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1

New potential AChE inhibitor candidates.  

PubMed

We have theoretically studied new potential candidates of acetylcholinesterase (AChE) inhibitors designed from cardanol, a non-isoprenoid phenolic lipid of cashew Anacardium occidentale nut-shell liquid. The electronic structure calculations of fifteen molecule derivatives from cardanol were performed using B3LYP level with 6-31G, 6-31G(d), and 6-311+G(2d,p) basis functions. For this study we used the following groups: methyl, acetyl, N,N-dimethylcarbamoyl, N,N-dimethylamine, N,N-diethylamine, piperidine, pyrrolidine, and N,N-methylbenzylamine. Among the proposed compounds we identified that the structures with substitution by N,N-dimethycarbamoyl, N,N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine, and represent possible AChE inhibitors against Alzheimer disease. PMID:19446931

de Paula, A A N; Martins, J B L; dos Santos, M L; Nascente, L de C; Romeiro, L A S; Areas, T F M A; Vieira, K S T; Gambôa, N F; Castro, N G; Gargano, R

2009-04-16

2

Neuronal AChE splice variants and their non-hydrolytic functions: redefining a target of AChE inhibitors?  

PubMed

AChE enzymatic inhibition is a core focus of pharmacological intervention in Alzheimer's disease (AD). Yet, AChE has also been ascribed non-hydrolytic functions, which seem related to its appearance in various isoforms. Neuronal AChE presents as a tailed form (AChE-T) predominantly found on the neuronal synapse, and a facultatively expressed readthough form (AChE-R), which exerts short to medium-term protective effects. Notably, this latter form is also found in the periphery. While these non-hydrolytic functions of AChE are most controversially discussed, there is evidence for them being additional targets of AChE inhibitors. This review aims to provide clarification as to the role of these AChE splice variants and their interplay with other cholinergic parameters and their being targets of AChE inhibition: AChE-R is particularly involved in the mediation of (anti-)apoptotic events in cholinergic cells, involving adaptation of various cholinergic parameters and a time-dependent link to the expression of neuroprotective factors. The AChE-T C-terminus is central to AChE activity regulation, while isolated AChE-T C-terminal fragments mediate toxic effects via the ?7 nicotinic acetylcholine receptor. There is direct evidence for roles of AChE-T and AChE-R in neurodegeneration and neuroprotection, with these roles involving AChE as a key modulator of the cholinergic system: in vivo data further encourages the use of AChE inhibitors in the treatment of neurodegenerative conditions such as AD since effects on both enzymatic activity and the enzyme's non-hydrolytic functions can be postulated. It also suggests that novel AChE inhibitors should enhance protective AChE-R, while avoiding the concomitant up-regulation of AChE-T. PMID:23991627

Zimmermann, M

2013-11-01

3

Silanetriols as in vitro inhibitors for AChE.  

PubMed

Three stable silanetriols with increasing steric protection of the silicon atom have been tested for inhibition of acetylcholinesterase (AChE). For all tested silanetriols we found reversible inhibition of the AChE activity at a 100 ?M concentration. The highest inhibition rate was found for the sterically least hindered cyclohexylsilanetriol with 45% inhibition relative to galanthamine hydrobromide for which an IC(50) value of 121 ± 3 ?M was determined as well. The cytotoxicity of the silanetriols used was found to be negligible at concentrations relevant for inhibition. PMID:21111617

Blunder, Martina; Hurkes, Natascha; Spirk, Stefan; List, Martina; Pietschnig, Rudolf

2010-11-05

4

Silanetriols as in vitro inhibitors for AChE  

PubMed Central

Three stable silanetriols with increasing steric protection of the silicon atom have been tested for inhibition of acetylcholinesterase (AChE). For all tested silanetriols we found reversible inhibition of the AChE activity at a 100 ?M concentration. The highest inhibition rate was found for the sterically least hindered cyclohexylsilanetriol with 45% inhibition relative to galanthamine hydrobromide for which an IC50 value of 121 ± 3 ?M was determined as well. The cytotoxicity of the silanetriols used was found to be negligible at concentrations relevant for inhibition.

Blunder, Martina; Hurkes, Natascha; Spirk, Stefan; List, Martina; Pietschnig, Rudolf

2011-01-01

5

Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors  

Microsoft Academic Search

In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured the activities of AChE and butyrylcholinesterase (BuChe) and the concentrations of #-amyloid (1-42), F and phosphorylated F proteins in the cerebrospinal fluid (CSF). A total of 91 patients suffering from probable AD of mild to moderate degree

L. Parnetti; S. Amici; A. Lanari; C. Romani; C. Antognelli; N. Andreasen; L. Minthon; P. Davidsson; H. Pottel; K. Blennow; V. Gallai

2002-01-01

6

Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors.  

PubMed

In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured the activities of AChE and butyrylcholinesterase (BuChe) and the concentrations of beta-amyloid (1-42), tau and phosphorylated tau proteins in the cerebrospinal fluid (CSF). A total of 91 patients suffering from probable AD of mild to moderate degree were treated for 6 months with donepezil (n=59), galantamine (n=15), rivastigmine (n=10), or placebo (n=7). AChE activity in CSF was significantly increased after treatment with donepezil and galantamine; the opposite was observed in the rivastigmine-treated group. Untreated patients did not show any AChE activity variation. BuChE did not show any change in any of the groups studied. Mean values of beta-amyloid(1-42), total tau and phosphorylated tau also did not vary significantly. We conclude that AChE inhibitors induce different effects on CSF AChE activity, while other CSF biomarkers are not significantly affected by treatment. PMID:12548360

Parnetti, L; Amici, S; Lanari, A; Romani, C; Antognelli, C; Andreasen, N; Minthon, L; Davidsson, P; Pottel, H; Blennow, K; Gallai, V

2002-09-01

7

Electronic structure calculations toward new potentially AChE inhibitors  

NASA Astrophysics Data System (ADS)

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.

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

2007-10-01

8

Pharmacogenetic regulation of acetylcholinesterase activity in Drosophila reveals the regulatory mechanisms of AChE inhibitors in synaptic plasticity.  

PubMed

We conducted experiments in Drosophila to investigate the consequences of altered acetylcholinesterase (AChE) activity in the nervous system. In ace hypomorphic mutant larvae, the amount of ace mRNA and the activity of AChE both in vivo and in vitro were significantly reduced compared with those of controls. Reduced Ace in Drosophila larvae resulted in significant down-regulation of branch length and the number of boutons in Type 1 glutamatergic neuromuscular junctions (NMJs). These defects in ace hypomorphic mutant larvae were suppressed when Musca domestica AChE was transgenically expressed. Because AChE inhibitors are utilized for medications for Alzheimer's disease, we investigated whether pharmacological inhibition of AChE activity induced any synaptic defects. We found that controls exposed to a sublethal dose of DDVP phenocopied the synaptic structural defects of the ace hypomorphic mutant. These results suggest that down-regulation of AChE activity, regardless of whether it is due to genetic or pharmacological manipulations, results in altered synaptic architecture. Our study suggests that exposure to AChE inhibitors for 6-12 months may induce altered synaptic architectures in human brains with Alzheimer's diseases, similar to those reported here. These changes may underlie or contribute to the loss of efficacy of AChE inhibitors after prolonged treatment. PMID:21305389

Kim, Wontae; Lee, Daeweon; Choi, Jinkyu; Kim, Ayoung; Han, Sangmi; Park, Kwanho; Choi, Jiyoung; Kim, Jonggil; Choi, Youngcheol; Lee, Si Hyeock; Koh, Young Ho

2011-02-09

9

Molecular dynamics simulation study and molecular docking descriptors in structure-based QSAR on acetylcholinesterase (AChE) inhibitors.  

