a series of 15 Low Altitude Mapping Orbit (LAMO)-based quadrangle maps. In this abstract we discuss the geologic evolution of the Ac-H-13 Urvara Quadrangle. At the time of this writing LAMO images (35 m/pixel) are just becoming available. Thus, our geologic maps are based on HAMO images (140 m/pixel) and Survey (400 m/pixel) digital ter-rain models (for topographic information). Dawn Framing Camera (FC) color images are also used to provide context for map unit identification. The maps to be presented as posters will be updated from analyses of LAMO images. The Urvara Quadrangle is dominated by the 170-km diameter impact basin Urvara (46.4°S, 248.6°E) and includes cratered terrain to the west. Named features include the impact craters Meanderi (40.9°S, 193.7°E, 103 km diameter), Sekhet (66.4°S, 254.9°E, 41 km diameter), and Fluusa (31.5°S, 277.9°E), as well as the crater chains Gerber Catena (38.1°S, 214.8°E) and Sam-hain Catena (19.6°S, 210.3°E). Based on preliminary geologic mapping [3,4], we interpret the two prominent catenae as pit craters associated with large scale tectonism rather than secondary impacts. We interpret two large curvilinear depressions near the eastern quadrangle boundary as secondary crater chains resulting from the Urvara impact. Textural and morphological asymme-tries in crater materials within the quadrangle indicate heterogeneities in subsurface composition and volatile content. Features on the Urvara basin floor are consistent with impact fluidization of target materials; post impact extrusion of volatile rich material may have also played a minor role. References: [1] Williams D.A. et al. (2014) Icarus, 244, 1-12. [2] Yingst R.A. et al. (2014) PSS, 103, 2-23. [3] Sizemore et al. (2015) GSA Abstracts with Program

  2. Geological Mapping of the Ac-H-7 Kerwan Quadrangle of Ceres from NASA Dawn Mission.

    NASA Astrophysics Data System (ADS)

    Williams, David; Mest, Scott; Kneissl, Thomas; Hendrik Pasckert, Jan; Hiesinger, Harald; Neesemann, Adrian; Schmedemann, Nico; Buczkowski, Debra; Scully, Jennifer; Marchi, Simone; Schenk, Paul; Jaumann, Ralf; Roatsch, Thomas; Preusker, Frank; Nathues, Andreas; Schaefer, Michael; Hoffmann, Martin; Raymond, Carol; Russell, Christopher

    2016-04-01

    NASA's Dawn Science Team is conducting a geologic mapping campaign for Ceres similar to that done for Vesta [1,2], including a series of 15 Low Altitude Mapping Orbit (LAMO)-based quadrangle maps. Ac-H-7 Kerwan Quadrangle is located between 22°S-22°N and 72-144°E, and hosts several primary features and terrains: 1) The 280 km diameter impact basin Kerwan occur in the center and SE corner of the quad-rangle. Kerwan's rim is very degraded and there is no obvious ejecta field, indicating it is one of the oldest visible large impact basins on Ceres. Kerwan's interior is filled with a 'smooth terrain' that also extends beyond the rim to the east and west. This smooth terrain hosts a significantly lower impact crater density than most of the rest of Ceres' surface. Preliminary crater counts of the Kerwan smooth terrain derive cratering model ages of ~3 Ga using the lunar-derived chronology and ~600-800 Ma using the asteroid flux-derived chronology (H. Hiesinger, pers. comm., 2016). Our working interpretation is that the Kerwan impact occurred when Ceres' crust had a greater proportion of ice than at present, and that impact heating melted crustal material resulting in resurfacing of the Kerwan region by an icy impact melt, or possibly initiated cryovolcanic flows. There are hints of possible flow margins on the Kerwan floor in HAMO images, that have to be confirmed or denied by study of LAMO images. 2) Part of the 126 km diameter crater Dantu and its ejecta field covers the NE corner of the quadrangle. FC color data show both bright and dark materials in the ejecta field, suggesting ex-cavation of terrains of different compositions. Alternatively, because Dantu is one of two longitudes on Ceres where water vapor release has been detected [3], another interpretation is that the bright and/or dark deposits in the Dantu region could result from explosive cryovolcanism. Further study of LAMO data is required to investigate these hypotheses. 3) Other features include the

  3. Geological Mapping of the Ac-H-2 Coniraya Quadrangle of Ceres from NASA's Dawn Mission.

    NASA Astrophysics Data System (ADS)

    Hendrik Pasckert, Jan; Hiesinger, Harald; Williams, David; Crown, David; Mest, Scott; Buczkowski, Debra; Scully, Jennifer; Schmedemann, Nico; Jaumann, Ralf; Roatsch, Thomas; Preusker, Frank; Naß, Andrea; Nathues, Andreas; Hoffmann, Martin; Schäfer, Michael; De Sanctis, Maria Cristina; Raymond, Carol; Russell, Christopher

    2016-04-01

    Dwarf planet Ceres (˜950 km) is located at ˜2.8 AU in the main asteroid belt [1], and is currently orbited by NASA's Dawn spacecraft. Similar to Vesta [2], the 15 quadrangles of Ceres will be mapped on the basis of Framing Camera mosaics from Low Altitude Mapping Orbits (LAMO) with a spatial resolution of ˜35 m/px. Here we report on our preliminary geological map of the Ac-H-2 Coniraya Quadrangle (located between 21-66 ° N and 0-90 ° E) based on High Altitude Mapping Orbit (HAMO) data (˜120 m/px), as LAMO images are just becoming available. The Coniraya Quadrangle is dominated by craters of different sizes and degradation stages. Most of the craters are highly degraded and no ejecta blankets are visible (e.g., Coniraya: 136 km; 65.8° E/40.5° N). Only some craters like Gaue and Ikapati seem to be relatively fresh, and still have ejecta blankets. Such fresher impact craters could already be mapped in detail on HAMO data, and subdivided into crater ejecta, crater wall, crater floor, and crater central peak materials. At the crater floor and around Ikapati crater we also identified smooth materials that fill local depressions. The formation of the smooth material seems to be related to the formation of the impact crater, as crater densities of the smooth materials and the ejecta blanket are similar, as are their absolute model ages (AMAs), derived from crater size-frequency distribution (CSFD) measurements. Using the lunar derived chronology, CSFD measurements of Ikapati's ejecta blanket and the smooth materials located in and around the crater show AMAs of 300 to 390 Ma. CSFD measurements of Gaue crater show AMAs of 910-980 Ma. Both craters show background AMAs of 3.1 to 3.5 Ga, which might be related to old large craters (e.g., Coniraya or Kerwan). Apart from crater related units, we identified one dome-like structure (˜65 km wide; ˜3 km high) at the crater floor of a large degraded crater at the western edge of this quadrangle. This might be an indication

  4. Geological Mapping of the Ac-H-11 Sintana Quadrangle of Ceres from NASA's Dawn Mission.

    NASA Astrophysics Data System (ADS)

    Schulzeck, Franziska; Krohn, Katrin; Jaumann, Ralf; Williams, David A.; Buczkowski, Debra L.; Mest, Scott C.; Scully, Jennifer E. C.; Gathen, Isabel v. d.; Kersten, Elke; Matz, Klaus-Dieter; Naß, Andrea; Otto, Katharina; Pieters, Carle M.; Preusker, Frank; Roatsch, Thomas; De Sanctis, Maria C.; Schenk, Paul; Schröder, Stefanus; Stephan, Katrin; Wagner, Roland

    2016-04-01

    In December 2015, the Dawn spacecraft delivered the first images of the Low Altitude Mapping Orbit (LAMO) of the dwarf planet Ceres at a resolution of 35 m/pixel. This data will be used to finish the geological mapping of Ceres' surface in order to identify composition and surface forming processes. Mapping was already done using Survey Orbit and High Altitude Mapping Orbit (HAMO) data. With the new images, an updated map will be presented. To this point, the data material consists of a HAMO clear-filter mosaic (140 m/pixel) [1], a digital elevation model (DTM) [2] derived from Survey orbit (415 m/pixel) data, color-filter ratios and photometrically corrected images. Ceres' surface has been divided into 15 mapping quadrangles. The Ac-H-11 Sintana quadrangle is located in the southern hemisphere of Ceres between 21 66°S and 0 90°E. Geological units identified so far are cratered terrain, which covers most of the area, and a younger unit of relatively smooth material. The latter is characterized by a low crater density. Material of the same unit was found in adjacent quadrangles as well. Interest is taken in the diversity of crater shapes. Many craters show different forms of asymmetries. One and the same crater for instance displays different stages of rim degradation and some crater walls are partly terraced and their slopes' steepness is varying alongside the crater rim. Several mass wasting features, which partly cause the observed asymmetries, have been identified. Next to the multiple collapsed rims, landslides due to later cratering on the primary crater rim are observed. Whereas collapse structures are mostly blocky, single landslides are characterized by lobate margins. Occurrence and type of mass wasting feature might hint to subsurface differences. Further, there is a diversity of inner crater structures, like relaxed crater floors, ridges, central peaks, mounds and smooth plains. Processes like mass wasting and relaxation have modified many craters

  5. Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators.

    PubMed

    Ashani, Yacov; Bhattacharjee, Apurba K; Leader, Haim; Saxena, Ashima; Doctor, Bhupendra P

    2003-07-15

    Oxime-induced reactivation of phosphonylated cholinesterases (ChEs) produces charged phosphonyl pyridine oxime intermediates (POXs) that are most potent organophosphate (OP) inhibitors of ChEs. To understand the role of cationic pyridine oxime leaving groups in the enhanced anti-ChE activity of POXs, the bimolecular rate constants for the inhibition (k(i)) of acetylcholinesterases (AChE) and butyrylcholinesterases (BChE), and the rate of decomposition (k(d)) of authentic O-alkyl methylphosphonyl pyridine oximes (AlkMeP-POXs) and N,N-dimethylamidophosphoryl pyridine oximes (EDMP-POXs), were studied. Stability ranking order in aqueous solutions correlated well with the electronic features and optimized geometries that were obtained by ab initio calculations at 6-31G(**) basis set level. AlkMeP-POXs of the 2-pyridine oxime series were found to be 4- to 8-fold more stable (t(1/2)=0.7 to 1.5 min) than the homologous O,O-diethylphosphoryl (DEP) oxime. Results suggest that re-inhibition of enzyme activity by POX is less likely during the reactivation of DEP-ChEs (obtained by use of DEP-containing pesticides) by certain oximes, compared to nerve agent-inhibited ChEs. The greatest inhibition was observed for the O-cyclohexyl methylphosphonyl-2PAM derivative (4.0 x 10(9)M(-1)min(-1); mouse AChE) and is 10-fold higher than the k(i) of cyclosarin. Increasing the size of the O-alkyl substituent of AlkMeP-POXs had only a small to moderate effect on the k(i) of ChEs, signifying a major role for the cationic pyridine oxime leaving group in the inhibition reaction. The shape of plots of logk(i) vs. pK(a) of the leaving groups for AlkMeP-PAMs and DEP-PAMs, could be used as a diagnostic tool to highlight and rationalize the unique properties of the cationic moiety of pyridine oxime reactivators.

  6. Ice Age Earth: Late Quaternary geology and climate

    SciTech Connect

    Dawson, A.G.

    1992-01-01

    This book is a concise and readable account of the most important geologic records of the late Quaternary. It provides a synopsis of the major environmental changes that took place from approximately 13,000 to 7,000 years ago, highlighting the complexity and rapidity of past climate changes and the environmental responses they produced. The text is well illustrated, though some figures are rough and need more explanation. Also needed is a critical appraisal of the geochronology which places the paleoenvironmental records into the temporal domain. However, as a whole the book reaches its objective of summarizing the most important scientific findings about the nature of the late Quaternary climate changes.

  7. In vivo labelling of hippocampal beta-amyloid in triple-transgenic mice with a fluorescent acetylcholinesterase inhibitor released from nanoparticles.

    PubMed

    Härtig, Wolfgang; Kacza, Johannes; Paulke, Bernd-Reiner; Grosche, Jens; Bauer, Ute; Hoffmann, Anke; Elsinghorst, Paul W; Gütschow, Michael

    2010-01-01

    The drastic loss of cholinergic projection neurons in the basal forebrain is a hallmark of Alzheimer's disease (AD), and drugs most frequently applied for the treatment of dementia include inhibitors of the acetylcholine-degrading enzyme acetylcholinesterase (AChE). This protein is known to act as a ligand of beta-amyloid (Abeta) in senile plaques, a further neuropathological sign of AD. Recently, we have shown that the fluorescent, heterodimeric AChE inhibitor PE154 allows for the histochemical staining of cortical Abeta plaques in triple-transgenic (TTG) mice with age-dependent beta-amyloidosis and tau hyperphosphorylation, an established animal model for aspects of AD. In the present study, we have primarily demonstrated the targeting of Abeta-immunopositive plaques with PE154 in vivo for 4 h up to 1 week after injection into the hippocampi of 13-20-month-old TTG mice. Numerous plaques, double-stained for PE154 and Abeta-immunoreactivity, were revealed by confocal laser-scanning microscopy. Additionally, PE154 targeted hippocampal Abeta deposits in aged TTG mice after injection of carboxylated polyglycidylmethacrylate nanoparticles delivering the fluorescent marker in vivo. Furthermore, biodegradable core-shell polystyrene/polybutylcyanoacrylate nanoparticles were found to be suitable, alternative vehicles for PE154 as a useful in vivo label of Abeta. Moreover, we were able to demonstrate that PE154 targeted Abeta, but neither phospho-tau nor reactive astrocytes surrounding the plaques. In conclusion, nanoparticles appear as versatile carriers of AChE inhibitors and other promising drugs for the treatment of AD.

  8. 2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase.

    PubMed

    Leong, Sze Wei; Abas, Faridah; Lam, Kok Wai; Shaari, Khozirah; Lajis, Nordin H

    2016-08-15

    In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer. PMID:27328658

  9. Potent acetylcholinesterase inhibitors: Synthesis, biological assay and docking study of nitro acridone derivatives.

    PubMed

    Parveen, Mehtab; Aslam, Afroz; Nami, Shahab A A; Malla, Ali Mohammed; Alam, Mahboob; Lee, Dong-Ung; Rehman, Sumbul; Silva, P S Pereira; Silva, M Ramos

    2016-08-01

    The reaction of o-halobenzoic acid with aniline derivatives and their subsequent cyclization reaction yielded the acridone derivatives. The series of nitro acridone derivatives were prepared by Ullmann condensation in presence of copper as catalyst and were characterized by FTIR, (1)H, (13)C NMR and mass spectra. The structure of 5-nitro-(2-phenyl amino) benzoic acid (4) was confirmed by X-ray crystallography and was found to crystallize in P21/c space group. The in vitro efficacy of the compounds for their acetylcholinesterase (AChE) and antimicrobial inhibitory activities have been evaluated against the standard drugs Ampicillin and Gentamicin against Gram positive and Gram negative bacteria. 1,7-Dinitroacridone was found to be the most potent AChE inhibitor (IC50=0.22μM). Moreover, the compounds have been screened for their antioxidant activity using the DPPH assay. Also, docking study results were found to be in good agreement with the results obtained through in vitro experiments. The docking study further predicted possible binding conformation. PMID:27295412

  10. Assessment of the functionality and stability of detergent purified nAChR from Torpedo using lipidic matrixes and macroscopic electrophysiology.

    PubMed

    Padilla-Morales, Luis F; Colón-Sáez, José O; González-Nieves, Joel E; Quesada-González, Orestes; Lasalde-Dominicci, José A

    2016-01-01

    In our previous study we examined the functionality and stability of nicotinic acetylcholine receptor (nAChR)-detergent complexes (nAChR-DCs) from affinity-purified Torpedo californica (Tc) using fluorescence recovery after photobleaching (FRAP) in Lipidic Cubic Phase (LCP) and planar lipid bilayer (PLB) recordings for phospholipid and cholesterol like detergents. In the present study we enhanced the functional characterization of nAChR-DCs by recording macroscopic ion channel currents in Xenopus oocytes using the two electrode voltage clamp (TEVC). The use of TEVC allows for the recording of macroscopic currents elicited by agonist activation of nAChR-DCs that assemble in the oocyte plasma membrane. Furthermore, we examined the stability of nAChR-DCs, which is obligatory for the nAChR crystallization, using a 30 day FRAP assay in LCP for each detergent. The present results indicate a marked difference in the fractional fluorescence recovery (ΔFFR) within the same detergent family during the 30 day period assayed. Within the cholesterol analog family, sodium cholate and CHAPSO displayed a minimum ΔFFR and a mobile fraction (MF) over 80%. In contrast, CHAPS and BigCHAP showed a marked decay in both the mobile fraction and diffusion coefficient. nAChR-DCs containing phospholipid analog detergents with an alkylphosphocholine (FC) and lysofoscholine (LFC) of 16 carbon chains (FC-16, LFC-16) were more effective in maintaining a mobile fraction of over 80% compared to their counterparts with shorter acyl chain (C12, C14). The significant differences in macroscopic current amplitudes, activation and desensitization rates among the different nAChR-DCs evaluated in the present study allow to dissect which detergent preserves both, agonist activation and ion channel function. Functionality assays using TEVC demonstrated that LFC16, LFC14, and cholate were the most effective detergents in preserving macroscopic ion channel function, however, the nAChR-cholate complex

  11. Assessment of the functionality and stability of detergent purified nAChR from Torpedo using lipidic matrixes and macroscopic electrophysiology.

    PubMed

    Padilla-Morales, Luis F; Colón-Sáez, José O; González-Nieves, Joel E; Quesada-González, Orestes; Lasalde-Dominicci, José A

    2016-01-01

    In our previous study we examined the functionality and stability of nicotinic acetylcholine receptor (nAChR)-detergent complexes (nAChR-DCs) from affinity-purified Torpedo californica (Tc) using fluorescence recovery after photobleaching (FRAP) in Lipidic Cubic Phase (LCP) and planar lipid bilayer (PLB) recordings for phospholipid and cholesterol like detergents. In the present study we enhanced the functional characterization of nAChR-DCs by recording macroscopic ion channel currents in Xenopus oocytes using the two electrode voltage clamp (TEVC). The use of TEVC allows for the recording of macroscopic currents elicited by agonist activation of nAChR-DCs that assemble in the oocyte plasma membrane. Furthermore, we examined the stability of nAChR-DCs, which is obligatory for the nAChR crystallization, using a 30 day FRAP assay in LCP for each detergent. The present results indicate a marked difference in the fractional fluorescence recovery (ΔFFR) within the same detergent family during the 30 day period assayed. Within the cholesterol analog family, sodium cholate and CHAPSO displayed a minimum ΔFFR and a mobile fraction (MF) over 80%. In contrast, CHAPS and BigCHAP showed a marked decay in both the mobile fraction and diffusion coefficient. nAChR-DCs containing phospholipid analog detergents with an alkylphosphocholine (FC) and lysofoscholine (LFC) of 16 carbon chains (FC-16, LFC-16) were more effective in maintaining a mobile fraction of over 80% compared to their counterparts with shorter acyl chain (C12, C14). The significant differences in macroscopic current amplitudes, activation and desensitization rates among the different nAChR-DCs evaluated in the present study allow to dissect which detergent preserves both, agonist activation and ion channel function. Functionality assays using TEVC demonstrated that LFC16, LFC14, and cholate were the most effective detergents in preserving macroscopic ion channel function, however, the nAChR-cholate complex

  12. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  13. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  14. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  15. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  16. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  17. HDAC Inhibitors.

    PubMed

    Olzscha, Heidi; Bekheet, Mina E; Sheikh, Semira; La Thangue, Nicholas B

    2016-01-01

    Lysine acetylation in proteins is one of the most abundant posttranslational modifications in eukaryotic cells. The dynamic homeostasis of lysine acetylation and deacetylation is dictated by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Important substrates for HATs and HDACs are histones, where lysine acetylation generally leads to an open and transcriptionally active chromatin conformation. Histone deacetylation forces the compaction of the chromatin with subsequent inhibition of transcription and reduced gene expression. Unbalanced HAT and HDAC activity, and therefore aberrant histone acetylation, has been shown to be involved in tumorigenesis and progression of malignancy in different types of cancer. Therefore, the development of HDAC inhibitors (HDIs) as therapeutic agents against cancer is of great interest. However, treatment with HDIs can also affect the acetylation status of many other non-histone proteins which play a role in different pathways including angiogenesis, cell cycle progression, autophagy and apoptosis. These effects have led HDIs to become anticancer agents, which can initiate apoptosis in tumor cells. Hematological malignancies in particular are responsive to HDIs, and four HDIs have already been approved as anticancer agents. There is a strong interest in finding adequate biomarkers to predict the response to HDI treatment. This chapter provides information on how to assess HDAC activity in vitro and determine the potency of HDIs on different HDACs. It also gives information on how to analyze cellular markers following HDI treatment and to analyze tissue biopsies from HDI-treated patients. Finally, a protocol is provided on how to detect HDI sensitivity determinants in human cells, based on a pRetroSuper shRNA screen upon HDI treatment. PMID:27246222

  18. A combined molecular docking and charge density analysis is a new approach for medicinal research to understand drug-receptor interaction: curcumin-AChE model.

    PubMed

    Renuga Parameswari, A; Rajalakshmi, G; Kumaradhas, P

    2015-01-01

    In the present study, a molecular docking analysis has been performed on diketone form of curcumin molecule with acetylcholinesterase (AChE). The calculated lowest docked energy of curcumin molecule in the active site of AChE is -11.21 kcal/mol; this high negative value indicates that the molecule exhibits large binding affinity towards AChE. When the curcumin molecule present in the active site of AChE, subsequently, its conformation has altered significantly and the molecule adopts a U-shape geometry as it is linear in gas phase (before entering into the active site). This conformational transition facilitates curcumin to form strong interaction with Phe330 of acyl-binding pocket and the choline binding site with indole ring of Trp84 and Asp72. The gas phase and the active site analysis of curcumin allows to understand the conformational geometry, nature of molecular flexibility, charge density redistribution and the variation of electrostatic properties of curcumin in the active site. To obtain the gas phase structure, the curcumin molecule was optimized using Hartree-Fock and density functional methods (B3LYP) with the basis set 6-311G(∗∗). A charge density analysis on both gas phase as well as the molecule lifted from the active site was carried out using Bader's theory of atoms in molecules (AIM). The difference in molecular electrostatic potential between the two forms of curcumin displays the difference in charge distribution. The large dipole moment of curcumin (7.54 D) in the active site reflects the charge redistribution as it is much less in the gas phase (4.34 D).

  19. An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer's disease.

    PubMed

    Greig, Nigel H; Sambamurti, Kumar; Yu, Qian-sheng; Brossi, Arnold; Bruinsma, Gosse B; Lahiri, Debomoy K

    2005-07-01

    Existing cholinesterase (ChE) inhibitor therapies for Alzheimer's disease (AD), while effective in improving cognitive, behavioral and functional impairments, do not alter disease progression. Novel drug design studies have focused on the classical ChE inhibitor, (-)-physostigmine, producing alterations in chemical composition and three-dimensional structure, which may offer an improved therapeutic index. The phenylcarbamate derivative, (-)-phenserine, is a selective, non-competitive inhibitor of acetylcholinesterase (AChE). In vivo, (-)-phenserine produces rapid, potent, and long-lasting AChE inhibition. As a possible result of its preferential brain selectivity, (-)-phenserine is significantly less toxic than (-)-physostigmine. In studies using the Stone maze paradigm, (-)-phenserine has been shown to improve cognitive performance in both young learning-impaired and elderly rats. In addition to reducing inactivation of acetylcholine in the brain, (-)-phenserine appears to have a second mode of action. Reduced secretion of beta-amyloid (Abeta) has been observed in cell lines exposed to (-)-phenserine, occurring through translational regulation of beta-amyloid precursor protein (beta-APP) mRNA via a non-cholinergic mechanism. These in vitro findings appear to translate in vivo into animal models and humans. In a small study of patients with AD, (-)-phenserine treatment tended to reduce beta-APP and Abeta levels in plasma samples. Clinical studies also reveal that (-)-phenserine (5-10 mg b.i.d.) had a favorable safety and pharmacological profile, produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks. Further randomized, double-blind, placebo-controlled Phase III studies assessing the efficacy, safety/tolerability and potential disease-modifying effects of (-)-phenserine in patients with AD are currently ongoing.

  20. Chronic ethanol (EtOH) feeding increases muscarinic receptor (mAChR) density in esophagus without parallel change in dose response (D-R) to cholinergic agonists

    SciTech Connect

    Keshavarzian, A.; Gordon, J.H.; Urban, G.; Fields, J.Z. VA Hospital, Hines, IL )

    1991-03-11

    The mAChR/effector pathway for signal transduction is important in the physiology of esophagus and mAChR alterations are involved in EtOH induced changes in several organs. To see if EtOH-induced increases in lower esophageal sphincter pressure (LESP) are due to upregulation of mAChR, the authors evaluated mAChR binding and D-R curves for bethanechol (IV) induced increases in LESP, and compared these values to changes in LESP after acute and chronic EtOH. EtOH was given to cats acutely or chronically. The number of mAChR sites (Bmax) in esophagus was lowered by acute EtOH, withdrawal from chronic EtOH raised Bmax. Acute injection of EtOH to cats in withdrawal reversed this increase in mAChR density. These changes correlated with the earlier data on EtOH-induced changes in LESP. In contrast, the D-R curve for bethanechol shifted to the right. Thus, the withdrawal-associated increase in Bmax is more likely to be a compensatory response to deficits distal to the receptor recognition site than to proximal deficits and doesn't cause LESP hyperactivity. Also, receptor binding changes do not necessarily translate into physiological changes.

  1. Geological Mapping of the Ac-H-5 Fejokoo Quadrangle of Ceres from NASA's Dawn Mission

    NASA Astrophysics Data System (ADS)

    Hughson, Kynan; Russell, Christopher; Williams, David; Buczkowski, Debra; Mest, Scott; Scully, Jennifer; Kneissl, Thomas; Ruesch, Ottaviano; Frigeri, Alessandro; Combe, Jean-Philippe; Jaumann, Ralf; Roatsch, Thomas; Preusker, Frank; Platz, Thomas; Nathues, Andreas; Hoffmann, Martin; Schaefer, Michael; Park, Ryan; Marchi, Simone; Raymond, Carol

    2016-04-01

    NASA's Dawn spacecraft arrived at Ceres on March 6, 2015, and has been studying the dwarf planet through a series of successively lower orbits, obtaining morphological & topographical image, mineralogical, elemental abundance, and gravity data. Ceres is the largest object in the asteroid belt with a mean diameter of ~950 km. The Dawn Science Team is conducting a geologic mapping campaign for Ceres similar to that done for the asteroid Vesta [1, 2], including production of a Survey- and High Altitude Mapping Orbit (HAMO)-based global map, and a series of 15 Low Altitude Mapping Orbit (LAMO)-based quadrangle maps. In this abstract we present the LAMO-based geologic map of the Ac-H-5 Fejokoo quadrangle (21-66 °N and 270-360 °E) and discuss its geologic evolution. At the time of this writing LAMO images (35 m/pixel) are just becoming available. Thus, our geologic maps are based on HAMO images (~140 m/pixel) and Survey (~400 m/pixel) digital terrain models (for topographic information) [3, 4]. Dawn Framing Camera (FC) color images are also used to provide context for map unit identification. The maps to be presented as posters will be updated from analyses of LAMO images (~35 m/pixel). The Fejokoo quadrangle hosts six primary geologic features: (1) the centrally located, ~80 km diameter, distinctly hexagonal impact crater Fejokoo; (2) Victa crater with its large exterior dark lobate flow feature, and interior lobate and furrowed deposits; (3) Abellio crater, which exhibits a well formed ejecta blanket and has an arcuately textured infilled floor whose morphology is similar to those of homologously sized craters on some of the icy Saturnian satellites [5]; (4) Cozobi crater, whose floor is filled with an unusually bulbous and smooth deposit, thin sheeted multi-lobed flow-like features that are reminiscent of fluidized ejecta as seen on Mars are also observed to be emanating outwards from the N and S rims of this crater [6]; (5) the peculiar Oxo crater on the eastern

  2. Geological Mapping of the Ac-H-3 Dantu Quadrangle of Ceres from NASA's Dawn Mission.

    NASA Astrophysics Data System (ADS)

    Kneissl, Thomas; Schmedemann, Nico; Neesemann, Adrian; Williams, David A.; Crown, David A.; Mest, Scott C.; Buczkowski, Debra L.; Scully, Jennifer E. C.; Frigeri, Allessandro; Ruesch, Ottaviano; Hiesinger, Harald; Walter, Sebastian H. G.; Jaumann, Ralf; Roatsch, Thomas; Preusker, Frank; Kersten, Elke; Naß, Andrea; Nathues, Andreas; Platz, Thomas; Russell, Chistopher T.

    2016-04-01

    The Dawn Science Team is conducting a geologic mapping campaign for Ceres similar to that done for Vesta [1,2], including production of a Survey- and High Altitude Mapping Orbit (HAMO)-based global map and a series of 15 Low Altitude Mapping Orbit (LAMO)-based quadrangle maps. In this abstract we discuss the geologic evolution of the Ac-H-3 Dantu Quadrangle. The current map is based on a Framing Camera (FC) clear-filter image mosaic from HAMO data (~140 m/px) as well as a digital terrain model (DTM) derived from imagery of the Survey phase [3]. Albedo variations were identified and mapped using a mosaic of photometrically corrected HAMO images provided by DLR. FC color images provided further context for map unit identification. LAMO images (35m/pixel), which have just become available at the time of writing, will be used to update the map to be presented as a poster. The quadrangle is located between 21-66°N and 90-180°E in a large-scale depression north of the impact basin Kerwan. The northern and southeastern parts of the quadrangle are characterized by cratered terrain while the south and southwest are dominated by the partially smooth ejecta blankets of craters Dantu and Gaue. East-west oriented pit/crater chains in the southern half of the quadrangle might be related to tectonic processes [4,5]. Dantu crater (d=~126 km) is a complex impact crater showing slump terraces and a partially smooth crater floor with concentric and radial fractures. Furthermore, Dantu shows a central pit structure with pitted terrain on its floor as well as several bright spots in the interior and exterior of the crater. High-resolution measurements of crater size-frequency distributions (CSFDs) superposed on Dantu indicate a formation/modification age of ~200 - 700 Ma. Most of the ejecta appear to be relatively bright and correspond to parts of the #2 high albedo region observed with the Hubble Space Telescope [6]. However, the southwestern portion of the ejecta blanket is

  3. Geological Mapping of the Ac-H-14 Yalode Quadrangle of Ceres from NASA's Dawn Mission

    NASA Astrophysics Data System (ADS)

    Crown, David; Yingst, Aileen; Mest, Scott; Platz, Thomas; Sizemore, Hanna; Berman, Daniel; Williams, David; Roatsch, Thomas; Preusker, Frank; Nathues, Andreas; Hoffman, Martin; Schäfer, Michael; Raymond, Carol; Russell, Christopher

    2016-04-01

    The Dawn Science Team is conducting a geologic mapping campaign for Ceres that includes production of a Survey- and High Altitude Mapping Orbit (HAMO)-based global map and a series of 15 Low Altitude Mapping Orbit (LAMO)-based quadrangle maps. In this abstract we discuss the surface geology and geologic evolution of the Ac-H-14 Yalode Quadrangle (21-66°S, 270-360°E). The current geologic map was produced using ArcGIS software based on HAMO images (140 m/pixel) for surface morphology and stratigraphic relationships, Survey (400 m/pixel) digital terrain models for topographic information, and Dawn Framing Camera (FC) color images as context for map unit identification. The map will be updated through analysis of LAMO images (35 m/pixel) that are just becoming available. The Yalode Quadrangle is dominated by the 260-km diameter impact basin Yalode (42.3°S, 293.6°E) and includes rugged and smooth terrains to the east. Preliminary geologic mapping defined two regional units (cratered terrain and smooth material), which dominate the quadrangle, as well as a series of impact crater material units. Mapped geologic features include crater rims, graben, ridges, troughs, scarp, lineaments, and impact crater chains. Geologic contacts are typically not distinct in Survey and HAMO images. Impact craters in Yalode Quadrangle display a range of preservation states. Degraded features, including Yalode basin and numerous smaller craters, exhibit subdued rims, lack discrete ejecta deposits, and have infilled interiors. More pristine features (including Mondamin, Besua, Lono and craters on the Yalode basin floor) have well-defined, quasi-circular forms with prominent rims and in some cases discernible ejecta. Some of these craters have bowl-shaped interiors, and others contain hills or mounds on their floors that are interpreted as central peaks. Yalode basin has a variably preserved rim, which is continuous and sharply defined to the north/northwest and is irregular or degraded

  4. Identification of a binding site for quaternary amines in factor Xa.

    PubMed

    Monnaie, D; Arosio, D; Griffon, N; Rose, T; Rezaie, A R; Di Cera, E

    2000-05-01

    In the process of characterizing the Na(+)-binding properties of factor Xa, a specific inhibition of this enzyme by quaternary amines was identified, consistent with previous observations. The binding occurs with K(i) in the low millimolar range, with trimethylphenylammonium (TMPA) showing the highest specificity. Binding of TMPA inhibits substrate hydrolysis in a competitive manner, does not inhibit the binding of p-aminobenzamidine to the S1 pocket, and is positively linked to Na(+) binding. Inhibition by TMPA is also seen in thrombin and tissue plasminogen activator (tPA), though to a lesser extent compared to factor Xa. Computer modeling using the crystal structure of factor Xa suggests that TMPA binds to the S2/S3 specificity sites, with its hydrophobic moiety making van der Waals interactions with the side chains of Y99, F174, and W215, and the charged amine coupling electrostatically with the carboxylates of E97. Site-directed mutagenesis of factor Xa, thrombin, and tPA confirms the predictions drawn by docking calculations and reveal a dominant role for residue Y99. Binding of TMPA to factor Xa is drastically (25-fold) reduced by the Y99T replacement. Likewise, the Y99L substitution compromises binding of TMPA to tPA. On the other hand, the affinity of TMPA is enhanced 4-fold in thrombin with the substitution L99Y. The identification of a binding site for quaternary amines in factor Xa has a bearing on the rational design of selective inhibitors of this clotting enzyme. PMID:10820005

  5. {alpha}7-nAChR-mediated suppression of hyperexcitability of colonic dorsal root ganglia neurons in experimental colitis.