PubMed

In this study we present an approach for predicting the inhibitory activity of acetylcholinesterase (AChE) inhibitors by combining molecular dynamics (MD) simulation and docking studies in a structure-based quantitative structure-activity relationship (QSAR) model. The MD simulation was performed on AChE to obtain enzyme conformation in a water environment. The resulting conformation of the enzyme was used for docking with the most potent inhibitor (26a). Docking analysis revealed that hydrophobic interactions play important roles in the AChE-inhibitor complex. Then, all inhibitors that could bind simultaneously at the catalytic site and at the peripheral anionic site of AChE were docked into the enzyme and their interactions with AChE were used as new interpretable descriptors in a structure-based QSAR model. The least squares support vector regression was constructed using the four most relevant docking descriptors and one molecular structure descriptor. The Q (2) value of the model was found to be 0.790. Furthermore, to study the enzyme conformation stability, a second MD simulation was performed on AChE-inhibitor 26a complex. In MD simulation, the topological parameters of the inhibitor were derived from the PRODRG server, and partial atomic charges were modified using the B3LYP/6-31G level of theory. The radius of gyration for the complex showed that AChE conformation did not change in the presence of the inhibitors. PMID:23863115

Gharaghani, S; Khayamian, T; Ebrahimi, M

2013-07-17

10

Continuous flow immobilized enzyme reactor-tandem mass spectrometry for screening of AChE inhibitors in complex mixtures.  

PubMed

A method is described for identifying bioactive compounds in complex mixtures based on the use of capillary-scale monolithic enzyme-reactor columns for rapid screening of enzyme activity. A two-channel nanoLC system was used to continuously infuse substrate coupled with automated injections of substrate/small molecule mixtures, optionally containing the chromogenic Ellman reagent, through sol-gel derived acetylcholinesterase (AChE) doped monolithic columns. This is the first report of AChE encapsulated in monolithic silica for use as an immobilized enzyme reactor (IMER), and the first use of such IMERs for mixture screening. AChE IMER columns were optimized to allow rapid functional screening of compound mixtures based on changes in the product absorbance or the ratio of mass spectrometric peaks for product and substrate ions in the eluent. The assay had robust performance and produced a Z' factor of 0.77 in the presence of 2% (v/v) DMSO. A series of 52 mixtures consisting of 1040 compounds from the Canadian Compound Collection of bioactives was screened and two known inhibitors, physostigmine and 9-aminoacridine, were identified from active mixtures by manual deconvolution. The activity of the compounds was confirmed using the enzyme reactor format, which allowed determination of both IC(50) and K(I) values. Screening results were found to correlate well with a recently published fluorescence-based microarray screening assay for AChE inhibitors. PMID:21591743

Forsberg, Erica M; Green, James R A; Brennan, John D

2011-06-02

11

3D QSAR studies of AChE inhibitors based on molecular docking scores and CoMFA  

Microsoft Academic Search

Three-dimensional quantitative structure–activity relationship (3D QSAR) studies were performed on acetylcholinesterase (AChE) inhibitors, based on molecular docking scores obtained by using FlexX and FlexiDock and comparative molecular field analysis (CoMFA). The docking scores were used as molecular descriptors along with the steric and electrostatic field values of CoMFA, for partial least square (PLS) analysis. The high leave one out (LOO)

Nagaraju Akula; Laurent Lecanu; Janet Greeson; Vassilios Papadopoulos

2006-01-01

12

Quaternary ammonium sulfanilamide: a membrane-impermeant carbonic anhydrase inhibitor  

Microsoft Academic Search

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

1987-01-01

13

Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation.  

PubMed

We have proposed that activation of cerebral perivascular sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03-0.1 microM) but inhibited at higher concentrations (0.3-10 microM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1-30 mM)-evoked inward currents were reversibly blocked by 1-30 microM mecamylamine, 1-30 microM methyllycaconitine, 10-300 nM alpha-bungarotoxin, and 0.1-10 microM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone. PMID:16772524

Long, Cheng; Chen, Mei-Fang; Sarwinski, Susan J; Chen, Po-Yi; Si, Minliang; Hoffer, Barry J; Evans, M Steven; Lee, Tony J F

2006-07-01

14

Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: New dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease.  

PubMed

6-Chloro-pyridonepezils are chloropyridine-donepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils1-8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine-3,5-dicarbonitrile (14)] with suitable 2-(1-benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC50 = 0.47 ± 0.08 ?M). 6-Chloro-pyridonepezils4, 7 and 8 are potent hAChE inhibitors showing IC50 in the 0.013-0.054 ?M range. Particularly, 6-chloro-pyridonepezil8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils4, 6-8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils1-8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer's therapy. PMID:23838422

Samadi, Abdelouahid; de la Fuente Revenga, Mario; Pérez, Concepción; Iriepa, Isabel; Moraleda, Ignacio; Rodríguez-Franco, María Isabel; Marco-Contelles, José

2013-06-25

15

Life without acetylcholinesterase: the implications of cholinesterase inhibitor toxicity in AChE-knockout mice  

Microsoft Academic Search

The acetylcholinesterase (AChE)-knockout mouse is a new tool for identifying physiologically relevant targets of organophosphorus toxicants (OP). If AChE were the only important target for OP toxicity, then mice with zero AChE would have been expected to be resistant to OP. The opposite was found. AChE?\\/? mice were more sensitive to the lethality of DFP, chlorpyrifos oxon, iso-OMPA, and the

Oksana Lockridge; Ellen G. Duysen; Troy Voelker; Charles M. Thompson; Lawrence M. Schopfer

2005-01-01

16

Studies of corrosion inhibitors for zinc–manganese batteries: quinoline quaternary ammonium phenolates  

Microsoft Academic Search

Three compounds, hydroxyethyl quinoline quaternary ammonium phenolate, hydroxyethyl quinoline quaternary ammonium para-methyl phenolate and hydroxyethyl quinoline quaternary ammonium para-nitro phenolate were synthesized and tested as corrosion inhibitors for zinc–manganese batteries. Such quaternary ammonium salts derived from heterocylic molecule containing N atoms possess a higher density electron cloud around the functional groups and provide a larger projective area. From the analysis

Dongshe Zhang; Lidong Li; Lixin Cao; Neifen Yang; Chubao Huang

2001-01-01

17

Quaternary ammonium sulfanilamide: a membrane-impermeant carbonic anhydrase inhibitor  

SciTech Connect

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.

Henry, R.P.

1987-05-01

18

1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-? aggregation crossing the blood-brain barrier.  

PubMed

Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid ? fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC??=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction. PMID:23643737

Prinz, Michaela; Parlar, Sülünay; Bayraktar, Gül?ah; Alptüzün, Vildan; Erciyas, Ercin; Fallarero, Adyary; Karlsson, Daniela; Vuorela, Pia; Burek, Malgorzata; Förster, Carola; Turunc, Ezgi; Armagan, Guliz; Yalcin, Ayfer; Schiller, Carola; Leuner, Kristina; Krug, Manuel; Sotriffer, Christoph A; Holzgrabe, Ulrike

2013-05-02

19

Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer's disease.  