    PubMed

    Abdrakhmanova, Galya R; AlSharari, Shakir; Kang, Minho; Damaj, M Imad; Akbarali, Hamid I

    2010-09-01

    Controlled clinical trials of nicotine transdermal patch for treatment of ulcerative colitis have been shown to improve histological and global clinical scores of colitis. Here we report that nicotine (1 microM) suppresses in vitro hyperexcitability of colonic dorsal root ganglia (DRG) (L(1)-L(2)) neurons in the dextran sodium sulfate (DSS)-induced mouse model of acute colonic inflammation. Nicotine gradually reduced regenerative multiple-spike action potentials in colitis mice to a single action potential. Nicotine's effect on hyperexcitability of inflamed neurons was blocked in the presence of an alpha(7)-nicotinic acetylcholine receptor (nAChR) antagonist, methyllicaconitine, while choline, the alpha(7)-nAChR agonist, induced a similar effect to that of nicotine. Consistent with these findings, nicotine failed to suppress hyperexcitability in colonic DRG neurons from DSS-treated alpha(7) knockout mice. Furthermore, colonic DRG neurons from DSS-treated alpha(7) knockout mice were characterized by lower rheobase (10 +/- 5 vs. 77 +/- 13 pA, respectively) and current threshold (28 +/- 4 vs. 103 +/- 8 pA, respectively) levels than DSS-treated C57BL/J6 mice. An interesting observation of this study is that 8 of 12 colonic DRG (L(1)-L(2)) neurons from control alpha(7) knockout mice exhibited multiple-spike action potential firing while no wild-type neurons did. Overall, our findings suggest that nicotine at low 1 microM concentration suppresses in vitro hyperexcitability of inflamed colonic DRG neurons in a mouse model of acute colonic inflammation via activation of alpha(7)-nAChRs.

  6. Nicotinic acetylcholine receptors (nAChRs) at zebrafish red and white muscle show different properties during development.

    PubMed

    Ahmed, Kazi T; Ali, Declan W

    2016-08-01

    Nicotinic acetylcholine receptors (nAChRs) are highly expressed at the vertebrate neuromuscular junction (NMJ) where they are required for muscle activation. Understanding the factors that underlie NMJ development is critical for a full understanding of muscle function. In this study we performed whole cell and outside-out patch clamp recordings, and single-cell RT-qPCR from zebrafish red and white muscle to examine the properties of nAChRs during the first 5 days of development. In red fibers miniature endplate currents (mEPCs) exhibit single exponential time courses at 1.5 days postfertilization (dpf) and double exponential time courses from 2 dpf onwards. In white fibers, mEPCs decay relatively slowly, with a single exponential component at 1.5 dpf. By 2 and 3 dpf, mEPC kinetics speed up, and decay with a double exponential component, and by 4 dpf the exponential decay reverts back to a single component. Single channel recordings confirm the presence of two main conductance classes of nAChRs (∼45 pS and ∼65 pS) in red fibers with multiple time courses. Two main conductance classes are also present in white fibers (∼55 pS and ∼73 pS), but they exhibit shorter mean open times by 5 dpf compared with red muscle. RT-qPCR of mRNA for nicotinic receptor subunits supports a switch from γ to ε subunits in white fibers but not in red. Our findings provide a developmental profile of mEPC properties from red and white fibers in embryonic and larval zebrafish, and reveal previously unknown differences between the NMJs of these muscle fibers.© 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 916-936, 2016.

  7. Topographic Characterization of Cu-Ni NPs @ a-C:H Films by AFM and Multifractal Analysis.

    PubMed

    Ţălu, Ştefan; Stach, Sebastian; Ghodselahi, Tayebeh; Ghaderi, Atefeh; Solaymani, Shahram; Boochani, Arash; Garczyk, Żaneta

    2015-04-30

    In the present work three-dimensional (3-D) surface topography of Cu-Ni nanoparticles in hydrogenated amorphous carbon (Cu-Ni NPs @ a-C:H) with constant thickness of Cu and three thicknesses of Ni prepared by RF-Plasma Enhanced Chemical Vapor Deposition (RF-PECVD) system were investigated. The thin films of Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni deposited by radio frequency (RF)-sputtering and RF-PECVD systems, were characterized. To determine the mass thickness and atomic structure of the films, the Rutherford backscattering spectroscopy (RBS) spectra was applied. The absorption spectra were applied to study localized surface plasmon resonance (LSPR) peaks of Cu-Ni NPs (observed around 608 nm in visible spectra), which is widened and shifted to lower wavelengths as the thickness of Ni over layer increases, and their changes are also evaluated by the 3-D surface topography. These nanostructures were investigated over square areas of 1 μm × 1 μm using atomic force microscopy (AFM) and multifractal analysis. Topographic characterization of surface samples (in amplitude, spatial distribution, and pattern of surface characteristics) highlighted 3-D surfaces with multifractal features which can be quantitatively estimated by the multifractal measures. The 3-D surface topography Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni prepared by RF-PECVD system can be characterized using the multifractal geometry in correlation with the surface statistical parameters. PMID:25839675

  8. The identification and restitution of human remains from an Aché girl named "Damiana": an interdisciplinary approach.

    PubMed

    Koel-Abt, Katrin; Winkelmann, Andreas

    2013-10-01

    In June 2010, the postcranial skeleton of an adolescent girl was returned by the Natural History Museum of La Plata, Argentina, to the Aché community in Paraguay. In March 2011 the missing skull was identified in the anatomical collection of Charité in Berlin. We initiated a historical and anthropological investigation to confirm the identity of the human remains and to reconstruct the fate of the individual in question in its historical context. Anthropological publications from Argentina had indicated that the girl named "Damiana" was abducted by colonising settlers in Southern Paraguay in 1897 at the age of 3-4 years, later taken to La Plata in Argentina where she grew up as a "maidservant", and died in 1907 of "galloping consumption". In accordance with these reports, the present palaeopathological investigation confirms tuberculous meningitis as a likely cause of death. It also demonstrates some markers of "stress", the nature of which, however, is difficult to determine. Surviving letters and publications by Berlin anatomist Hans Virchow reveal that the girl's preserved head was sent from La Plata to Berlin in January 1908 for comparative investigations in the context of the racial theories of the time. We were convinced that the justified wishes of the Aché community to bury these remains alongside those restituted in 2010 outweighed any future scientific interest in these remains. In April 2012, the skull and two related specimens were returned from the Charité to the Aché community, mediated by the Paraguayan ambassador in Berlin.

  9. Topographic Characterization of Cu-Ni NPs @ a-C:H Films by AFM and Multifractal Analysis.

    PubMed

    Ţălu, Ştefan; Stach, Sebastian; Ghodselahi, Tayebeh; Ghaderi, Atefeh; Solaymani, Shahram; Boochani, Arash; Garczyk, Żaneta

    2015-04-30

    In the present work three-dimensional (3-D) surface topography of Cu-Ni nanoparticles in hydrogenated amorphous carbon (Cu-Ni NPs @ a-C:H) with constant thickness of Cu and three thicknesses of Ni prepared by RF-Plasma Enhanced Chemical Vapor Deposition (RF-PECVD) system were investigated. The thin films of Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni deposited by radio frequency (RF)-sputtering and RF-PECVD systems, were characterized. To determine the mass thickness and atomic structure of the films, the Rutherford backscattering spectroscopy (RBS) spectra was applied. The absorption spectra were applied to study localized surface plasmon resonance (LSPR) peaks of Cu-Ni NPs (observed around 608 nm in visible spectra), which is widened and shifted to lower wavelengths as the thickness of Ni over layer increases, and their changes are also evaluated by the 3-D surface topography. These nanostructures were investigated over square areas of 1 μm × 1 μm using atomic force microscopy (AFM) and multifractal analysis. Topographic characterization of surface samples (in amplitude, spatial distribution, and pattern of surface characteristics) highlighted 3-D surfaces with multifractal features which can be quantitatively estimated by the multifractal measures. The 3-D surface topography Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni prepared by RF-PECVD system can be characterized using the multifractal geometry in correlation with the surface statistical parameters.

  10. Quaternary Ammonium Disinfectant Issues Encountered in an Environmental Services Department.

    PubMed

    Boyce, John M; Sullivan, Linda; Booker, Arica; Baker, James

    2016-03-01

    We identified several factors affecting the use of quaternary ammonium-based (Quat) disinfectant in our facility. Microfiber wipers, cotton towels, and 1 of 2 types of disposable wipes soaked in a Quat disinfectant revealed significant binding of the disinfectant. Concentrations of Quat delivered by automated disinfectant dispensers varied widely.

  11. Quaternary Glacial Mapping in Western Wisconsin Using Soil Survey Information

    ERIC Educational Resources Information Center

    Oehlke, Betsy M.; Dolliver, Holly A. S.

    2011-01-01

    The majority of soils in the western Wisconsin have developed from glacial sediments deposited during the Quaternary Period (2.6 million years before present). In many regions, multiple advances and retreats have left a complex landscape of diverse glacial sediments and landforms. The soils that have developed on these deposits reflect the nature…

  12. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Quaternary ammonium chloride combination. 172.165 Section 172.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Food...

  13. Application of Analytic Geometry to Ternary and Quaternary Diagrams.

    ERIC Educational Resources Information Center

    MacCarthy, Patrick

    1986-01-01

    Advantages of representing ternary and quaternary composition diagrams by means of rectangular coordinates were pointed out in a previous paper (EJ 288 693). A further advantage of that approach is that analytic geometry, based on rectangular coordinates, is directly applicable as demonstrated by the examples presented. (JN)

  14. NSC23766, a widely used inhibitor of Rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors.

    PubMed

    Levay, Magdolna; Krobert, Kurt Allen; Wittig, Karola; Voigt, Niels; Bermudez, Marcel; Wolber, Gerhard; Dobrev, Dobromir; Levy, Finn Olav; Wieland, Thomas

    2013-10-01

    Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride]. We found that NSC23766 inhibits the M2 muscarinic acetylcholine receptor (M2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rho-dependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly Giβγ-mediated, adenosine-induced activation of Gi protein-regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K(+) current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A1 receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca(2+) concentrations in human embryonic kidney 293 (HEK-293) cells expressing M1, M2, or M3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M2 and M3 mAChR crystal

  15. Improved resolution of single channel dwell times reveals mechanisms of binding, priming, and gating in muscle AChR.

    PubMed

    Mukhtasimova, Nuriya; daCosta, Corrie J B; Sine, Steven M

    2016-07-01

    The acetylcholine receptor (AChR) from vertebrate skeletal muscle initiates voluntary movement, and its kinetics of activation are crucial for maintaining the safety margin for neuromuscular transmission. Furthermore, the kinetic mechanism of the muscle AChR serves as an archetype for understanding activation mechanisms of related receptors from the Cys-loop superfamily. Here we record currents through single muscle AChR channels with improved temporal resolution approaching half an order of magnitude over our previous best. A range of concentrations of full and partial agonists are used to elicit currents from human wild-type and gain-of-function mutant AChRs. For each agonist-receptor combination, rate constants are estimated from maximum likelihood analysis using a kinetic scheme comprised of agonist binding, priming, and channel gating steps. The kinetic scheme and rate constants are tested by stochastic simulation, followed by incorporation of the experimental step response, sampling rate, background noise, and filter bandwidth. Analyses of the simulated data confirm all rate constants except those for channel gating, which are overestimated because of the established effect of noise on the briefest dwell times. Estimates of the gating rate constants were obtained through iterative simulation followed by kinetic fitting. The results reveal that the agonist association rate constants are independent of agonist occupancy but depend on receptor state, whereas those for agonist dissociation depend on occupancy but not on state. The priming rate and equilibrium constants increase with successive agonist occupancy, and for a full agonist, the forward rate constant increases more than the equilibrium constant; for a partial agonist, the forward rate and equilibrium constants increase equally. The gating rate and equilibrium constants also increase with successive agonist occupancy, but unlike priming, the equilibrium constants increase more than the forward rate

  16. A geometricla error in some Computer Programs based on the Aki-Christofferson-Husebye (ACH) Method of Teleseismic Tomography

    USGS Publications Warehouse

    Julian, B.R.; Evans, J.R.; Pritchard, M.J.; Foulger, G.R.

    2000-01-01

    Some computer programs based on the Aki-Christofferson-Husebye (ACH) method of teleseismic tomography contain an error caused by identifying local grid directions with azimuths on the spherical Earth. This error, which is most severe in high latitudes, introduces systematic errors into computed ray paths and distorts inferred Earth models. It is best dealt with by explicity correcting for the difference between true and grid directions. Methods for computing these directions are presented in this article and are likely to be useful in many other kinds of regional geophysical studies that use Cartesian coordinates and flat-earth approximations.

  17. Neuroprotective effects of donepezil against Aβ42-induced neuronal toxicity are mediated through not only enhancing PP2A activity but also regulating GSK-3β and nAChRs activity.

    PubMed

    Noh, Min-Young; Koh, Seong H; Kim, Sung-Min; Maurice, Tangui; Ku, Sae-Kwang; Kim, Seung H

    2013-11-01

    The main purpose of this study was to evaluate whether donepezil, acetylcholinesterase inhibitor, shown to play a protective role through inhibiting glycogen synthesis kinase-3β (GSK-3β) activity, could also exert neuroprotective effects by stimulating protein phosphatase 2A (PP2A) activity in the amyloid-beta (Aβ)42-induced neuronal toxicity model of Alzheimer's disease. In Aβ42-induced toxic conditions, each PP2A and GSK-3β activity measured at different times showed time-dependent reverse pattern toward the direction of accelerating neuronal deaths with the passage of time. In addition, donepezil pre-treatment showed dose-dependent stepwise increase of neuronal viability and stimulation of PP2A activity. However, such effects on them were significantly reduced through the depletion of PP2A activity with either okadaic acid or PP2Ac siRNA. In spite of blocked PP2A activity in this Aβ42 insult, however, donepezil pretreatment showed additional significant recovering effect on neuronal viability when compared to the value without donepezil. Moreover, donepezil partially recovered its dephosphorylating effect on hyperphosphorylated tau induced by Aβ42. This observation led us to assume that additional mechanisms of donepezil, including its inhibitory effect on GSK-3β activity and/or the activation role of nicotinic acetylcholine receptors (nAChRs), might be involved. Taken together, our results suggest that the neuroprotective effects of donepezil against Aβ42-induced neurotoxicity are mediated through activation of PP2A, but its additional mechanisms including regulation of GSK-3β and nAChRs activity would partially contribute to its effects. We investigated neuroprotective mechanisms of donepezil against Aβ42 toxicity: Donepezil increased neuronal viability with reduced p-tau by enhancing PP2A activity. Despite of blocked PP2A activity, donepezil showed additional recovering effect on neuronal viability, which findings led us to assume that additional

  18. Acute toxicity of a commercial glyphosate formulation on European sea bass juveniles (Dicentrarchus labrax L.): gene expressions of heme oxygenase-1 (ho-1), acetylcholinesterase (AChE) and aromatases (cyp19a and cyp19b).

    PubMed

    Prevot-D'Alvise, N; Richard, S; Coupé, S; Bunet, R; Grillasca, J P

    2013-12-31

    Acute toxicity of Roundup, a commercial glyphosate--based herbicide, was evaluated in a teleost marine fish, the European sea bass, after 96 h of exposure. The LC50 96-h value of Roundup was 529 mg/L. Juveniles (Dicentrarchus labrax L.) were exposed to a sublethal concentration (35% of the LC50, i.e. 193 mg/L) of Roundup for 96-h. The study of heme oxygenase-1 (ho-1) gene expression was performed in four tissues (liver, gills, brain and gonads) and highlighted the disruption of antioxidant defence system. Results showed that ho-1 mRNA levels in liver and gills significantly decreased (p<0.001 and p<0.01 respectively) in fish exposed to 193 mg/L of Roundup, whereas in brain and gonads, ho-1 mRNA level was not altered. The analysis of acetylcholinesterase expression was used to evaluate the overall neurotoxicity of the herbicide and aromatase genes to assess the alteration of the endocrine system. Results showed that AChE and cyp19b gene transcriptions significantly increased (p<0.01) in brain of sea bass, whereas aromatase gene expression (cyp19a) in gonads was not significantly altered. Our results showed complex tissue-specific transcriptional responses after 96 h of exposure to a sublethal concentration. All these disruptions confirmed the deleterious effects of this glyphosate-based herbicide in a marine species.

  19. α4β2 nicotinic receptors play a role in the nAChR-mediated decline in L-dopa-induced dyskinesias in parkinsonian rats

    PubMed Central

    Quik, Maryka; Campos, Carla; Bordia, Tanuja; Strachan, Jon-Paul; Zhang, Jenny; McIntosh, J. Michael; Letchworth, Sharon; Jordan, Kristen

    2013-01-01

    L-dopa-induced dyskinesias are a serious long-term side effect of dopamine replacement therapy for Parkinson’s disease for which there are few treatment options. Our previous studies showed that nicotine decreased L-dopa-induced abnormal involuntary movements (AIMs). Subsequent work with knockout mice demonstrated that α6β2* nicotinic receptors (nAChRs) play a key role. The present experiments were done to determine if α4β2* nAChRs are also involved in L-dopa-induced dyskinesias. To approach this, we took advantage of the finding that α6β2* nAChRs are predominantly present on striatal dopaminergic nerve terminals, while a significant population of α4β2* nAChRs are located on other neurons. Thus, a severe dopaminergic lesion would cause a major loss in α6β2*, but not α4β2* nAChRs. Experiments were therefore done in which rats were unilaterally lesioned with 6-hydroxydopamine, at a dose that lead to severe nigrostriatal damage. The dopamine transporter, a dopamine nerve terminal marker, was decreased by >99%. This lesion also decreased striatal α6β2* nAChRs by 97%, while α4β2* nAChRs were reduced by only 12% compared to control. A series of β2* nAChR compounds, including TC-2696, TI-10165, TC-8831, TC-10600 and sazetidine reduced L-dopa-induced AIMs in these rats by 23–32%. TC-2696, TI-10165, TC-8831 were also tested for parkinsonism, with no effect on this behavior. Tolerance did not develop with up to 3 months of treatment. Since α4a5β2 nAChRs are also predominantly on striatal dopamine terminals, these data suggest that drugs targeting α4β2 nAChRs may reduce L-dopa-induced dyskinesias in late stage Parkinson’s disease. PMID:23583932

  20. Characterization of Quaternary and suspected Quaternary faults, regional studies, Nevada and California

    SciTech Connect

    Anderson, R.E.; Bucknam, R.C.; Crone, A.J.; Haller, K.M.; Machette, M.N.; Personius, S.F.; Barnhard, T.P.; Cecil, M.J.; Dart, R.L.

    1995-12-31

    This report presents the results of geologic studies that help define the Quaternary history of selected faults in the region around Yucca Mountain, Nevada. These results are relevant to the seismic-design basis of a potential nuclear waste repository at Yucca Mountain. The relevancy is based, in part, on a need for additional geologic data that became apparent in ongoing studies that resulted in the identification of 51 relevant and potentially relevant individual and compound faults and fault zones in the 100-km-radius region around the Yucca Mountain site. Geologic data used to characterize the regional faults and fault zones as relevant or potentially relevant seismic sources includes age and displacement information, maximum fault lengths, and minimum distances between the fault and the Yucca Mountain site. For many of the regional faults, no paleoseismic field studies have previously been conducted, and age and displacement data are sparse to nonexistent. In November 1994, the Branch of Earthquake and Landslide Hazards entered into two Memoranda of Agreement with the Yucca Mountain Project Branch to conduct field reconnaissance, analysis, and interpretation of six relevant and six potentially relevant regional faults. This report describes the results of study of those faults exclusive of those in the Pahrump-Stewart Valley-Ash Meadows-Amargosa Valley areas. We also include results of a cursory study of faults on the west flank of the Specter Range and in the northern part of the Last Chance Range. A four-phase strategy was implemented for the field study.

  1. Identification and Characterization of ML352: A Novel, Noncompetitive Inhibitor of the Presynaptic Choline Transporter

    PubMed Central

    2015-01-01

    The high-affinity choline transporter (CHT) is the rate-limiting determinant of acetylcholine (ACh) synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. To expand CHT pharmacology, we pursued a high-throughput screen for novel CHT-targeted small molecules based on the electrogenic properties of transporter-mediated choline transport. In this effort, we identified five novel, structural classes of CHT-specific inhibitors. Chemical diversification and functional analysis of one of these classes identified ML352 as a high-affinity (Ki = 92 nM) and selective CHT inhibitor. At concentrations that fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase (AChE) or cholineacetyltransferase (ChAT) and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and synaptosomes and reduced the apparent density of hemicholinium-3 (HC-3) binding sites in membrane assays, suggesting allosteric transporter interactions. Pharmacokinetic studies revealed limited in vitro metabolism and significant CNS penetration, with features predicting rapid clearance. ML352 represents a novel, potent, and specific tool for the manipulation of CHT, providing a possible platform for the development of cholinergic imaging and therapeutic agents. PMID:25560927

  2. Comparative analyses of quaternary arrangements in homo-oligomeric proteins in superfamilies: Functional implications.

    PubMed

    Sudha, Govindarajan; Srinivasan, Narayanaswamy

    2016-09-01

    A comprehensive analysis of the quaternary features of distantly related homo-oligomeric proteins is the focus of the current study. This study has been performed at the levels of quaternary state, symmetry, and quaternary structure. Quaternary state and quaternary structure refers to the number of subunits and spatial arrangements of subunits, respectively. Using a large dataset of available 3D structures of biologically relevant assemblies, we show that only 53% of the distantly related homo-oligomeric proteins have the same quaternary state. Considering these homologous homo-oligomers with the same quaternary state, conservation of quaternary structures is observed only in 38% of the pairs. In 36% of the pairs of distantly related homo-oligomers with different quaternary states the larger assembly in a pair shows high structural similarity with the entire quaternary structure of the related protein with lower quaternary state and it is referred as "Russian doll effect." The differences in quaternary state and structure have been suggested to contribute to the functional diversity. Detailed investigations show that even though the gross functions of many distantly related homo-oligomers are the same, finer level differences in molecular functions are manifested by differences in quaternary states and structures. Comparison of structures of biological assemblies in distantly and closely related homo-oligomeric proteins throughout the study differentiates the effects of sequence divergence on the quaternary structures and function. Knowledge inferred from this study can provide insights for improved protein structure classification and function prediction of homo-oligomers. Proteins 2016; 84:1190-1202. © 2016 Wiley Periodicals, Inc.

  3. Biochemical and functional properties of distinct nicotinic acetylcholine receptors in the superior cervical ganglion of mice with targeted deletions of nAChR subunit genes.

    PubMed

    David, Reinhard; Ciuraszkiewicz, Anna; Simeone, Xenia; Orr-Urtreger, Avi; Papke, Roger L; McIntosh, J M; Huck, Sigismund; Scholze, Petra

    2010-03-01

    Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission in ganglia of the autonomic nervous system. Here, we determined the subunit composition of hetero-pentameric nAChRs in the mouse superior cervical ganglion (SCG), the function of distinct receptors (obtained by deletions of nAChR subunit genes) and mechanisms at the level of nAChRs that might compensate for the loss of subunits. As shown by immunoprecipitation and Western blots, wild-type (WT) mice expressed: alpha 3 beta 4 (55%), alpha 3 beta 4 alpha 5 (24%) and alpha 3 beta 4 beta 2 (21%) nAChRs. nAChRs in beta 4 knockout (KO) mice were reduced to < 15% of controls and no longer contained the alpha 5 subunit. Compound action potentials, recorded from the postganglionic (internal carotid) nerve and induced by preganglionic nerve stimulation, did not differ between alpha 5 beta 4 KO and WT mice, suggesting that the reduced number of receptors in the KO mice did not impair transganglionic transmission. Deletions of alpha 5 or beta2 did not affect the overall number of receptors and we found no evidence that the two subunits substitute for each other. In addition, dual KOs allowed us to study the functional properties of distinct alpha 3 beta4 and alpha 3 beta 2 receptors that have previously only been investigated in heterologous expression systems. The two receptors strikingly differed in the decay of macroscopic currents, the efficacy of cytisine, and their responses to the alpha-conotoxins AuIB and MII. Our data, based on biochemical and functional experiments and several mouse KO models, clarify and significantly extend previous observations on the function of nAChRs in heterologous systems and the SCG. PMID:20377613

  4. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease.

    PubMed

    Parsons, Chris G; Danysz, Wojciech; Dekundy, Andrzej; Pulte, Irena

    2013-10-01

    This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy-with the N-methyl-D-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)-for the treatment of Alzheimer's disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their complementary mechanisms offer superior benefit as combination therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AChEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over-stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combination treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may produce greater effects than either drug individually.

  5. PACAP induces plasticity at autonomic synapses by nAChR-dependent NOS1 activation and AKAP-mediated PKA targeting.

    PubMed

    Jayakar, Selwyn S; Pugh, Phyllis C; Dale, Zack; Starr, Eric R; Cole, Samantha; Margiotta, Joseph F

    2014-11-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide found at synapses throughout the central and autonomic nervous system. We previously found that PACAP engages a selective G-protein coupled receptor (PAC1R) on ciliary ganglion neurons to rapidly enhance quantal acetylcholine (ACh) release from presynaptic terminals via neuronal nitric oxide synthase (NOS1) and cyclic AMP/protein kinase A (PKA) dependent processes. Here, we examined how PACAP stimulates NO production and targets resultant outcomes to synapses. Scavenging extracellular NO blocked PACAP-induced plasticity supporting a retrograde (post- to presynaptic) NO action on ACh release. Live-cell imaging revealed that PACAP stimulates NO production by mechanisms requiring NOS1, PKA and Ca(2+) influx. Ca(2+)-permeable nicotinic ACh receptors composed of α7 subunits (α7-nAChRs) are potentiated by PKA-dependent PACAP/PAC1R signaling and were required for PACAP-induced NO production and synaptic plasticity since both outcomes were drastically reduced following their selective inhibition. Co-precipitation experiments showed that NOS1 associates with α7-nAChRs, many of which are perisynaptic, as well as with heteromeric α3*-nAChRs that generate the bulk of synaptic activity. NOS1-nAChR physical association could facilitate NO production at perisynaptic and adjacent postsynaptic sites to enhance focal ACh release from juxtaposed presynaptic terminals. The synaptic outcomes of PACAP/PAC1R signaling are localized by PKA anchoring proteins (AKAPs). PKA regulatory-subunit overlay assays identified five AKAPs in ganglion lysates, including a prominent neuronal subtype. Moreover, PACAP-induced synaptic plasticity was selectively blocked when PKA regulatory-subunit binding to AKAPs was inhibited. Taken together, our findings indicate that PACAP/PAC1R signaling coordinates nAChR, NOS1 and AKAP activities to induce targeted, retrograde plasticity at autonomic synapses. Such

  6. Mapping a buried Quaternary valley and pre-Quaternary faults through seismic methods in Copenhagen, Denmark.

    NASA Astrophysics Data System (ADS)

    Martinez, Kerim; Alfredo Mendoza, Jose; Henrik, Olsen

    2010-05-01

    Limited knowledge of the subsurface geology motivates the use of geophysical techniques before large engineering projects are conducted. These applications are normally restricted to satisfy the project aims, like mapping the near surface sediments, unconsolidated rocks and/or geological structures that may affect the construction locally. However, the applications can also contribute to the general knowledge of the regional geology around the location of interest. This report highlights the mapping of a buried Quaternary valley and identification of regional faults by a reflection and refraction seismic survey performed in Copenhagen. A 13.9 Km seismic survey was carried out at Copenhagen city along six crooked lines in order to determine the velocity fields in the near subsurface segment of a planned metro line and reflection patterns in deeper levels. The aim of the survey was to collect information needed for designing the underground metro. In particular it was sought to map the interface between Quaternary sedimentary layers of clay, till and sand, and the underlying layers of Palaeogene limestone found between 7 and 40 m below the ground surface. The data acquisition was carried out using a 192 channels array, receiver groups with 5 m spacing and a Vibroseis as a source at 5 m spacing following a roll along technique to complete the survey spreads. The urban environment demanded extensive survey planning including traffic control, notifications to residents and a fluent coordination with municipal authorities in order to minimize disturbances and ensure data acquisition. The reflection data was processed under a conventional scheme and the refraction data was interpreted using a non-linear traveltime tomography algorithm. The reflection results indicate the presence of faults oriented NW-SE to NNW-SSE affecting the limestone sequences. The faults may be associated to the Sorgenfrei-Tornquist Zone at the transition between the Danish Basin and the Baltic

  7. Esterase detoxication of acetylcholinesterase inhibitors using human liver samples in vitro.

    PubMed

    Moser, Virginia C; Padilla, Stephanie

    2016-04-15

    Organophosphorus (OP) and N-methylcarbamate pesticides inhibit acetylcholinesterase (AChE), but differences in metabolism and detoxication can influence potency of these pesticides across and within species. Carboxylesterase (CaE) and A-esterase (paraoxonase, PON1) are considered factors underlying age-related sensitivity differences. We used an in vitro system to measure detoxication of AChE-inhibiting pesticides mediated via these esterases. Recombinant human AChE was used as a bioassay of inhibitor concentration following incubation with detoxifying tissue: liver plus Ca(+2) (to stimulate PON1s, measuring activity of both esterases) or EGTA (to inhibit PON1s, thereby measuring CaE activity). AChE inhibitory concentrations of aldicarb, chlorpyrifos oxon, malaoxon, methamidophos, oxamyl, paraoxon, and methylparaoxon were incubated with liver homogenates from adult male rat or one of 20 commercially provided human (11-83 years of age) liver samples. Detoxication was defined as the difference in inhibition produced by the pesticide alone and inhibition measured in combination with liver plus Ca(+2) or liver plus EGTA. Generally, rat liver produced more detoxication than did the human samples. There were large detoxication differences across human samples for some pesticides (especially malaoxon, chlorpyrifos oxon) but not for others (e.g., aldicarb, methamidophos); for the most part these differences did not correlate with age or sex. Chlorpyrifos oxon was fully detoxified only in the presence of Ca(+2) in both rat and human livers. Detoxication of paraoxon and methylparaoxon in rat liver was greater with Ca(+2), but humans showed less differentiation than rats between Ca(+2) and EGTA conditions. This suggests the importance of PON1 detoxication for these three OPs in the rat, but mostly only for chlorpyrifos oxon in human samples. Malaoxon was detoxified similarly with Ca(+2) or EGTA, and the differences across humans correlated with metabolism of p

  8. Active tectonics of the Oran (Algeria) Quaternary plain

    NASA Astrophysics Data System (ADS)

    youcef, Bouhadad; rabah, Bensalem; e-hadi, oubaiche

    2016-04-01

    The Oran region, in north-western Algeria, has been hit several times in the past by destructive moderate-sized and strong earthquakes. The Oran October 9th , 1790 (I0= X) was among the strongest seismic events in the western Mediterranean area comparable, if we consider the described effects, to the El- Asnam (1980, Ms=7.3) and Zemmouri (2003, Mw=6.8) earthquakes. Such strong seismic events requires the presence of major active geological structures that are re-activated several times in the past. In this work we present results of a multi- disciplinary study combining geomorphic analysis, field earthquake geological investigations and geophysical methods, undertaken to study the southern border of the Oran Quaternary plain. A 50 km long, SW-dipping and NE-SW trending active fault has been identified that showing clear quaternary deformation. Keywords: earthquake geology, active fault, geomorphic, geophysics, Algeria.