PubMed

The optimization of our previous lead compound 1 (AChE IC(50)=3.31 ?M) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC(50)=2.57?M), 6b (IC(50)=0.70 ?M) and 6i (IC(50)=2.56 ?M) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC(50)=1.11 ?M). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE-carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE-carbamate Michaelis complexes have been investigated. PMID:23026084

Roy, Kuldeep K; Tota, Santoshkumar; Tripathi, Tusha; Chander, Subhash; Nath, Chandishwar; Saxena, Anil K

2012-09-12

20

Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: a case report  

PubMed Central

Background Visual hallucinations are commonly seen in various neurological and psychiatric disorders including schizophrenia. Current models of visual processing and studies in diseases including Parkinsons Disease and Lewy Body Dementia propose that Acetylcholine (Ach) plays a pivotal role in our ability to accurately interpret visual stimuli. Depletion of Ach is thought to be associated with visual hallucination generation. AchEI's have been used in the targeted treatment of visual hallucinations in dementia and Parkinson's Disease patients. In Schizophrenia, it is thought that a similar Ach depletion leads to visual hallucinations and may provide a target for drug treatment Case Presentation We present a case of a patient with Schizophrenia presenting with treatment resistant and significantly distressing visual hallucinations. After optimising treatment for schizophrenia we used Rivastigmine, an AchEI, as an adjunct to treat her symptoms successfully. Conclusions This case is the first to illustrate this novel use of an AchEI in the targeted treatment of visual hallucinations in a patient with Schizophrenia. Targeted therapy of this kind can be considered in challenging cases although more evidence is required in this field.

2010-01-01

21

Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors?  

PubMed Central

We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.

Yang, Wengang; Zhao, Yongsen; Fabrycki, Joanne; Hou, Xiaohong; Nie, Xingtie; Sanchez, Amy; Phadke, Avinash; Deshpande, Milind; Agarwal, Atul; Huang, Mingjun

2008-01-01

22

Efficient quaternary ammonium salt as corrosion inhibitor for steel pickling in sulphuric acid media  

Microsoft Academic Search

A study is carried out on the resistance to corrosion of mild steel in 5 per cent H2SO4 solutions at temperatures between 30 and 60°C. The effectiveness of quaternary ammonium salt used as corrosion inhibitor under the same experimental conditions was also investigated. Weight loss results and electrochemical data showed the good inhibiting action of the inhibitor, acting as anodic

H. A. El Dahan; T. Y. S. Mohamed; S. A. Abo El-Enin

1999-01-01

23

Selection of replicon variants resistant to ACH-806, a novel hepatitis C virus inhibitor with no cross-resistance to NS3 protease and NS5B polymerase inhibitors.  

PubMed

We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism. PMID:18411324

Yang, Wengang; Zhao, Yongsen; Fabrycki, Joanne; Hou, Xiaohong; Nie, Xingtie; Sanchez, Amy; Phadke, Avinash; Deshpande, Milind; Agarwal, Atul; Huang, Mingjun

2008-04-14

24

Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: A review of the literature  

PubMed Central

Background Visual hallucinations occur in various neurological diseases, but are most prominent in Lewy body dementia, Parkinson's disease and schizophrenia. The lifetime prevalence of visual hallucinations in patients with schizophrenia is much more common than conventionally thought and ranges from 24% to 72%. Cortical acetylcholine (ACh) depletion has been associated with visual hallucinations; the level of depletion being related directly to the severity of the symptoms. Current understanding of neurobiological visual processing and research in diseases with reduced cholinergic function, suggests that AChEI's may prove beneficial in treating visual hallucinations. This offers the potential for targeted drug therapy of clinically symptomatic visual hallucinations in patients with schizophrenia using acetylcholinesterase inhibition. Methods A systematic review was carried out investigating the evidence for the effects of AChEI's in treating visual hallucinations in Schizophrenia. Results No evidence was found relating to the specific role of AChEI's in treating visual hallucinations in this patient group. Discussion Given the use of AChEI's in targeted, symptom specific treatment in other neuropsychiatric disorders, it is surprising to find no related literature in schizophrenia patients. The use of AChEI's in schizophrenia has investigated effects on cognition primarily with non cognitive effects measured more broadly. Conclusions We would suggest that more focused research into the effects of AChEI's on positive symptoms of schizophrenia, specifically visual hallucinations, is needed.

2010-01-01

25

Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds.  

PubMed

The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multifunctional compounds to combat causes and symptoms of such neurodegeneration. To this aim we designed, synthesized, and tested a series of compounds by introducing halophenylalkylamidic functions on the scaffold of AP2238, which is a dual binding site acetylcholinesterase inhibitor. The inhibitory activity was successfully extended to the beta-site amyloid precursor protein cleavage enzyme, leading to the discovery of a potent inhibitor of this enzyme (3) and affording multifunctional compounds (2, 6, 8) for the treatment of AD. PMID:17998161

Piazzi, Lorna; Cavalli, Andrea; Colizzi, Francesco; Belluti, Federica; Bartolini, Manuela; Mancini, Francesca; Recanatini, Maurizio; Andrisano, Vincenza; Rampa, Angela

2007-10-04

26

Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds  

Microsoft Academic Search

The complex etiology of Alzheimer’s disease (AD) prompts scientists to develop multifunctional compounds to combat causes and symptoms of such neurodegeneration. To this aim we designed, synthesized, and tested a series of compounds by introducing halophenylalkylamidic functions on the scaffold of AP2238, which is a dual binding site acetylcholinesterase inhibitor. The inhibitory activity was successfully extended to the beta-site amyloid

Lorna Piazzi; Andrea Cavalli; Francesco Colizzi; Federica Belluti; Manuela Bartolini; Francesca Mancini; Maurizio Recanatini; Vincenza Andrisano; Angela Rampa

2008-01-01

27

Interactions of AChE with A? Aggregates in Alzheimer's Brain: Therapeutic Relevance of IDN 5706  

PubMed Central

Acetylcholinesterase (AChE; EC 3.1.1.7) plays a crucial role in the rapid hydrolysis of the neurotransmitter acetylcholine, in the central and peripheral nervous system and might also participate in non-cholinergic mechanism related to neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-? (A?) peptide accumulation and synaptic alterations. We have previously shown that AChE is able to accelerate the A? peptide assembly into Alzheimer-type aggregates increasing its neurotoxicity. Furthermore, AChE activity is altered in brain and blood of Alzheimer’s patients. The enzyme associated to amyloid plaques changes its enzymatic and pharmacological properties, as well as, increases its resistant to low pH, inhibitors and excess of substrate. Here, we reviewed the effects of IDN 5706, a hyperforin derivative that has potential preventive effects on the development of AD. Our results show that treatment with IDN 5706 for 10?weeks increases brain AChE activity in 7-month-old double transgenic mice (APPSWE–PS1) and decreases the content of AChE associated with different types of amyloid plaques in this Alzheimer’s model. We concluded that early treatment with IDN 5706 decreases AChE–A? interaction and this effect might be of therapeutic interest in the treatment of AD.

Carvajal, Francisco J.; Inestrosa, Nibaldo C.

2011-01-01

28

Centrally acting oximes in reactivation of tabun-phosphoramidated AChE.  

PubMed

Organophosphates (OP) inhibit acetylcholinesterase (AChE, EC 3.1.1.7), both in peripheral tissues and central nervous system (CNS), causing adverse and sometimes fatal effects due to the accumulation of neurotransmitter acetylcholine (ACh). The currently used therapy, focusing on the reactivation of inhibited AChE, is limited to peripheral tissues because commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier (BBB) at therapeutically relevant levels. A directed library of thirty uncharged oximes that contain tertiary amine or imidazole protonable functional groups that should cross the BBB as unionized species was tested as tabun-hAChE conjugate reactivators along with three reference oximes: DAM (diacetylmonoxime), MINA (monoisonitrosoacetone), and 2-PAM. The oxime RS150D [N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide] was highlighted as the most promising reactivator of the tabun-hAChE conjugate. We also observed that oximes RS194B [N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide] and RS41A [2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide], which emerged as lead uncharged reactivators of phosphylated hAChE with other OPs (sarin, cyclosarin and VX), exhibited only moderate reactivation potency for tabun inhibited hAChE. This implies that geometry of oxime access to the phosphorus atom conjugated to the active serine is an important criterion for efficient reactivation, along with the chemical nature of the conjugated moiety: phosphorate, phosphonate, or phosphoramidate. Moreover, modification of the active center through mutagenesis enhances the rates of reactivation. The phosphoramidated-hAChE choline-binding site mutant Y337A showed three-times enhanced reactivation capacity with non-triazole imidazole containing aldoximes (RS113B, RS113A and RS115A) and acetamide derivative (RS194B) than with 2PAM. PMID:22960624

Kovarik, Zrinka; Ma?ek, Nikolina; Sit, Rakesh K; Radi?, Zoran; Fokin, Valery V; Barry Sharpless, K; Taylor, Palmer

2012-09-07

29

Acetylcholinesterases of Rhipicephalus (Boophilus) microplus – Multiple gene expression presents an opportune model system for elucidation of multiple functions of AChEs.  

Technology Transfer Automated Retrieval System (TEKTRAN)

Acetylcholinesterase (AChE) is a key neural enzyme of both vertebrates and invertebrates, and is the biochemical target of organophosphate and carbamate pesticides for invertebrates, as well as vertebrate nerve agents, e.g., soman, tabun, VX, and others. AChE inhibitors are also key drugs among thos...

30

Galantamine improves apomorphine-induced deficits in prepulse inhibition via muscarinic ACh receptors in mice  

PubMed Central

Background and purpose Galantamine, a weak acetylcholine esterase (AChE) inhibitor and allosteric potentiator of nicotinic ACh receptors (nAChRs), improves apomorphine-induced deficits in prepulse inhibition (PPI), sensory information-processing deficits, via a nAChR-independent mechanism. The present study examined the role of muscarinic ACh receptors (mAChRs) in the effect of galantamine, and studied the mechanism of galantamine-induced increases in prefrontal ACh levels in mice. Experimental approach Apomorphine (1 mg kg?1) was administered to male ddY mice (9–10 weeks old) to create a PPI deficit model. Extracellular ACh concentrations in the prefrontal cortex were measured by in vivo microdialysis. Key results Galantamine- and donepezil-mediated improvements in apomorphine-induced PPI deficits were blocked by the preferential M1 mAChR antagonist telenzepine. The mAChR agonist oxotremorine also improved apomorphine-induced PPI deficits. Galantamine, like donepezil, increased extracellular ACh concentrations in the prefrontal cortex. Galantamine-induced increases in prefrontal ACh levels were partially blocked by the dopamine D1 receptor antagonist SCH23390, but not by antagonists of mAChRs (telenzepine) and nAChRs (mecamylamine). Galantamine increased dopamine, but not 5-HT, release in the prefrontal cortex. Conclusions and implications Galantamine improves apomorphine-induced PPI deficits by stimulating mAChRs through increasing brain ACh levels via a dopamine D1 receptor-dependent mechanism and AChE inhibition.

Yano, K; Koda, K; Ago, Y; Kobayashi, H; Kawasaki, T; Takuma, K; Matsuda, T

2009-01-01

31

Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones.  

PubMed

This work describes the enantioselective synthesis of a new series of terpenic chiral 9-aminotetrahydroacridine analogues. Several chiral ketones were synthesized from natural monoterpenes in an optically active form and subjected to the cyclodehydration reactions with anthranilonitrile in the presence of BF(3).Et(2)O as catalyst. The 9-aminotetrahydroacridine analogues were tested as acetylcholinesterase (AChE) inhibitors. Based on qualitative structure-activity relationship some trends are suggested. PMID:19954865

dos Santos Pisoni, Diego; Sobieski da Costa, Jessé; Gamba, Douglas; Petzhold, Cesar Liberato; de Amorim Borges, Antonio César; Ceschi, Marco Antonio; Lunardi, Paula; Saraiva Gonçalves, Carlos Alberto

2009-11-10

32

Design and synthesis of imidazole and triazole derivatives as Lp-PLA? inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.  

PubMed

New Lp-PLA(2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo. PMID:23385210

Wang, Kai; Xu, Wenwei; Liu, Yang; Zhang, Wei; Wang, Wenyi; Shen, Jianhua; Wang, Yiping

2013-01-16

33

Formation of a quaternary complex of HIV-1 reverse transcriptase with a nucleotide-competing inhibitor and its ATP enhancer.  

PubMed

Nucleotide-competing reverse transcriptase inhibitors were shown to bind reversibly to the nucleotide-binding site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus type 1 (HIV-1). Here, we show that the presence of ATP can enhance the inhibitory effects of the prototype compound INDOPY-1. We employed a combination of cell-free and cell-based assays to shed light on the underlying molecular mechanism. Binding studies and site-specific footprinting experiments demonstrate the existence of a stable quaternary complex with HIV-1 RT, its nucleic acid substrate, INDOPY-1, and ATP. The complex is frozen in the post-translocational state that usually accommodates the incoming nucleotide substrate. Structure-activity relationship studies show that both the base and the phosphate moieties of ATP are elements that play important roles in enhancing the inhibitory effects of INDOPY-1. In vitro susceptibility measurements with mutant viruses containing amino acid substitutions K70G, V75T, L228R, and K219R in the putative ATP binding pocket revealed unexpectedly a hypersusceptible phenotype with respect to INDOPY-1. The same mutational cluster was previously shown to reduce susceptibility to the pyrophosphate analog phosphonoformic acid. However, in the absence of INDOPY-1, ATP can bind and act as a pyrophosphate donor under conditions that favor formation of the pre-translocated RT complex. We therefore conclude that the mutant enzyme facilitates simultaneous binding of INDOPY-1 and ATP to the post-translocated complex. Based on these data, we propose a model in which the bound ATP traps the inhibitor, which, in turn, compromises its dissociation. PMID:23598281

Ehteshami, Maryam; Nijhuis, Monique; Bernatchez, Jean A; Ablenas, Christopher J; McCormick, Suzanne; de Jong, Dorien; Jochmans, Dirk; Götte, Matthias

2013-04-18

34

Pulmonary Toxicity of Cholinesterase Inhibitors.  

National Technical Information Service (NTIS)

The lungs are a major organ system of entry into the body and a target for the toxic effects of organophosphorus (OP) corn- pounds, potent inhibitors of the enzyme acetyicholinesterase (AChE). In general, AChE inhibitors (AChEIs) were developed for a vari...

C. Hilmas M. Adler R. C. Gupta S. I. Baskin

2006-01-01

35

Indole alkaloids of Psychotria as multifunctional cholinesterases and monoamine oxidases inhibitors.  