  9. Community ecology in a changing environment: Perspectives from the Quaternary

    PubMed Central

    Jackson, Stephen T.; Blois, Jessica L.

    2015-01-01

    Community ecology and paleoecology are both concerned with the composition and structure of biotic assemblages but are largely disconnected. Community ecology focuses on existing species assemblages and recently has begun to integrate history (phylogeny and continental or intercontinental dispersal) to constrain community processes. This division has left a “missing middle”: Ecological and environmental processes occurring on timescales from decades to millennia are not yet fully incorporated into community ecology. Quaternary paleoecology has a wealth of data documenting ecological dynamics at these timescales, and both fields can benefit from greater interaction and articulation. We discuss ecological insights revealed by Quaternary terrestrial records, suggest foundations for bridging between the disciplines, and identify topics where the disciplines can engage to mutual benefit. PMID:25901314

  10. New quantum codes constructed from quaternary BCH codes

    NASA Astrophysics Data System (ADS)

    Xu, Gen; Li, Ruihu; Guo, Luobin; Ma, Yuena

    2016-10-01

    In this paper, we firstly study construction of new quantum error-correcting codes (QECCs) from three classes of quaternary imprimitive BCH codes. As a result, the improved maximal designed distance of these narrow-sense imprimitive Hermitian dual-containing quaternary BCH codes are determined to be much larger than the result given according to Aly et al. (IEEE Trans Inf Theory 53:1183-1188, 2007) for each different code length. Thus, families of new QECCs are newly obtained, and the constructed QECCs have larger distance than those in the previous literature. Secondly, we apply a combinatorial construction to the imprimitive BCH codes with their corresponding primitive counterpart and construct many new linear quantum codes with good parameters, some of which have parameters exceeding the finite Gilbert-Varshamov bound for linear quantum codes.

  11. Community ecology in a changing environment: Perspectives from the Quaternary

    NASA Astrophysics Data System (ADS)

    Jackson, Stephen T.; Blois, Jessica L.

    2015-04-01

    Community ecology and paleoecology are both concerned with the composition and structure of biotic assemblages but are largely disconnected. Community ecology focuses on existing species assemblages and recently has begun to integrate history (phylogeny and continental or intercontinental dispersal) to constrain community processes. This division has left a "missing middle": Ecological and environmental processes occurring on timescales from decades to millennia are not yet fully incorporated into community ecology. Quaternary paleoecology has a wealth of data documenting ecological dynamics at these timescales, and both fields can benefit from greater interaction and articulation. We discuss ecological insights revealed by Quaternary terrestrial records, suggest foundations for bridging between the disciplines, and identify topics where the disciplines can engage to mutual benefit.

  12. Achieving optimum loop shapes in quaternary Pr-Co alloys

    NASA Astrophysics Data System (ADS)

    Branagan, D. J.; Kramer, M. J.; Tang, Yali; McCallum, R. W.

    2000-05-01

    The magnetic properties and microstructures of a quaternary Pr-Co-Ti-C alloy were investigated. After heat treating at 800 °C, the quaternary alloy developed high coercivity (16.7 kOe) and high energy product (8.6 MGOe). Hysteretic loop shapes exhibiting single-phase magnetic character were achieved which was a problem which previously plagued development of Pr-Co alloys. The optimum microstructure contained 75-100 nm Pr1Co5 hard magnetic grains, 75-100 nm Pr1Co2 second phases, and <10 nm TiC grain boundary precipitates. The important factors in achieving optimum loop shapes in Pr-Co alloys were examined in detail.

  13. Community ecology in a changing environment: Perspectives from the Quaternary

    USGS Publications Warehouse

    Jackson, Stephen T.; Blois, Jessica L.

    2015-01-01

    Community ecology and paleoecology are both concerned with the composition and structure of biotic assemblages but are largely disconnected. Community ecology focuses on existing species assemblages and recently has begun to integrate history (phylogeny and continental or intercontinental dispersal) to constrain community processes. This division has left a “missing middle”: Ecological and environmental processes occurring on timescales from decades to millennia are not yet fully incorporated into community ecology. Quaternary paleoecology has a wealth of data documenting ecological dynamics at these timescales, and both fields can benefit from greater interaction and articulation. We discuss ecological insights revealed by Quaternary terrestrial records, suggest foundations for bridging between the disciplines, and identify topics where the disciplines can engage to mutual benefit.

  14. New quantum codes constructed from quaternary BCH codes

    NASA Astrophysics Data System (ADS)

    Xu, Gen; Li, Ruihu; Guo, Luobin; Ma, Yuena

    2016-07-01

    In this paper, we firstly study construction of new quantum error-correcting codes (QECCs) from three classes of quaternary imprimitive BCH codes. As a result, the improved maximal designed distance of these narrow-sense imprimitive Hermitian dual-containing quaternary BCH codes are determined to be much larger than the result given according to Aly et al. (IEEE Trans Inf Theory 53:1183-1188, 2007) for each different code length. Thus, families of new QECCs are newly obtained, and the constructed QECCs have larger distance than those in the previous literature. Secondly, we apply a combinatorial construction to the imprimitive BCH codes with their corresponding primitive counterpart and construct many new linear quantum codes with good parameters, some of which have parameters exceeding the finite Gilbert-Varshamov bound for linear quantum codes.

  15. Helix Bundle Quaternary Structure from [alpha]/[beta]-Peptide Foldamers

    SciTech Connect

    Horne, W. Seth; Price, Joshua L.; Keck, James L.; Gellman, Samuel H.

    2008-11-18

    The function of a protein generally depends on adoption of a specific folding pattern, which in turn is determined by the side chain sequence along the polypeptide backbone. Here we show that the sequence-encoded structural information in peptides derived from yeast transcriptional activator GCN4 can be used to prepare hybrid {alpha}/{beta}-peptide foldamers that adopt helix bundle quaternary structures. Crystal structures of two hybrid {alpha}/{beta}-peptides are reported along with detailed structural comparison to {alpha}-peptides of analogous side chain sequence. There is considerable homology between {alpha}- and {alpha}/{beta}-peptides at the level of helical secondary structure, with modest but significant differences in the association geometry of helices in the quaternary structure.

  16. Luminescence dating of quaternary deposits in geology in Brazil.

    PubMed

    Tatumi, Sonia Hatsue; Gozzi, Giuliano; Yee, Márcio; de Oliveira, Victor Inácio; Sallun, Alethéa Ernandes Martins; Suguio, Kenitiro

    2006-01-01

    In the present work, systematic dating by luminescence methods has been done on 50 Quaternary geological samples within the study area of São Paulo State, Brazil. Bleaching experiments showed that residual TL intensity of 375 degrees C peak, of the quartz, was obtained after 10 h of sunlight exposition. Intensities decays of the 325 and 375 degrees C TL peaks can be fitted using second order exponential equation. Paleodose values were evaluated using regeneration methods with multiple aliquots. Samples dated indicate preliminary ages varying from 9 +/- 1 to 935 +/- 130 ka for colluvio-elluvial deposits, and from 17 +/- 2 to 215 +/- 30 ka for alluvial deposits of the study area. They cover four peneplained surfaces shaped during the Quaternary: I (1000-400 ka), II (400-120 ka), III (120-10 ka) and IV (10 ka until today), in decreasing order.

  17. Proton pump inhibitors

    MedlinePlus

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  18. α6 nAChR subunit residues that confer α-conotoxin BuIA selectivity.

    PubMed

    Kim, Hyun-Woo; McIntosh, J Michael

    2012-10-01

    Nicotinic acetylcholine receptors (nAChRs) containing α6 and/or α4 subunits modulate the release of dopamine. However, few compounds can effectively discriminate between ligand-binding sites that contain α6 vs. α4 nAChR subunits. Using a chimeric (α6/α4) subunit, we showed that α-conotoxin BuIA binds the extracellular rat α6β2 vs. α4β2 interface with ∼60,000-fold selectivity. Chimeras containing residues from the α6 subunit were inserted into the homologous position of the α4 subunit to identify critical sequence segments. The region between residues 184 and 207 in the α6 subunit accounted for the potency difference. Chimeras within this region followed by point mutations were constructed for further definition. α6 Lys185, Thr187, and Ile188 form a triad of key residues that influence BuIA binding; when these 3 α6 residues were inserted into the α4 subunit, there was an ∼2000-fold increase in toxin potency. We used a crystal structure of BuIA bound to the acetylcholine-binding protein together with the structure of the Torepedo marmorata nAChR to build a homology model of BuIA bound to the interface between α6 and β2 subunits. The results indicate that the triad of α6 residues lies outside the C loop and is distantly located from bound BuIA (>10 Å). This suggests that alterations in potency are not caused by the direct interaction between the triad and BuIA. Instead, alterations in C-loop 3-dimensional structure and/or flexibility may account for differential potency. Thr198 and Tyr205 also contributed to BuIA potency. In addition, Thr198 caused BuIA potency differences between the closely related α6 and α3 subunits. Together, the findings provide insight into differences between the α6 and other α subunits that may be exploited by α-conotoxins to achieve binding selectivity. PMID:22751014

  19. Organocatalytic Asymmetric Synthesis of Dihydrobenzoxazinones Bearing Trifluoromethylated Quaternary Stereocenters.

    PubMed

    Lou, Hengqiao; Wang, Yongtao; Jin, Enze; Lin, Xufeng

    2016-03-01

    Chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of trifluoromethyl benzoxazinones with pyrroles is reported. Under mild conditions, a range of enantioenriched dihydrobenzoxazinones bearing trifluoromethylated quaternary stereocenters could be obtained in good to excellent yield and ee. A remarkable fluorine effect is observed, and preliminary mechanistic studies combined with theory calculations suggest that triple-hydrogen-bonding interactions hold the transition structure rigidly and allow the bulky substituents of the catalyst to influence the enantioselectivity. PMID:26882280

  20. Quaternary fluvial archives: achievements of the Fluvial Archives Group

    NASA Astrophysics Data System (ADS)

    Bridgland, David; Cordier, Stephane; Herget, Juergen; Mather, Ann; Vandenberghe, Jef; Maddy, Darrel

    2013-04-01

    In their geomorphological and sedimentary records, rivers provide valuable archives of environments and environmental change, at local to global scales. In particular, fluvial sediments represent databanks of palaeoenvironment and palaeoclimatic (for example) of fossils (micro- and macro-), sedimentary and post-depositional features and buried soils. Well-dated sequences are of the most value, with dating provided by a wide range of methods, from radiometric (numerical) techniques to included fossils (biostratigraphy) and/or archaeological material. Thus Quaternary fluvial archives can also provide important data for studies of Quaternary biotic evolution and early human occupation. In addition, the physical disposition of fluvial sequences, be it as fragmented terrace remnants or as stacked basin-fills, provides valuable information about geomorphological and crustal evolution. Since rivers are long-term persistent features in the landscape, their sedimentary archives can represent important frameworks for regional Quaternary stratigraphy. Fluvial archives are distributed globally, being represented on all continents and across all climatic zones, with the exception of the frozen polar regions and the driest deserts. In 1999 the Fluvial Archives Group (FLAG) was established, as a working group of the Quaternary Research Association (UK), aimed at bringing together those interested in such archives. This has evolved into an informal organization that has held regular biennial combined conference and field-trip meetings, has co-sponsored other meetings and conference sessions, and has presided over two International Geoscience Programme (IGCP) projects: IGCP 449 (2000-2004) 'Global Correlation of Late Cenozoic Fluvial Deposits' and IGCP 518 (2005-2007) 'Fluvial sequences as evidence for landscape and climatic evolution in the Late Cenozoic'. Through these various activities a sequence of FLAG publications has appeared, including special issues in a variety of

  1. The impact of Quaternary Ice Ages on mammalian evolution.

    PubMed Central

    Lister, Adrian M

    2004-01-01

    The Quaternary was a time of extensive evolution among mammals. Most living species arose at this time, and many of them show adaptations to peculiarly Quaternary environments. The latter include continental northern steppe and tundra, and the formation of lakes and offshore islands. Although some species evolved fixed adaptations to specialist habitats, others developed flexible adaptations enabling them to inhabit broad niches and to survive major environmental changes. Adaptation to short-term (migratory and seasonal) habitat change probably played a part in pre-adapting mammal species to the longer-term cyclical changes of the Quaternary. Fossil evidence indicates that environmental changes of the order of thousands of years have been sufficient to produce subspeciation, but speciation has typically required one hundred thousand to a few hundred thousand years, although there are both shorter and longer exceptions. The persistence of taxa in environments imposing strong selective regimes may have been important in forcing major adaptive change. Individual Milankovitch cycles are not necessarily implicated in this process, but nor did they generally inhibit evolutionary change among mammals: many evolutionary divergences built over multiple climatic cycles. Deduction of speciation timing requires input from fossils and modern phenotypic and breeding data, to complement and constrain mitochondrial DNA coalescence dates which appear commonly to overestimate taxic divergence dates and durations of speciation. Migrational and evolutionary responses to climate change are not mutually exclusive but, on the contrary, may be synergistic. Finally, preliminary analysis suggests that faunal turnover, including an important element of speciation, was elevated in the Quaternary compared with the Neogene, at least in some biomes. Macroevolutionary species selection or sorting has apparently resulted in a modern mammalian fauna enriched with fast-reproducing and/or adaptively

  2. Multiple sources of alkanes in Quaternary oceanic sediment of Antarctica

    USGS Publications Warehouse

    Kvenvolden, K.A.; Rapp, J.B.; Golan-Bac, M.; Hostettler, F.D.

    1987-01-01

    Normal alkanes (n-C13n-C36), isoprenoid hydrocarbons (i-C15, i-C16, i-C18, i-C19, and i-C20) triterpanes (C27C32), and (C27C29) are present in low concentrations offshore Antarctica in near-surface, Quaternary sediment of the Wilkes Land continental margin and of the western Ross Sea. The distributions of these hydrocarbons are interpreted relative to possible sources and processes. The hydrocarbons appear to be mixtures of primary and recycled material from marine and terrigenous sources. The n-alkanes are most abundant and are characterized by two distinct populations, one of probable marine origin and the other likely from terrigenous, vascular plant sources. Because the continent of Antarctica today is devoid of higher plants, the plant-derived hydrocarbons in these offshore sediments probably came from wind-blown material and recycled Antarctic sediment that contains land-plant remains from an earlier period of time. Isoprenoid hydrocarbons are partially recycled and mainly of marine origin; the dominance of pristane over phytane suggests oxic paleoenvironmental conditions. Both modern and ancient triterpanes and steranes are present, and the distribution of these indicates a mixture of primary and recycled bacterial, algal, and possible higher-plant materials. Although the sampled sediments were deposited during the Quaternary, they apparently contain a significant component of hydrocarbons of pre-Quaternary age. ?? 1987.