PubMed

Thirteen Psychotria alkaloids were evaluated regarding their interactions with acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A and MAO-B), which are enzymatic targets related with neurodegenerative diseases. Two quaternary ?-carboline alkaloids, prunifoleine and 14-oxoprunifoleine, inhibited AChE, BChE and MAO-A with IC(50) values corresponding to 10 and 3.39 ?M for AChE, 100 and 11 ?M for BChE, and 7.41 and 6.92 ?M for MAO-A, respectively. Both compounds seem to behave as noncompetitive AChE inhibitors and time-dependent MAO-A inhibitors. In addition, the monoterpene indole alkaloids (MIAs) angustine, vallesiachotamine lactone, E-vallesiachotamine and Z-vallesiachotamine inhibited BChE and MAO-A with IC(50) values ranging from 3.47 to 14 ?M for BChE inhibition and from 0.85 to 2.14 ?M for MAO-A inhibition. Among the tested MIAs, angustine is able to inhibit MAO-A in a reversible and competitive way while the three vallesiachotamine-like alkaloids display a time-dependent inhibition on this target. Docking calculations were performed in order to understand the binding mode between the most active ligands and the selected targets. Taken together, our findings established molecular details of AChE, BChE and MAO-A inhibition by quaternary ?-carboline alkaloids and MIAs from Psychotria, suggesting these secondary metabolites are scaffolds for the development of multifunctional compounds against neurodegeneration. PMID:23261030

Passos, Carolina S; Simões-Pires, Claudia A; Nurisso, Alessandra; Soldi, Tatiane C; Kato, Lucilia; de Oliveira, Cecilia M A; de Faria, Emiret O; Marcourt, Laurence; Gottfried, Carmem; Carrupt, Pierre-Alain; Henriques, Amélia T

2012-12-19

36

Activated transformations of organophosphorus insecticides in the case of non-AChE inhibitory oxons.  

PubMed

Many organophosphorus (OP) compounds are of the thiono form and in insects or animals are converted by microsomal mixed function oxidases (MFO) into the oxon forms which inhibit acetylcholinesterase (AChE) and give toxic activity. However, certain S-alkyl phosphorothiolates (RS-P(O) <) such as methamidophos, profenophos and prothiophos oxon are strongly insecticidal, but very poor inhibitors of AChE in vitro. Their oxons are converted further to the S-oxides, which either inhibit AChE or decompose, depending on the alkyl substituents on the sulfur atom. It is also inferred in the case of prothiophos oxon that its S-oxide not only inhibits AChE but also conjugates with glutathione (GSH) by the action of glutathione S-transferase (GST), and the conjugate inhibits AChE. Certain phosphoramidates (R2N-P(O) <) such as isofenphos oxon, schradan and propetamphos oxon are weak AChE inhibitors, but strongly insecticidal. It is well known that isofenphos oxon is converted into the stable N-desalkyl form (H2N-P(O) <) by oxidative dealkylation to inhibit AChE. The authors have studied activation of phosphoramidates using 2,4-dichlorophenyl methyl N-alkylphosphoramidates as model compounds using various approaches including computational chemistry, and these studies indicated that the O-aminophosphate structure (R2N-O-P(O) <) is an activated form. PMID:12449529

Kasagami, Takeo; Miyamoto, Toru; Yamamoto, Izuru

2002-11-01

37

Reaction Gorge Fluctuation in Acetylcholinesterase (AChE)  

NSDL National Science Digital Library

Scientists Huan-Xiang Zhou, Stanislaw Wlodek, and Andrew McCammon created this animation showing "the 'breathing' motions of the gorge or channel that leads from the region outside the enzyme Acetylcholinesterase (AChE), to the active site." The enzyme AChE controls the communication among nerve and muscle cells. This animation demonstrates, for the first time, the role of molecular dynamics in enzyme specificity. It is based on "a combination of computational models and theoretical calculations," which were published in the August 4, 1998 issue of the Proceedings of the National Academy of Sciences.

Wlodeck, Stanislaw T.; Mccammon, J. A.

1998-01-01

38

Determination of AChE levels and genotoxic effects in farmers occupationally exposed to pesticides  

Microsoft Academic Search

Pesticides can cause cytogenetic effects and lower the acetyl cholinesterase (AChE) levels in farmers exposed to pesticides. In this study, 210 farmers exposed to pesticides and 160 non-exposed individuals were enrolled for determining the genotoxicity and AChE levels. The AChE levels were determined in plasma and RBC lysate from blood samples collected from farmers and control subjects. AChE (true and

Rambabu Naravaneni; Kaiser Jamil

2007-01-01

39

ACH-126443 Achillion/Yale University.  

PubMed

Achillion, under license from Vion, is developing the nucleoside analog ACH-126443 (beta-L-Fd4C), a reverse transcriptase (RT) inhibitor, for the potential treatment of HIV and hepatitis B virus (HBV) infection. The compound is one of a series of antiviral compounds developed by Yale University [213319]. By February 2002, it had entered phase II trials for chronic HBV infection [435422]; these were ongoing in June 2002, by which time, additional phase II clinical studies for chronic HBV infection had been planned [452185], [454316]. PMID:12476956

Patel, Jignesh; Mitra, Ashim K

2002-11-01

40

PRiMA directs a restricted localization of tetrameric AChE at synapses.  

PubMed

Acetylcholinesterase (AChE), a highly polymorphic enzyme with various splicing variants and molecular isoforms, plays an essential role in the cholinergic neurotransmission by hydrolyzing acetylcholine into choline and acetate. The AChE(T) variant is expressed in the brain and muscle: this subunit forms non-amphiphilic tetramers with a collagen tail (ColQ) as asymmetric AChE (A(12) AChE) in muscle, and amphiphilic tetramers with a proline-rich membrane anchor (PRiMA) as globular AChE (G(4) AChE) in the brain and muscle. During the brain development, the expression of amphiphilic G(4) AChE is up regulated and becomes the predominant form of AChE there. This up-regulation of G(4) AChE can be attributed to the increased expressions of both AChE(T) and PRiMA. A significant portion of this membrane-bound G(4) AChE is localized at the membrane rafts of the cell membranes derived from the brain. This raft association could be directed by PRiMA via its CRAC (cholesterol recognition/interaction amino acid consensus) motif and C-terminus. In cultured cortical neurons and muscles, the PRiMA-linked AChE was clustered and partially co-localized with synaptic proteins. The restricted localizations suggest that the raft association of PRiMA-linked AChE could account for its synaptic localization and function. PMID:20178777

Xie, Heidi Q; Leung, K Wing; Chen, Vicky P; Chan, Gallant K L; Xu, Sherry L; Guo, Ava J Y; Zhu, Kevin Y; Zheng, Ken Y Z; Bi, Cathy W; Zhan, Janis Y X; Chan, Wallace K P; Choi, Roy C Y; Tsim, Karl W K

2010-02-21

41

A monoclonal antibody against synaptic AChE: a useful tool for detecting apoptotic cells.  

PubMed

The classical function of acetylcholinesterase (AChE) is to terminate synaptic transmission at cholinergic synapses by rapidly hydrolyzing the neurotransmitter acetylcholine (ACh). Non-classical functions of AChE involve accelerating the assembly of Abeta peptide into amyloid fibrils and participating in haematopoiesis and neurite growth. Although numerous antibodies have been raised against AChE, many researchers have questioned their reliability to identify the AChE in situ, especially with the regard to its non-classical roles. Researchers attended the Ninth International Meeting on Cholinesterase raised this question by showing different Western blot patterns of AChE detected by different Abs. Producing more effective and reliable Abs for measuring AChE in vivo or in situ has become an important issue in many scientific fields. In this paper, we introduce a monoclonal antibody raised against synaptic AChE that we identified by Western blot assays, immunofluorescent staining and immunoprecipitation of AChE, and mass spectrometry. Our results strongly demonstrate the specificity of our monoclonal antibody to recognize synaptic AChE; hence our antibody can be used as an effective tool to study the various functions of AChE. Since the apoptosis-related AChE was its synaptic form, our antibody can be used as a tool to detect apoptotic cells. PMID:18538755

Su, Wei; Wu, Jun; Ye, Wei-Yuan; Zhang, Xue-Jun

2008-05-03

42

Corrosion inhibition by quaternary amines  

Microsoft Academic Search

Quaternary ammonium compounds are excellent inhibitors of acid corroison, and seem to influence the anodic partial reaction more than the cathodic. This behavior is not readily interpreted in terms of physical vs. chemical adsorption, since these compounds do not possess bonding for chemisorption. Increasing the hydrogen bulk in the inhibitor molecule markedly increases the inhibition efficiency, which is to be

R. M. Hurd; H. Raiszadeh

1970-01-01

43

Quaternary Ammonium Salts From Hydrolysed Fatty Oil Based on Novel Tertiary Amines Used as Corrosion Inhibitors for Pipelines Carbon Steel at Acid Job in Petroleum Industry  

Microsoft Academic Search

Ten new quaternary ammonium salts were designed and synthesized from hydrolyzed fatty oils; the hydrolysed oils were used as a source of alkyl halides to prepare the quaternary ammonium salts by refluxing the fatty alkyl halide with ethoxylated amines as untraditional 3° amines in acetone. The structure of the prepared quaternary ammonium salts were characterized by FTIR and H NMR

A. M. Al-Sabagh; N. G. Kandile; Nahed Amer; Omaima Ramadan; E. A. Khamis

2011-01-01

44

Quaternary investigation  

SciTech Connect

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.

Stieve, A.

1991-05-15

45

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

PubMed

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

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

2012-04-30

46

Bactericidal Activity of ACH-702 against Nondividing and Biofilm Staphylococci  

PubMed Central

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.

Podos, Steven D.; Thanassi, Jane A.; Leggio, Melissa

2012-01-01

47

Myeloperoxidase-mediated oxidation of organophosphorus pesticides as a pre-step in their determination by AChE based bioanalytical methods  

Microsoft Academic Search

In order to improve the sensitivity of assays for inhibitors of the enzyme acetylcholine esterase (AChE), an effective method\\u000a was developed for the conversion of the organophosphate pesticides (OPs) diazinon, malathion, chlorpyrifos, azinphos-methyl\\u000a and phorate into more toxic inhibitors. This was accomplished by converting them from the thio form into their oxo form using\\u000a the enzyme myeloperoxidase. The oxo forms,

Tamara Lazarevi? Pašti; Tatjana Momi?; Antonije Onjia; Ljubodrag Vujisi?; Vesna Vasi?

2010-01-01

48

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

PubMed

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. PMID:16263378

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

2005-04-25

49

Interaction of monosulfonate tetraphenyl porphyrin, a competitive inhibitor, with acetylcholinesterase.  

PubMed

Monosulfonate tetraphenyl porphyrin (TPPS(1)) forms a 1:1 complex with electric eel acetylcholinesterase (AChE) inducing a loss in TPPS(1) absorbance at 402 nm and the appearance of a new absorbance centered at 442 nm. In the presence of AChE, the fluorescence of TPPS(1) at 652 nm is slightly narrowed, with the maximal 652 nm fluorescence shifted from 407 to 412 nm excitation wavelength. The fluorescence peak of TPPS(1) at 712 nm shifts to 716 nm in the presence of AChE. TPPS(1) is a competitive inhibitor of AChE. The addition of acetylcholine iodide (AChI) or the competitive inhibitor tetracaine to the preformed AChE-TPPS(1) complex results in a loss of the 442 nm absorbance band as the porphyrin is displaced from AChE. The absorbance peak does not decrease in the presence of procaine, a non-competitive inhibitor. PMID:11959466

White, Brandy J; Harmon, H James

2002-06-01

50

Phosphodiesterase 5 inhibition restores impaired ACh relaxation in hypertensive conduit pulmonary arteries.  

PubMed

Responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were compared in large (LPA) and small pulmonary artery (SPA) rings from normoxic and chronically hypoxic (CH) rats. In addition, the effects of a selective phosphodiesterase (PDE) 5 inhibitor, E-4021, on ACh-induced relaxation were evaluated. Chronic hypoxia markedly decreased both ACh- and SNP-induced relaxations in LPA but not in SPA rings. Pretreatment with E-4021 caused a much greater leftward shift of the concentration-response curve for ACh in hypoxic than in normoxic LPA rings, eliminating the difference in response to ACh between these two vessels. These results suggest that cGMP-dependent relaxation is impaired in the proximal but not in the distal pulmonary artery of CH rats and that increased PDE5 activity could be a mechanism responsible for this impaired responsiveness. PMID:11159025

Oka, M

2001-03-01

51

The Alaska Quaternary Center  

NSDL National Science Digital Library

This website illustrates the Alaska Quaternary Center's (at the University of Alaska, Fairbanks) commitment "to the promotion of interdisciplinary research and the enhancement of interdisciplinary instruction in Quaternary sciences." Users can view images of the field work and learn how to obtain quaternary data from the AQC Quaternary Research Geodatabase.

1969-12-31

52

Irish Quaternary Association (IQUA)  

NSDL National Science Digital Library

The Irish Quaternary Association (IQUA) website publicizes its aim "to promote Quaternary studies in Ireland through its publications, and the organization of field meetings and conferences." Visitors can learn about the importance of quaternary studies, find out the latest news and upcoming meetings, and find links to Quaternary studies journals.

1969-12-31

53

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

PubMed

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?g/L (24h) and 1000?g/L (12h and 24h). 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 12h after exposure at both 100 and 1000?g/L, while the Bk-AChE mRNA expression was significantly downregulated over 6 to 24h after exposure to 1000?g/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

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

2013-09-09

54

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

PubMed

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

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

2012-10-06

55

Quaternary Ammonium Salts from Hydrolyzed Fatty Oil Based on Novel Tertiary Amines Used as Corrosion Inhibitors for Pipelines Carbon Steel at Acid Job in Petroleum Industry  

Microsoft Academic Search

Ten new quaternary ammonium salts (QASs) were designed and synthesized from hydrolyzed fatty oils; the hydrolyzed oils were used as a source of alkyl halides to prepare the QASs by refluxing the fatty alkyl halide with ethoxylated amines as untraditional 3° amines in acetone. The structure of the prepared QASs were characterized by FTIR and H NMR spectroscopy. The prepared

A. M. Al-Sabagh; N. G. Kandile; Nahed Amer; Omaima Ramadan; E. A. Khamis

2012-01-01

56

In vitro studies on the reactivation by oximes of phosphylated acetylcholinesterase--II. On the formation of O,O-diethyl phosphorylated AChE and O-ethyl methylphosphonylated AChE and their reactivation by PS2.  