  3. Protein flexibility facilitates quaternary structure assembly and evolution.

    PubMed

    Marsh, Joseph A; Teichmann, Sarah A

    2014-05-01

    The intrinsic flexibility of proteins allows them to undergo large conformational fluctuations in solution or upon interaction with other molecules. Proteins also commonly assemble into complexes with diverse quaternary structure arrangements. Here we investigate how the flexibility of individual protein chains influences the assembly and evolution of protein complexes. We find that flexibility appears to be particularly conducive to the formation of heterologous (i.e., asymmetric) intersubunit interfaces. This leads to a strong association between subunit flexibility and homomeric complexes with cyclic and asymmetric quaternary structure topologies. Similarly, we also observe that the more nonhomologous subunits that assemble together within a complex, the more flexible those subunits tend to be. Importantly, these findings suggest that subunit flexibility should be closely related to the evolutionary history of a complex. We confirm this by showing that evolutionarily more recent subunits are generally more flexible than evolutionarily older subunits. Finally, we investigate the very different explorations of quaternary structure space that have occurred in different evolutionary lineages. In particular, the increased flexibility of eukaryotic proteins appears to enable the assembly of heteromeric complexes with more unique components.

  4. Evolution of quaternary structure in a homotetrameric enzyme.

    PubMed

    Griffin, Michael D W; Dobson, Renwick C J; Pearce, F Grant; Antonio, Laurence; Whitten, Andrew E; Liew, Chu K; Mackay, Joel P; Trewhella, Jill; Jameson, Geoffrey B; Perugini, Matthew A; Gerrard, Juliet A

    2008-07-18

    Dihydrodipicolinate synthase (DHDPS) is an essential enzyme in (S)-lysine biosynthesis and an important antibiotic target. All X-ray crystal structures solved to date reveal a homotetrameric enzyme. In order to explore the role of this quaternary structure, dimeric variants of Escherichia coli DHDPS were engineered and their properties were compared to those of the wild-type tetrameric form. X-ray crystallography reveals that the active site is not disturbed when the quaternary structure is disrupted. However, the activity of the dimeric enzymes in solution is substantially reduced, and a tetrahedral adduct of a substrate analogue is observed to be trapped at the active site in the crystal form. Remarkably, heating the dimeric enzymes increases activity. We propose that the homotetrameric structure of DHDPS reduces dynamic fluctuations present in the dimeric forms and increases specificity for the first substrate, pyruvate. By restricting motion in a key catalytic motif, a competing, non-productive reaction with a substrate analogue is avoided. Small-angle X-ray scattering and mutagenesis data, together with a B-factor analysis of the crystal structures, support this hypothesis and lead to the suggestion that in at least some cases, the evolution of quaternary enzyme structures might serve to optimise the dynamic properties of the protein subunits.

  5. Quaternary diversification in a sexual Holarctic zooplankter, Daphnia galeata.

    PubMed

    Ishida, Seiji; Taylor, Derek J

    2007-02-01

    The effects of Quaternary glacial range partitioning on the diversification of Holarctic biota remain unclear. Glacial refugial lineages may form vicariant species, hybrid products, or merge after secondary contact. Here, we assess the effects of Quaternary glaciation on a Holarctic sexual zooplankter, Daphnia galeata, with apparently marked dispersal capacity and a widespread hybrid lineage in the New World. We collected samples of this species from 148 Holarctic lakes, analysed the nuclear and mitochondrial gene sequences, and tested predictions for hypotheses that account for the origin and spread of the New World D. galeata. We detected five nuclear phylogroups and four mitochondrial phylogroups, most of which were restricted to either the New World or the Old World. The oldest mitochondrial phylogroup was restricted to Japan. One major mitochondrial clade was distributed throughout the Holarctic, but only four haplotypes were shared among continents, and analysis of molecular variance indicated significant structure at the continental level. Haplotype sharing among continents could largely be attributed to anthropogenic introductions. Mismatch distributions, haplotype networks, phylogenetic trees, longitudinal haplotype diversity erosion and coalescence analyses are consistent with colonization from an Old World and a New World refugium. Our nuclear and mitochondrial DNA sequence evidence supports the hypothesis that the New World D. galeata underwent introgression with Daphnia dentifera, with dispersal being enhanced by glaciation. We conclude that Quaternary glaciation had a pronounced effect on the diversification of a Holarctic sexual zooplankter.

  6. Quaternary diversification in a sexual Holarctic zooplankter, Daphnia galeata.

    PubMed

    Ishida, Seiji; Taylor, Derek J

    2007-02-01

    The effects of Quaternary glacial range partitioning on the diversification of Holarctic biota remain unclear. Glacial refugial lineages may form vicariant species, hybrid products, or merge after secondary contact. Here, we assess the effects of Quaternary glaciation on a Holarctic sexual zooplankter, Daphnia galeata, with apparently marked dispersal capacity and a widespread hybrid lineage in the New World. We collected samples of this species from 148 Holarctic lakes, analysed the nuclear and mitochondrial gene sequences, and tested predictions for hypotheses that account for the origin and spread of the New World D. galeata. We detected five nuclear phylogroups and four mitochondrial phylogroups, most of which were restricted to either the New World or the Old World. The oldest mitochondrial phylogroup was restricted to Japan. One major mitochondrial clade was distributed throughout the Holarctic, but only four haplotypes were shared among continents, and analysis of molecular variance indicated significant structure at the continental level. Haplotype sharing among continents could largely be attributed to anthropogenic introductions. Mismatch distributions, haplotype networks, phylogenetic trees, longitudinal haplotype diversity erosion and coalescence analyses are consistent with colonization from an Old World and a New World refugium. Our nuclear and mitochondrial DNA sequence evidence supports the hypothesis that the New World D. galeata underwent introgression with Daphnia dentifera, with dispersal being enhanced by glaciation. We conclude that Quaternary glaciation had a pronounced effect on the diversification of a Holarctic sexual zooplankter. PMID:17257114

  7. Quaternary diversification in European alpine plants: pattern and process.

    PubMed Central

    Kadereit, Joachim W; Griebeler, Eva Maria; Comes, Hans Peter

    2004-01-01

    Molecular clock approaches applied previously to European alpine plants suggest that Primula sect. Auricula, Gentiana sect. Ciminalis and Soldanella diversified at the beginning of the Quaternary or well within this period, whereas Globularia had already started diversifying in the (Late-)Tertiary. In the first part of this paper we present evidence that, in contrast to Globularia and Soldanella, the branching patterns of the molecular internal transcribed spacer phylogenies of both Primula and Gentiana are incompatible with a constant-rates birth-death model. In both of these last two taxa, speciation probably decreased through Quaternary times, perhaps because of some niche-filling process and/or a decrease in specific range size. In the second part, we apply nonlinear regression analyses to the lineage-through-time plots of P. sect. Auricula to test a range of capacity-dependent models of diversification, and the effect of Quaternary climatic oscillations on diversification and extinction. At least for one major clade of sect. Auricula there is firm evidence that both diversification and extinction are a function of temperature. Intriguingly, temperature appears to be correlated positively with extinction, but negatively with diversification. This suggests that diversification did not take place, as previously assumed, in geographical isolation in high-altitude interglacial refugia, but rather at low altitudes in geographically isolated glacial refugia. PMID:15101582

  8. Polycationic antimicrobial dendrimers: a comparison of alkyl pyridinium,quaternary ammonium, quaternary phosphonium and tertiary sulfonium salts

    NASA Astrophysics Data System (ADS)

    Chen, Chris; Cooper, Stuart

    2000-03-01

    Polycationic biocides usually kill bacteria through the interactions of the positively charged head groups with negatively charged bacteria and the interactions of the hydrophobic segments with phospholipid cell membranes, which implies that high local charge densities and a large number of hydrophobic groups would lead to enhanced biocidal potency. The advent of dendrimers offers us the first-ever opportunity to achieve the desired high local density. We have demonstrated that dimethyl dodecyl ammonium chloride functionalized polypropylene imine dendrimers are over 100 times more potent than their small molecule ounterparts. In this study, quaternary ammonium, quaternary phosphonium, alkyl pyridinium and tertiary sulfonium salts based on polypropylene imine dendrimers have been synthesized and characterized. Their antimicrobial properties have been quantified with a novel bioluminescence method. The structure-activity relationship of these polycationic dendrimers has also been investigated to elucidate the molecular mechanism for the enhanced antimicrobial effects.

  9. From the Cajal alumni Achúcarro and Río-Hortega to the rediscovery of never-resting microglia

    PubMed Central

    Tremblay, Marie-Ève; Lecours, Cynthia; Samson, Louis; Sánchez-Zafra, Víctor; Sierra, Amanda

    2015-01-01

    Under the guidance of Ramón y Cajal, a plethora of students flourished and began to apply his silver impregnation methods to study brain cells other than neurons: the neuroglia. In the first decades of the twentieth century, Nicolás Achúcarro was one of the first researchers to visualize the brain cells with phagocytic capacity that we know today as microglia. Later, his pupil Pío del Río-Hortega developed modifications of Achúcarro's methods and was able to specifically observe the fine morphological intricacies of microglia. These findings contradicted Cajal's own views on cells that he thought belonged to the same class as oligodendroglia (the so called “third element” of the nervous system), leading to a long-standing discussion. It was only in 1924 that Río-Hortega's observations prevailed worldwide, thus recognizing microglia as a unique cell type. This late landing in the Neuroscience arena still has repercussions in the twenty first century, as microglia remain one of the least understood cell populations of the healthy brain. For decades, microglia in normal, physiological conditions in the adult brain were considered to be merely “resting,” and their contribution as “activated” cells to the neuroinflammatory response in pathological conditions mostly detrimental. It was not until microglia were imaged in real time in the intact brain using two-photon in vivo imaging that the extreme motility of their fine processes was revealed. These findings led to a conceptual revolution in the field: “resting” microglia are constantly surveying the brain parenchyma in normal physiological conditions. Today, following Cajal's school of thought, structural and functional investigations of microglial morphology, dynamics, and relationships with neurons and other glial cells are experiencing a renaissance and we stand at the brink of discovering new roles for these unique immune cells in the healthy brain, an essential step to understand their

  10. Contributions of β2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice

    PubMed Central

    Cole, Robert D.; Poole, Rachel L.; Guzman, Dawn M.; Gould, Thomas J.; Parikh, Vinay

    2014-01-01

    Rationale Deficits in executive functions underlie compulsive drug use and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that β2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known. Objectives In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the β2-subunit containing nAChR gene (β2+/- or β2-/-) performing an operant cognitive flexibility task. Results Visual discrimination learning was not affected in saline-treated β2 nAChR mutants as compared to the wild-type (β2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in β2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between β2+/+ and β2-/- mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in β2+/- mice. Conclusions Collectively, these findings suggest that β2 subunit-containing nAChRs are not critical for visual discrimination learning and extradimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies. PMID:25281224

  11. Quaternary coastal evolution of Oman (Arabian Peninsula) - a quantitative approach

    NASA Astrophysics Data System (ADS)

    Hoffmann, G.; Rupprechter, M.; Roepert, A.; Quraishi, K. Al; Balushi, N. Al; Grützner, C.; Reicherter, K.

    2012-04-01

    The paper reviews the Quaternary coastal evolution of Oman. Emphasise is put on quantifying the different forcing factors. The plate tectonic setting, the Quaternary climate evolution, the sea-level history and the impact of natural hazards are identified as key factors of coastal evolution. The Arabian Plate is characterized by a northward movement forming a continent-continent collision zone in the west and the Makran Subduction Zone in the east. As a result differential land movement is observable in Oman. The Quaternary climate evolution is well understood. Besides other proxies notably spelothems and aeolian deposits allow to draw a consistent picture. It is understood that changes in the position of the intertropical convergence zone result in intensity-changes of the summer monsoon. These changes are related to global atmospheric circulation patterns. Data on the sea-level history are sparse; despite general assumptions of a sea-level lowstand, correlating with the last glacial maximum, resulting in terrestrial conditions within the Arabian Gulf. Furthermore, a mid-Holocene sea level highstand in the range of +2m is documented in several locations. The coastlines of Oman are affected by tsunami and hurricanes. However, almost no instrumental or historical data on the impact of such natural hazards are available due to the isolation of the country in the past. Several Quaternary deposits have been investigated in a reconnaissance survey. There is sound geological evidence for a tsunami to have affected the coastline in 1945, with the possibility of older tsunami events being also recorded in the geological record. There is strong evidence of differential land movement along the coastline; locally indicated by marine terraces in elevations of up to 400m (Rupprechter at al. 2012). By quantifying the differential land movement for numerous sites, the sea-level history will be revealed. Ultimately the data will be utilized to form the base of a modeling approach

  12. The Quaternary adakite distribution of Kyushu Island, Ryukyu Arc, Japan

    NASA Astrophysics Data System (ADS)

    Shibata, T.; Yoshikawa, M.; Takemura, K.

    2011-12-01

    The Quaternary volcanoes are widely distributed in Kyusu Island, Japan. Philippine Sea plate is subducting beneath Kyushu. Clear distribution of deep seismic foci is observed below the Quaternary volcanoes in southern area, but not in northern area. Notsu et al. (1990, JVGR) examined the contribution of subduction to the magma source, and emphasized that no slab derived material is observed in northern area from Sr isotopic compositions. Volcanic activity similar to the within-plate type volcanism has been also emphasized for the magma genesis of this area (e.g. Kita et al, 2001, JVGR). However, we found adakitic rocks, which show high Sr/Y ratios and low Y concentrations (e.g. Defant and Drummond, 1990, Nature) from some Quaternary volcanoes in north Kyushu on the basis of published data (Otha et al, 1990, GANKO; Itoh, 1990, GANKO). Therefore, the magma genesis is still controversial. We studied lateral variations of Sr, Nd and Pb isotopic and trace element compositions for Quaternary volcanics from Kyushu to investigate the magma genesis. From the results, a clear variation of Sr/Y ratio, decreasing from north to south, is observed along the volcanic front. Some of the Sr/Y ratio of the most northern part of Kyusu shows the value >100. The all analyzed Pb isotope compositions show a single liner trend in 208Pb/204Pb v.s. 206Pb/204Pb diagram. The liner trend of Pb isotope ratios can be explained by the binary mixing of the Shikoku Basin basalt and tereginious sediment which might be a constituent of the subducting slab. The similar binary mixing relationships are found in Sr and Nd isotopic systematics. The isotopic characteristics of the Quaternary magma in Kyushu can be explained by the magma generation process of island arc, in spite of the lack of deep seismic foci in northern area. It is considered that high and low Sr/Y ratios suggest the contributions of partial melt in the north and aqueous fluid derived from subducting slab in the south, respectively. If

  13. Quaternary tectonic faulting in the Eastern United States

    USGS Publications Warehouse

    Wheeler, R.L.