PubMed

The in vitro reactivation profiles of O,O-diethyl phosphorylated AChE and O-ethyl methyl phosphonylated AChE by P2S (2-hydroxy iminomethyl-1-methyl-pyridinium methane sulphonate) have been determined. Whilst reinhibition of the reactivated AChE by phosphorylated oxime (POX) is not important in determining the reactivation profile of O,O-diethyl phosphorylated AChE, reinhibition of the reactivated AChE by phosphonylated oxime can, however, be important in determining the reactivation profile of O-ethyl methylphosphonylated AChE and the extent of this reinhibition is determined by the initial concentration of phosphonylated AChE. Kinetic analysis of the reactivation profiles demonstrated that the generally accepted scheme for this reactivation process is incorrect and that phosphylated AChE cannot be considered as a single species although an adequate description of the present data is afforded by a model using a 1:1 mixture of two species each with its own rate of reactivation. In the case of O,O-diethyl phosphorylated AChE the main kinetic difference between these two species is found not in the formation or stability of the phosphorylated AChE-P2S complex but in its subsequent reaction. From results with O-ethyl methylphosphonylated AChE prepared from two pairs of enantiomers as well as from the racemic fluoridate it was concluded that phosphonylation of AChE may not always occur via a mechanism involving inversion of configuration at phosphorus but can also occur with retention of configuration. Reactivation by P2S of O-ethyl methylphosphonylated AChE prepared from (S) organophosphates proceeds with inversion of configuration at phosphorus. Inversion also occurs in the reinhibition of AChE by the POX produced in the initial reactivation. PMID:3954784

Harvey, B; Scott, R P; Sellers, D J; Watts, P

1986-03-01

57

Ultrasound-induced enhancement of ACh, AChE and GABA in fetal brain tissue of mouse.  

PubMed

Pregnant mice were exposed to continuous-wave (CW) ultrasound of 875 kHz frequency at 1 W/cm2 for 300 and 400 s, spread over five days, starting from the sixth day of pregnancy. The neurotransmitters, acetylcholine (ACh) and gamma amino butyric acid (GABA), and the associated enzyme acetylcholinesterase (AChE) levels, were estimated in the exposed fetal brains. Enhanced levels, significant at p < 0.001, were observed in the brains excised on day 10, day 15 and day 20 of gestation compared to sham-exposed and cage-control brains. PMID:8356785

Suneetha, N; Kumar, R P

1993-01-01

58

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

PubMed

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 ?M) 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. PMID:22019465

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

2011-10-05

59

Back-Scattering Interferometry: An Ultrasensitive Method for the Unperturbed Detection of Acetylcholinesterase-Inhibitor Interactions  

PubMed Central

A series of inhibitors of acetylcholinesterase (AChE) have been screened by back-scattering interferometry (BSI). Enzyme levels as low as 100 pM (22,000 molecules of AChE) can be detected. This method can be used to screen for mixed AChE inhibitors, agents that have shown high efficacy against Alzheimer's disease, by detecting dual-binding interactions.

Haddad, Gabrielle L.; Young, Sherri C.; Heindel, Ned D.; Bornhop, Darryl J.; Flowers, Robert A.

2013-01-01

60

A first principles investigation of aging processes in soman conjugated AChE.  

PubMed

We have examined the aging process of soman inhibited AChE using Density functional theory (DFT) calculations. The catalytic serine of AChE can be phosphonylated by the nerve agent soman, and subsequently can undergo an aging process. The consequences of irreversible inhibition of AChE due to the aging process is fatal for mammals. The DFT calculations shed light on some intricate features of aging process of soman inhibited AChE, which has been pondering in the literature. The DFT calculations (M05-2X/6-31G(?) level of theory) performed with the model systems revealed that the dealkylation of pinacolyl group and the methyl migration takes place simultaneously. The role of pre-protonation and electrostatic stabilization by histidine (His440(+)) in catalyzing the aging process of soman inhibited AChE is energetically comparable. The aging process catalyzed by the histidine (His440(+)) residue reduces the free energy of activation by ?14.0kcal/mol, which is in good agreement with the reported experimental results. Further, the calculated results reveal that tryptophan residue (Trp84) of the catalytic anionic subsite (CAS) assists the rearrangement reaction in the rearrangement process via cation-? interactions. PMID:23747845

Chandar, Nellore Bhanu; Ganguly, Bishwajit

2013-06-05

61

AChBP-targeted ?-conotoxin correlates distinct binding orientations with nAChR subtype selectivity  

PubMed Central

Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand-binding domain, to discover a novel ?-conotoxin (?-TxIA) in the venom of Conus textile. ?-TxIA bound with high affinity to AChBPs from different species and selectively targeted the ?3?2 nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20° backbone tilt compared to other AChBP–conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases.

Dutertre, Sebastien; Ulens, Chris; Buttner, Regina; Fish, Alexander; van Elk, Rene; Kendel, Yvonne; Hopping, Gene; Alewood, Paul F; Schroeder, Christina; Nicke, Annette; Smit, August B; Sixma, Titia K; Lewis, Richard J

2007-01-01

62

AChE biosensor based on aniline-MWNTs modified electrode for the detection of pesticides  

Microsoft Academic Search

com Abstract -Based on the change in electrochemical behavior of enzymatic activity induced by organophosphates (OP) compounds, a simple electrochemical method has been developed for investigation of Organophosphates (OP) compounds using acetylcholineste rase (AChE) biosensor. Aniline (AN) and multiwall carbon nanotubes (MWNTs) are modified on the surfuce of glassy carbon electrode(GCE). The electrochemical behavior of AChE-AN-MWNTs\\/GC E was studied, and

Xia Sun; Qingqing Li; Xiangyou Wang

2011-01-01

63

Characteristics of ACh-induced hyperpolarization and relaxation in rabbit jugular vein  

PubMed Central

BACKGROUND AND PURPOSE The roles played by endothelium-derived NO and prostacyclin and by endothelial cell hyperpolarization in ACh-induced relaxation have been well characterized in arteries. However, the mechanisms underlying ACh-induced relaxation in veins remain to be fully clarified. EXPERIMENTAL APPROACH ACh-induced smooth muscle cell (SMC) hyperpolarization and relaxation were measured in endothelium-intact and -denuded preparations of rabbit jugular vein. KEY RESULTS In endothelium-intact preparations, ACh (?10?8 M) marginally increased the intracellular concentration of Ca2+ ([Ca2+]i) in endothelial cells but did not alter the SMC membrane potential. However, ACh (10?10–10?8 M) induced a concentration-dependent relaxation during the contraction induced by PGF2? and this relaxation was blocked by the NO synthase inhibitor N?-nitro-l-arginine. ACh (10?8–10?6 M) concentration-dependently increased endothelial [Ca2+]i and induced SMC hyperpolarization and relaxation. These SMC responses were blocked in the combined presence of apamin [blocker of small-conductance Ca2+-activated K+ (SKCa, KCa2.3) channel], TRAM 34 [blocker of intermediate-conductance Ca2+-activated K+ (IKCa, KCa3.1) channel] and margatoxin [blocker of subfamily of voltage-gated K+ (KV) channel, KV1]. CONCLUSIONS AND IMPLICATIONS In rabbit jugular vein, NO plays a primary role in endothelium-dependent relaxation at very low concentrations of ACh (10?10–10?8 M). At higher concentrations, ACh (10?8?3 × 10?6 M) induces SMC hyperpolarization through activation of endothelial IKCa, KV1 and (possibly) SKCa channels and produces relaxation. These results imply that ACh regulates rabbit jugular vein tonus through activation of two endothelium-dependent regulatory mechanisms.