    2006-01-01

    Paleoseismological study of geologic features thought to result from Quaternary tectonic faulting can characterize the frequencies and sizes of large prehistoric and historical earthquakes, thereby improving the accuracy and precision of seismic-hazard assessments. Greater accuracy and precision can reduce the likelihood of both underprotection and unnecessary design and construction costs. Published studies proposed Quaternary tectonic faulting at 31 faults, folds, seismic zones, and fields of earthquake-induced liquefaction phenomena in the Appalachian Mountains and Coastal Plain. Of the 31 features, seven are of known origin. Four of the seven have nontectonic origins and the other three features are liquefaction fields caused by moderate to large historical and Holocene earthquakes in coastal South Carolina, including Charleston; the Central Virginia Seismic Zone; and the Newbury, Massachusetts, area. However, the causal faults of the three liquefaction fields remain unclear. Charleston has the highest hazard because of large Holocene earthquakes in that area, but the hazard is highly uncertain because the earthquakes are uncertainly located. Of the 31 features, the remaining 24 are of uncertain origin. They require additional work before they can be clearly attributed either to Quaternary tectonic faulting or to nontectonic causes. Of these 24, 14 features, most of them faults, have little or no published geologic evidence of Quaternary tectonic faulting that could indicate the likely occurrence of earthquakes larger than those observed historically. Three more features of the 24 were suggested to have had Quaternary tectonic faulting, but paleoseismological and other studies of them found no evidence of large prehistoric earthquakes. The final seven features of uncertain origin require further examination because all seven are in or near urban areas. They are the Moodus Seismic Zone (Hartford, Connecticut), Dobbs Ferry fault zone and Mosholu fault (New York

  14. Quaternary ammonium compounds as water channel blockers. Specificity, potency, and site of action.

    PubMed

    Detmers, Frank J M; de Groot, Bert L; Müller, E Matthias; Hinton, Andrew; Konings, Irene B M; Sze, Mozes; Flitsch, Sabine L; Grubmüller, Helmut; Deen, Peter M T

    2006-05-19

    Excessive water uptake through Aquaporins (AQP) can be life-threatening and reversible AQP inhibitors are needed. Here, we determined the specificity, potency, and binding site of tetraethylammonium (TEA) to block Aquaporin water permeability. Using oocytes, externally applied TEA blocked AQP1/AQP2/AQP4 with IC50 values of 1.4, 6.2, and 9.8 microM, respectively. Related tetraammonium compounds yielded some (propyl) or no (methyl, butyl, or pentyl) inhibition. TEA inhibition was lost upon a Tyr to Phe amino acid switch in the external water pore of AQP1/AQP2/AQP4, whereas the water permeability of AQP3 and AQP5, which lack a corresponding Tyr, was not blocked by TEA. Consistent with experimental data, multi-nanosecond molecular dynamics simulations showed one stable binding site for TEA, but not tetramethyl (TMA), in AQP1, resulting in a nearly 50% water permeability inhibition, which was reduced in AQP1-Y186F due to effects on the TEA inhibitory binding region. Moreover, in the simulation TEA interacted with charged residues in the C (Asp128) and E (Asp185) loop, and the A(Tyr37-Asn42-Thr44) loop of the neighboring monomer, but not directly with Tyr186. The loss of TEA inhibition in oocytes expressing properly folded AQP1-N42A or -T44A is in line with the computationally predicted binding mode. Our data reveal that the molecular interaction of TEA with AQP1 differs and is about 1000-fold more effective on AQPs than on potassium channels. Moreover, the observed experimental and simulated similarities open the way for rational design and virtual screening for AQP-specific inhibitors, with quaternary ammonium compounds in general, and TEA in particular as a lead compound. PMID:16551622

  15. Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome.

    PubMed

    Kim, Jang Hoon; Ryu, Young Bae; Lee, Woo Song; Kim, Young Ho

    2014-11-01

    Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30 μg/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1-7 (IC50 = 12.8 ± 1.5 to 65.2 ± 4.5 μM) showed stronger NA inhibitory activity than the tertiary alkaloids 8-10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor-ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth.

  16. Molecular docking studies of (X-methylphenyl)-5-nitro-6-amino-3-pyridinecarboxmide (X=2,3,4,5,6) as potential inhibitors for Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Premkumar, S.; Asath, R. Mohamed; Rekha, T. N.; Jawahar, A.; Mathavan, T.; Benial, A. Milton Franklin

    2016-05-01

    An insilico and density functional theory (DFT) calculations were carried out for (X-methylphenyl)-5-nitro-6-amino-3-pyridinecarboxmide (X-MPNAPC),{X=2,3,4,5,6} to evaluate the potential inhibitors for Alzheimer's disease. The molecular structure of 2-MPNAPC, 3-MPNAPC, 4-MPNAPC, 5-MPNAPC and 6-MPNAPC molecules was optimized by the DFT/B3LYP method with cc-pVTZ basis set using the Gaussian 09 program. The inhibitory nature of the molecules against enzyme acetylcholinesterase (AChE) catalyzes was evaluated by molecular docking studies. The molecular docking parameters such as binding energy, inhibition constant and intermolecular energy were calculated by the AutoDock 4.0 software. The higher binding energy, intermolecular energy and lower inhibition constant values suggested that the 2-MPNAPC molecule has higher inhibitory nature against the AChE catalyzes, which confirm that the 2-MPNAPC molecule is a potential inhibitor for the Alzheimer's disease. The molecular reactivity was also studied by the frontier molecular orbitals analysis.

  17. Digital release of the Alaska Quaternary fault and fold database

    NASA Astrophysics Data System (ADS)

    Koehler, R. D.; Farrell, R.; Burns, P.; Combellick, R. A.; Weakland, J. R.

    2011-12-01

    The Alaska Division of Geological & Geophysical Surveys (DGGS) has designed a Quaternary fault and fold database for Alaska in conformance with standards defined by the U.S. Geological Survey for the National Quaternary fault and fold database. Alaska is the most seismically active region of the United States, however little information exists on the location, style of deformation, and slip rates of Quaternary faults. Thus, to provide an accurate, user-friendly, reference-based fault inventory to the public, we are producing a digital GIS shapefile of Quaternary fault traces and compiling summary information on each fault. Here, we present relevant information pertaining to the digital GIS shape file and online access and availability of the Alaska database. This database will be useful for engineering geologic studies, geologic, geodetic, and seismic research, and policy planning. The data will also contribute to the fault source database being constructed by the Global Earthquake Model (GEM), Faulted Earth project, which is developing tools to better assess earthquake risk. We derived the initial list of Quaternary active structures from The Neotectonic Map of Alaska (Plafker et al., 1994) and supplemented it with more recent data where available. Due to the limited level of knowledge on Quaternary faults in Alaska, pre-Quaternary fault traces from the Plafker map are shown as a layer in our digital database so users may view a more accurate distribution of mapped faults and to suggest the possibility that some older traces may be active yet un-studied. The database will be updated as new information is developed. We selected each fault by reviewing the literature and georegistered the faults from 1:250,000-scale paper maps contained in 1970's vintage and earlier bedrock maps. However, paper map scales range from 1:20,000 to 1:500,000. Fault parameters in our GIS fault attribute tables include fault name, age, slip rate, slip sense, dip direction, fault line type

  18. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

    PubMed Central

    Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

    2015-01-01

    Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

  19. Database and Map of Quaternary Faults and Folds in Peru and its Offshore Region

    USGS Publications Warehouse

    Machare, Jose; Fenton, Clark H.; Machette, Michael N.; Lavenu, Alain; Costa, Carlos; Dart, Richard L.

    2003-01-01

    This publication consists of a main map of Quaternary faults and fiolds of Peru, a table of Quaternary fault data, a region inset map showing relative plate motion, and a second inset map of an enlarged area of interest in southern Peru. These maps and data compilation show evidence for activity of Quaternary faults and folds in Peru and its offshore regions of the Pacific Ocean. The maps show the locations, ages, and activity rates of major earthquake-related features such as faults and fault-related folds. These data are accompanied by text databases that describe these features and document current information on their activity in the Quaternary.

  20. Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase.

    PubMed

    Katalinić, Maja; Rusak, Gordana; Domaćinović Barović, Jelena; Sinko, Goran; Jelić, Dubravko; Antolović, Roberto; Kovarik, Zrinka

    2010-01-01

    Selected flavonoids: galangin, kaempferol, quercetin, myricetin, fisetin, apigenin, luteolin and rutin, reversibly inhibited human butyrylcholinesterase (BChE, EC 3.1.1.8). Inhibition potency of the flavonoids we attributed to their chemical structure, i.e., the number of OH groups and their side on the phenyl ring. The most potent BChE inhibitor among the tested flavonoids was galangin, which showed 12 times higher preference for binding to BChE (7 micromol/L) than to the related enzyme human acetylcholinesterase (AChE, EC 3.1.1.7). Docking study showed that flavonoids bind to the BChE active site by forming multiple hydrogen bonds and pi-pi interactions. The UV-VIS (200-500 nm) absorption spectra of the flavonoid phosphate buffer solution (pH 7.4), with the exception of rutin, revealed time dependant changes indicating precipitation of flavonoids or in the case of myricetin, a change in the chemical structure resulting in a BChE non-inhibiting specie. Selected flavonoids showed no cytotoxic effect on HepG2 and A549 cell lines at concentrations up to 200 micromol/L. Cytotoxicity was observed only for fisetin, apigenin and luteolin in the THP-1 cell line with IC50 of 30, 60 and 70 micromol/L, respectively.

  1. Activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.

    PubMed

    Costa, Robson; Motta, Emerson M; Manjavachi, Marianne N; Cola, Maíra; Calixto, João B

    2012-10-01

    In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.

  2. Auxofuran, a Novel Metabolite That Stimulates the Growth of Fly Agaric, Is Produced by the Mycorrhiza Helper Bacterium Streptomyces Strain AcH 505†

    PubMed Central

    Riedlinger, Julia; Schrey, Silvia D.; Tarkka, Mika T.; Hampp, Rüdiger; Kapur, Manmohan; Fiedler, Hans-Peter

    2006-01-01

    The mycorrhiza helper bacterium Streptomyces strain AcH 505 improves mycelial growth of ectomycorrhizal fungi and formation of ectomycorrhizas between Amanita muscaria and spruce but suppresses the growth of plant-pathogenic fungi, suggesting that it produces both fungal growth-stimulating and -suppressing compounds. The dominant fungal-growth-promoting substance produced by strain AcH 505, auxofuran, was isolated, and its effect on the levels of gene expression of A. muscaria was investigated. Auxofuran and its synthetic analogue 7-dehydroxy-auxofuran were most effective at a concentration of 15 μM, and application of these compounds led to increased lipid metabolism-related gene expression. Cocultivation of strain AcH 505 and A. muscaria stimulated auxofuran production by the streptomycete. The antifungal substances produced by strain AcH 505 were identified as the antibiotics WS-5995 B and C. WS-5995 B completely blocked mycelial growth at a concentration of 60 μM and caused a cell stress-related gene expression response in A. muscaria. Characterization of these compounds provides the foundation for molecular analysis of the fungus-bacterium interaction in the ectomycorrhizal symbiosis between fly agaric and spruce. PMID:16672502

  3. Electrical and Optical Properties of Si-Incorporated a-C:H Films via the Radio Frequency Plasma-Enhanced Chemical Vapor Deposition Method.

    PubMed

    Kim, In Jun; Choi, Won Seok; Hong, Byungyou

    2016-05-01

    The optical and electrical properties of silicon-incorporated hydrogenated amorphous carbon (a-C:H:Si) films deposited via the radio frequency (RF) plasma-enhanced chemical vapor deposition (PECVD) method using a mixture of CH4, H2, and SiH4 were observed. The silane gas whose ranged from 0 to 25 vol.% [SiH4/(SiH4 + CH4) was fed into the reactor while the other deposition parameters were kept constant. The basic properties of these films were investigated via Raman spectroscopy, UV-visible spectrometry, I-V measurement, and surface profiling. The experiment results showed that the film thickness increased from 300 nm to 800 nm for the same deposition time as the silane gas increased. The Raman spectrum obtained from the silicon-incorporated a-C:H films suggested that the film property changed from graphitic-like to more diamond-like. As the silane gas increased, the optical gap, E04, slightly increased from 1.98 eV to 2.62 eV. It was shown that the Si atoms incorporated into the a-C:H films reduced the size of the sp2 clusters. As for the I-V characteristics, the Si-incorporated a-C:H films had a lower leakage current than the a-C:H films without Si. PMID:27483937

  4. Notes on three new immigrant species of spilanthes jacq. (Asteraceae) in India and the identity of the common 'tooth - ache plant'.

    PubMed

    Sivarajan, V V; Mathew, P

    1984-01-01

    Three new immigrant species of Spilanthes Jacq. (Asteraceae) is described for the first time from India. Their current nomenclature and an artificial key for the identification of the 5 Indian species are provided. The identity of the commonly used 'tooth-ache' plant is also discussed. PMID:22557401

  5. Sharing the Vision, Leading the Way: Continuing Educators in the New Millennium. ACHE Proceedings (62nd, Myrtle Beach, South Carolina, October 14-17, 2000).

    ERIC Educational Resources Information Center

    Barrineau, Irene T., Ed.

    This document presents the proceedings of the 2000 annual meeting of the Association for Continuing Higher Education (ACHE). Part 1 contains the text of the presidential address, "Building Solid Communities within Higher Education" (Nancy Thomason), as well as summaries of the following addresses: "Riding the Rapids of Change: Survival Tactics for…

  6. Tertiary and Quaternary tectonic faulting in southernmost Illinois

    USGS Publications Warehouse

    Nelson, W.J.; Denny, F.B.; Devera, J.A.; Follmer, L.R.; Masters, J.M.

    1997-01-01

    Tertiary and/or Quaternary tectonic faulting is documented in three areas of southernmost Illinois: the Fluorspar Area Fault Complex (FAFC) in Pope and Massac Counties, the Ste. Genevieve Fault Zone (SGFZ) in Alexander and Union Counties, and the Commerce Fault Zone (CFZ) in Alexander County. In the FAFC, faults that strike NE and NNE displace Mounds Gravel (late Miocene to early Pleistocene) and, locally, the Metropolis terrace gravel (Pleistocene; pre-Woodfordian). No Woodfordian or younger deposits are deformed. Faults typically outline narrow, linear grabens that formed under tension with a component of strike slip. North-south to NW-trending vertical faults near the southeast end of the SGFZ displace Eocene sediments. Again, faults outline narrow grabens and show indications of strike slip. Deformed Quaternary sediments have not been observed. The CFZ, which trends northeast, displaces Mounds Gravel in Illinois and units as young as Peoria Silt (Woodfordian) in Missouri. Quaternary movement has been interpreted as right-lateral strike-slip. The CFZ coincides with a subtle gravity and magnetic lineament and seems to reflect a major feature in the basement. Surface expression in Illinois is subtle, but mafic and ultramafic intrusions, hydrothermal alteration and small faults align with the Commerce geophysical lineament. Earthquake foci in Missouri and Illinois lie on or close to the CFZ; some focal mechanisms fit the fault trend. Among these structures, only the CFZ exhibits slip that conforms to the current stress field (principal compressive stress axis E-W to ENE-WSW). Possibly, the stress field changed during Neogene time. Alternatively, high fluid pressures or local stress concentrations may have induced slip on less favorably oriented fractures. Tighter constraints are needed on timing, magnitude, and direction of Neogene displacement. ?? 1997 Elsevier Science B.V.

  7. An aminostratigraphy for the British Quaternary based on Bithynia opercula

    PubMed Central

    Penkman, Kirsty E.H.; Preece, Richard C.; Bridgland, David R.; Keen, David H.; Meijer, Tom; Parfitt, Simon A.; White, Tom S.; Collins, Matthew J.

    2013-01-01

    Aminostratigraphies of Quaternary non-marine deposits in Europe have been previously based on the racemization of a single amino acid in aragonitic shells from land and freshwater molluscs. The value of analysing multiple amino acids from the opercula of the freshwater gastropod Bithynia, which are composed of calcite, has been demonstrated. The protocol used for the isolation of intra-crystalline proteins from shells has been applied to these calcitic opercula, which have been shown to more closely approximate a closed system for indigenous protein residues. Original amino acids are even preserved in bithyniid opercula from the Eocene, showing persistence of indigenous organics for over 30 million years. Geochronological data from opercula are superior to those from shells in two respects: first, in showing less natural variability, and second, in the far better preservation of the intra-crystalline proteins, possibly resulting from the greater stability of calcite. These features allow greater temporal resolution and an extension of the dating range beyond the early Middle Pleistocene. Here we provide full details of the analyses for 480 samples from 100 horizons (75 sites), ranging from Late Pliocene to modern. These show that the dating technique is applicable to the entire Quaternary. Data are provided from all the stratotypes from British stages to have yielded opercula, which are shown to be clearly separable using this revised method. Further checks on the data are provided by reference to other type-sites for different stages (including some not formally defined). Additional tests are provided by sites with independent geochronology, or which can be associated with a terrace stratigraphy or biostratigraphy. This new aminostratigraphy for the non-marine Quaternary deposits of southern Britain provides a framework for understanding the regional geological and archaeological record. Comparison with reference to sites yielding independent geochronology, in

  8. Precise timing and rate of massive late Quaternary soil denudation

    NASA Astrophysics Data System (ADS)

    Cooke, M. Jennifer; Stern, Libby A.; Banner, Jay L.; Mack, Lawrence E.; Stafford, Thomas W., Jr.; Toomey, Rickard S., III

    2003-10-01

    Strontium isotopes are a unique tool to study soil-erosion dynamics. Changes in Sr isotope ratios (87Sr/86Sr) provide a record of late Quaternary landscape denudation of the Edwards Plateau of central Texas, United States. The use of Sr isotopes as a tracer for soil erosion is based on the observation that, in central Texas, the 87Sr/86Sr ratio of soil correlates with soil thickness. Plants and animals express the 87Sr/86Sr ratio of exchangeable Sr in the soil. Therefore, we use changes in Sr isotope ratios through a well-dated stratigraphic sequence of fossil plants and animals in Hall's Cave, Kerr County, Texas, as a proxy for temporal changes in soil thickness. By using this record we are able to characterize late Quaternary climate-driven soil-erosion dynamics on the Edwards Plateau. We find that continuous erosion removed at least 180 cm of soil at a constant minimum rate of 11 cm/k.y.; this continuous phase of erosion ended ca. 5 ka. The Sr isotope record of soil erosion is consistent with late Quaternary environmental change in central Texas that has been independently modeled by using local and regional climate records. However, the rate of this climate-driven soil-erosion event was an order of magnitude slower than recent soil erosion caused by human land use. These results link erosion to century- to millennial-scale climate change and are cautionary evidence that even greater landscape degradation may result from coincident climatic variability and anthropogenic influences.

  9. Quaternary geology and waste disposal in South Norfolk, England

    NASA Astrophysics Data System (ADS)

    Gray, J. M.

    South Norfolk is dominated by the till plain of the Anglian Glaciation in eastern England, and therefore there are very few disused gravel pits and quarries suitable for the landfilling of municipal waste. Consequently, in May 1991, Norfolk County Council applied for planning permission to develop an above ground or 'landraise' waste disposal site at a disused U.S. World War II Airfield at Hardwick in South Norfolk. The proposal involved excavating a pit 2-4 m deep into the Lowestoft Till and overfilling it to create a hill of waste up to 10 m above the existing till plain. In general, leachate containment was to be achieved by utilising the relatively low permeability till on the floor of the site, but with reworking of the till around the site perimeter because of sand lenses in the upper part of the till. This paper examines three aspects of the proposal and the wider issues relating to Quaternary geology and waste disposal planning in South Norfolk: (i) the suitability of the till as a natural leachate containment system; (ii) the appropriateness of the landraise landform; and (iii) alternative sites. A Public Inquiry into the proposals was held in January/February 1993 and notification of refusal of planning permission was published in August 1993. Among the grounds for refusal were an inadequate knowledge of the site's geology and hydrogeology and the availability of alternative sites. The paper concludes by stressing that a knowledge of Quaternary geology is crucial to both the planning and design of landfill sites in areas of glacial/Quaternary sediments.

  10. A Novel Route to Recognizing Quaternary Ammonium Cations Using Electrospray Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Shackman, Holly M.; Ding, Wei; Bolgar, Mark S.

    2015-01-01

    Characterizing and elucidating structures is a commonplace and necessary activity in the pharmaceutical industry with mass spectrometry and NMR being the primary tools for analysis. Although many functional groups are readily identifiable, quaternary ammonium cations have proven to be difficult to unequivocally identify using these techniques. Due to the lack of an N-H bond, quaternary ammonium groups can only be detected in the 1H NMR spectra by weak signals generated from long-range 14N-H coupling, which by themselves are inconclusive evidence of a quaternary ammonium functional group. Due to their low intensity, these signals are frequently not detected. Additionally, ions cannot be differentiated in a mass spectrum as an M+ or [M + H]+ ion without prior knowledge of the compound's structure. In order to utilize mass spectrometry as a tool for determining this functionality, ion cluster formation of quaternary ammonium cations and non-quaternary amines was studied using electrospray ionization. Several mobile phase modifiers were compared; however, the addition of small amounts of trifluoroacetic acid proved superior in producing characteristic and intense [M +2TFA]- clusters for compounds containing quaternary ammonium cations when using negative electrospray. By fragmenting this characteristic ion using CID, nearly all compounds studied could be unambiguously identified as containing a quaternary ammonium cation or a non-quaternary amine attributable to the presence (non-quaternary amine) or absence (quaternary ammonium cation) of the resulting [2TFA + H]- ion in the product spectra. This method of analysis provides a rapid, novel, and reliable technique for indicating the presence of quaternary ammonium cations in order to aid in structural elucidation.

  11. A novel route to recognizing quaternary ammonium cations using electrospray mass spectrometry.

    PubMed

    Shackman, Holly M; Ding, Wei; Bolgar, Mark S

    2015-01-01

    Characterizing and elucidating structures is a commonplace and necessary activity in the pharmaceutical industry with mass spectrometry and NMR being the primary tools for analysis. Although many functional groups are readily identifiable, quaternary ammonium cations have proven to be difficult to unequivocally identify using these techniques. Due to the lack of an N-H bond, quaternary ammonium groups can only be detected in the (1)H NMR spectra by weak signals generated from long-range (14)N-H coupling, which by themselves are inconclusive evidence of a quaternary ammonium functional group. Due to their low intensity, these signals are frequently not detected. Additionally, ions cannot be differentiated in a mass spectrum as an M(+) or [M + H](+) ion without prior knowledge of the compound's structure. In order to utilize mass spectrometry as a tool for determining this functionality, ion cluster formation of quaternary ammonium cations and non-quaternary amines was studied using electrospray ionization. Several mobile phase modifiers were compared; however, the addition of small amounts of trifluoroacetic acid proved superior in producing characteristic and intense [M +2TFA](-) clusters for compounds containing quaternary ammonium cations when using negative electrospray. By fragmenting this characteristic ion using CID, nearly all compounds studied could be unambiguously identified as containing a quaternary ammonium cation or a non-quaternary amine attributable to the presence (non-quaternary amine) or absence (quaternary ammonium cation) of the resulting [2TFA + H](-) ion in the product spectra. This method of analysis provides a rapid, novel, and reliable technique for indicating the presence of quaternary ammonium cations in order to aid in structural elucidation.

  12. Stegomastodon associated with Mammuthus in Arizona during the Quaternary

    NASA Astrophysics Data System (ADS)

    Madden, Cary T.

    1986-09-01

    The gomphothere, Stegomastodon, is the most morphologically progressive non-elephant proboscidean in North America. Prior to the appearance of mammoths during the earliest Pleistocene, stegomastodonts held niches later occupied by those elephants. Two proboscidean specimens from near Taylor, Arizona, show that elephant-like Stegomastodon coexisted with Mammuthus in the southwestern United States during the Quaternary. Other associations of Stegomastodon and Mammuthus are known from the early and middle Pleistocene of Texas and the early Pleistocene of Nebraska. The mammoth from the Taylor locality is the oldest known from Arizona.

  13. Mutagenic activity of quaternary ammonium salt derivatives of carbohydrates

    PubMed Central

    Sikora, Karol; Woziwodzka, Anna; Piosik, Jacek; Podgórska, Beata

    2016-01-01

    Summary This paper presents a study on a series of quaternary ammonium salt (QAS) derivatives of glucopyranosides with an elongated hydrophobic hydrocarbon chain. The new N-[6-(β-D-glucopyranosyloxy)hexyl]ammonium bromides and their O-acetyl derivatives were analyzed via 1H and 13C NMR spectroscopy. The mutagenic activity of the newly synthesized QAS was investigated using two different techniques: The Vibrio harveyi luminescence assay and the Ames test. The obtained results support previous findings contesting QAS safety and indicate that QAS, specifically pyridinium derivatives, might be mutagenic. PMID:27559394

  14. Quaternary geology of the Channeled Scabland and adjacent areas

    NASA Technical Reports Server (NTRS)

    Baker, V. R.

    1978-01-01

    The quaternary history of the channeled scabland is characterized by discrete episodes of catastrophic flooding and prolonged periods of loess accumulation and soil formation. The loess sequence was correlated with Richmond's Rocky Mountain glacial chronology. At least five major catastrophic flood events occurred in the general vicinity of the channeled scabland. The earliest episode occurred prior to the extensive deposition of the Palouse formation. The last major episode of flooding occurred between about 18,000 and 13,000 years ago. It probably consisted of two outbursts from glacial Lake Missoula.

  15. Mutagenic activity of quaternary ammonium salt derivatives of carbohydrates.

    PubMed

    Dmochowska, Barbara; Sikora, Karol; Woziwodzka, Anna; Piosik, Jacek; Podgórska, Beata

    2016-01-01

    This paper presents a study on a series of quaternary ammonium salt (QAS) derivatives of glucopyranosides with an elongated hydrophobic hydrocarbon chain. The new N-[6-(β-D-glucopyranosyloxy)hexyl]ammonium bromides and their O-acetyl derivatives were analyzed via (1)H and (13)C NMR spectroscopy. The mutagenic activity of the newly synthesized QAS was investigated using two different techniques: The Vibrio harveyi luminescence assay and the Ames test. The obtained results support previous findings contesting QAS safety and indicate that QAS, specifically pyridinium derivatives, might be mutagenic. PMID:27559394

  16. Spatial Response of Mammals to Late Quaternary Environmental Fluctuations

    PubMed

    Graham; Lundelius; Graham; Schroeder; Toomey; Anderson; Barnosky; Burns; Churcher; Grayson; Guthrie; Harington; Jefferson; Martin; McDonald; Morlan; Semken; Webb; Werdelin; Wilson

    1996-06-14

    Analyses of fossil mammal faunas from 2945 localities in the United States demonstrate that the geographic ranges of individual species shifted at different times, in different directions, and at different rates in response to late Quaternary environmental fluctuations. The geographic pattern of faunal provinces was similar for the late Pleistocene and late Holocene, but differing environmental gradients resulted in dissimilar species composition for these biogeographic regions. Modern community patterns emerged only in the last few thousand years, and many late Pleistocene communities do not have modern analogs. Faunal heterogeneity was greater in the late Pleistocene.

  17. Charophytes as lacustrine biomarkers during the quaternary in North Africa

    NASA Astrophysics Data System (ADS)

    Soulié-Märsche, I.

    The use of charophytes as biomarkers is discussed with emphasis on the differences in study methods for cosmopolitan and ecotype species. A first extensive inventory of Quaternary deposits of charophytes in Africa north of the equator comprising 18 sites from Senegal to the Sudan is drawn up with data on spatial and temporal distribution. The existence of relatively deep cold lakes in the Holocene is shown by the frequent presence of specimens of cold flora no longer present in Africa today. All the original data show the complementary nature of the study of fossil Charophyta for the multidisciplinary reconstitution of palaeoenvironments.

  18. Cigarette smoking during pregnancy regulates the expression of specific nicotinic acetylcholine receptor (nAChR) subunits in the human placenta

    SciTech Connect

    Machaalani, R.; Ghazavi, E.; Hinton, T.; Waters, K.A.; Hennessy, A.

    2014-05-01

    Smoking during pregnancy is associated with low birth weight, premature delivery, and neonatal morbidity and mortality. Nicotine, a major pathogenic compound of cigarette smoke, binds to the nicotinic acetylcholine receptors (nAChRs). A total of 16 nAChR subunits have been identified in mammals (9 α, 4 β, and 1 δ, γ and ε subunits). The effect of cigarette smoking on the expression of these subunits in the placenta has not yet been determined, thus constituting the aim of this study. Using RT-qPCR and western blotting, this study investigated all 16 mammalian nAChR subunits in the normal healthy human placenta, and compared mRNA and protein expressions in the placentas from smokers (n = 8) to controls (n = 8). Our data show that all 16 subunit mRNAs are expressed in the normal, non-diseased human placenta and that the expression of α2, α3, α4, α9, β2 and β4 subunits is greater than the other subunits. For mRNA, cigarette smoke exposure was associated with increased expression of the α9 subunit, and decreased expression of the δ subunit. At the protein level, expression of both α9 and δ was increased. Thus, cigarette smoking in pregnancy is sufficient to regulate nAChR subunits in the placenta, specifically α9 and δ subunits, and could contribute to the adverse effects of vasoconstriction and decreased re-epithelialisation (α9), and increased calcification and apoptosis (δ), seen in the placentas of smoking women. - Highlights: • All 16 mammalian nAChR subunits are expressed in the human placenta. • Cigarette smoking increases α9 mRNA and protein in the placenta. • Cigarette smoking decreases δ mRNA but increases δ protein in the placenta.

  19. Pharmacological stress is required for the anti-alcohol effect of the α3β4* nAChR partial agonist AT-1001.

    PubMed

    Cippitelli, Andrea; Brunori, Gloria; Gaiolini, Kelly A; Zaveri, Nurulain T; Toll, Lawrence

    2015-06-01

    Alcohol and nicotine are often taken together. The mechanisms underlying this frequent co-abuse are not well known. Genetic and pharmacological evidence suggests that the nicotinic acetylcholine receptors (nAChRs) containing the α3 and β4 subunits play a role in alcohol as well as nicotine addiction. AT-1001 is a high affinity α3β4 nAChR partial agonist recently found to block nicotine self-administration and relapse-like behavior in rats. Here, to study the involvement of α3β4 nAChRs in the mechanisms that regulate alcohol abuse we evaluated the effects of AT-1001 on alcohol taking and seeking in Sprague-Dawley rats. AT-1001 reduced operant alcohol self-administration at the highest dose examined (3.0 mg/kg), an effect also observed for food self-administration. A dose of 1.5 mg/kg AT-1001, which had no effect on alcohol or food self-administration, essentially eliminated reinstatement of alcohol seeking induced by yohimbine (0.625 mg/kg) whereas, reinstatement induced by alcohol-associated cues was not altered, nor did AT-1001 induce reinstatement of extinguished self-administration on its own. Finally, AT-1001 showed an anxiolytic activity when measured in the presence or absence of yohimbine stress in the elevated plus maze paradigm. Together, these observations do not support a specific involvement of the α3β4 nAChR in mediating alcohol reward or cue-induced relapse to alcohol seeking but rather indicate that the α3β4 nAChR partial agonism may constitute an attractive approach for treating alcohol use disorders exacerbated by elevated stress response.

  20. Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs

    PubMed Central

    Neveu, Cedric; Cabaret, Jacques; Cortet, Jacques; Peineau, Nicolas; Abongwa, Melanie; Courtot, Elise; Robertson, Alan P.; Martin, Richard J.

    2014-01-01

    Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important “classical” anthelmintics like levamisole and pyrantel, as well as “novel” anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms. PMID:24497826

  1. Novel quaternary ammonium salts derived from triglycerides and their application in skin and hair products.

    PubMed

    Baydar, A; Johnston, R

    1991-08-01

    Synopsis An investigation has been carried out into the synthesis of quaternary ammonium salts of triglycerides. The aim of this work was to produce such compounds without breaking the triglyceride skeleton. The reaction of chloracetyl chloride with the triglyceride of ricinoleic acid which is the major constituent (88-90%) of castor oil gave an intermediate derivative with pendant chloro groups. Quaternization with stearyl dimethylamine gave a 98% yield of a quaternary ammonium salt containing three quaternary groups per molecule. This reaction sequence overcame the steric hindrance problems encountered in unsuccessful attempts to quaternize halogen groups attached directly to the main chain. Using the same procedure, a quaternary salt was prepared from castor oil. In skin care studies this quaternary was used at a low level in a moisturizing lotion. Subjective assessment of the ease of application of the test lotion versus control was significantly in favour of the test. Viscoelastic measurements of the skin were made using two techniques before and after application of the lotion. Both showed an advantage to the test lotion. No difference between the test and control lotions was found when sebum levels and transepidermal water loss measurements were measured. A C-12 quaternary synthesized from dimethyl-dodecylamine exhibited antimicrobial activity. An aqueous dispersion of the C-18 quaternary when applied to bleached hair in order to improve combing, gave excellent results showing superiority to four other commercially available quaternary ammonium salts.

  2. 40 CFR 721.10342 - Quaternary ammonium compounds, fatty alkyl dialkyl hydroxide (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... alkyl dialkyl hydroxide (generic). 721.10342 Section 721.10342 Protection of Environment ENVIRONMENTAL... Significant New Uses for Specific Chemical Substances § 721.10342 Quaternary ammonium compounds, fatty alkyl... chemical substance identified generically as quaternary ammonium compounds, fatty alkyl dialkyl...