Itoh, Takeo; Maekawa, Takashi; Shibayama, Yasushi

2012-01-01

64

Synthesis and in vitro evaluation of xylene linked carbamoyl bis-pyridinium monooximes as reactivators of organophosphorus (OP) inhibited electric eel acetylcholinesterase (AChE)  

Microsoft Academic Search

A series of carbamoyl bis-pyridinium monooximes linked with xylene linker were synthesized and their in-vitro reactivation potential was evaluated against acetylcholinesterase (AChE) inhibited by organophosphorus inhibitors (OP) such as sarin, DFP and VX and the data were compared with reactivation obtained with 2-PAM and obidoxime. Amongst the synthesized compounds, 3-carbamoyl-2?hydroxyiminomethyl-1-1?-(1,4-phenylenedimethyl)-bispyridinium dibromide (5e) 3-carbamoyl-2?hydroxyiminomethy l-1-1?-(1,3-phenylenedimethyl)-bispyridinium dibromide (5k) and 4-carbamoyl-2?hydroxyiminomethyl-1-1?-(1,3-phenylenedimethyl)-bispyridinium dibromide (5l)

Jyotiranjan Acharya; Hemlata Rana; M. P. Kaushik

2011-01-01

65

Flexibility versus "rigidity" of the functional architecture of AChE active center  

PubMed Central

Functional architecture of the AChE active center appears to be characterized by both structural “rigidity”, necessary to stabilize the catalytic triad as well as by flexibility in accommodating the different, high affinity AChE ligands. These seemingly conflicting structural properties of the active center are demonstrated through combination of structural methods with kinetic studies of the enzyme and its mutant derivatives with plethora of structurally diverse ligands and in particular with series of stereoselective covalent and noncovalent AChE ligands. Thus, steric perturbation of the acyl pocket precipitates in a pronounced stereoselectivity toward methylphosphonates by disrupting the stabilizing environment of the catalytic histidine rather than through steric exclusion demonstrating the functional importance of the “rigid” environment of the catalytic machinery. The acyl pocket, the cation-binding subsite (Trp86) and the peripheral anionic subsite were also found to be directly involved in HuAChE stereoselectivity toward charged chiral phosphonates, operating through differential positioning of the ligand cationic moiety within the active center. Residue Trp86 is also a part of the “hydrophobic patch” which seems flexible enough to accommodate the structurally diverse ligands like tacrine, galanthamine and the two diastereomers of huperzine A. Also, we have recently discovered further aspects of the role of both the unique structure and the flexibility of the “hydrophobic patch” in determining the reactivity and stereoselectivity of HuAChE toward certain carbamates including analogs of physostigmine. In these cases the ligands are accommodated mostly through hydrophobic interactions and their stereoselectivity delineates precisely the steric limits of the pocket. Hence, the HuAChE stereoselectivity provides a sensitive tool in the in depth exploration of the functional architecture of the active center. These studies suggest that the combination of “rigidity” and flexibility within the HuAChE gorge are an essential element of its molecular design.

Shafferman, Avigdor; Barak, Dov; Stein, Dana; Kronman, Chanoch; Velan, Baruch; Greig, Nigel H.; Ordentlich, Arie

2008-01-01

66

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

PubMed

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 (?3Q) 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 ?3Q 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 ?3Q and a constructed mutant lacking all 5 consecutive glutamines (?5Q) 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. PMID:21112395

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

2010-11-26

67

Role of hydrogen peroxide in ACh-induced dilation of human submucosal intestinal microvessels.  

PubMed

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several mediators of vasodilation, which include prostacyclin (PGI(2)), nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently defined the role of nitric oxide and PGI(2) in the dilation of submucosal intestinal arterioles from patients with normal bowel function. However, significant endothelium-dependent dilator capacity to ACh remained after inhibiting both these mediators. The current study was designed to examine the potential role of EDHF in human intestinal submucosal arterioles. ACh elicited endothelium-dependent relaxation in the presence of inhibitors of nitric oxide synthase and cyclooxygenase (23 +/- 10%, n = 6). This ACh-induced relaxation was inhibited and converted to constriction by catalase (-53 +/- 10%, n = 6) or KCl (-30 +/- 3%, n = 7), whereas 17-octadecynoic acid and 6-(2-propargylloxyphenyl) hexanoic acid, two inhibitors of cytochrome P450 monooxygenase, had no significant effect (3 +/- 1% and 20 +/- 8%, n = 5, respectively). Exogenous H(2)O(2) elicited dose-dependent relaxation of intact microvessels (52 +/- 10%, n = 7) but caused frank vasoconstriction in arterioles denuded of endothelium (-73 +/- 8%, n = 7). ACh markedly increased the dichlorofluorescein fluorescence in intact arterioles in the presence of nitric oxide synthase and cyclooxygenase inhibitors compared with control and compared with catalase-treated microvessels (363.6 +/- 49, 218.8 +/- 10.6, 221.9 +/- 27.9, respectively, P < 0.05 ANOVA, n = 5 arbitrary units). No changes in the dichlorofluorescein fluorescence were recorded in vessels treated with ACh alone. These results indicate that endothelial production of H(2)O(2) occurs in response to ACh in human gut mucosal arterioles but that H(2)O(2) is not an EDHF in this tissue. Rather, we speculate that it stimulates the release of a chemically distinct EDHF. PMID:15345486

Hatoum, Ossama A; Binion, David G; Miura, Hiroto; Telford, Gordon; Otterson, Mary F; Gutterman, David D

2004-09-02

68

Enzyme inhibitor screening by electrospray mass spectrometry with immobilized enzyme on magnetic silica microspheres  

Microsoft Academic Search

In this study, a novel technique for screening inhibitors by electrospray mass spectrometry (ESI-MS) with immobilized enzyme\\u000a on magnetic microspheres has been demonstrated. First, the model enzyme acetylcholinesterase (AChE) is immobilized onto the\\u000a 3-glycidoxypropyltrimethoxysilane (GLYMO)-modified magnetic silica microspheres. AChE activity was monitored by biochemical\\u000a assay that is based on mixing of AChE immobilized microspheres and model substrate acetylcholine, separating and

Fengli Hu; Huiying Zhang; Huaqing Lin; Chunhui Deng; Xiangmin Zhang

2008-01-01

69

Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of alzheimer's disease  

Microsoft Academic Search

Rivastigmine (ENA 713, or carbamoylatine) is an acetylcholinesterase (AChE) inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system (CNS) compartment than in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase

Ronald J. Polinsky

1998-01-01

70

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

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.

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

2009-05-26

71

Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice.  

PubMed

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder which is characterized by the progressive deterioration of cognition and the emergence of behavioral and psychological symptoms in aging patients. Given that the clinical effectiveness of acetylcholinesterase inhibitors (AChEIs) has still been questioned due to dubious disease-modifying effects, the multi-target directed ligand (MTDL) design has become an emerging strategy for developing new drugs for AD treatment. Bis(9)-(-)-nor-meptazinol (Bis-Mep) was firstly reported by us as a novel MTDL for both potent cholinesterase and amyloid-? aggregation inhibition. In this study, we further explored its AChE inhibition kinetic features and cognitive amelioration. Bis-Mep was found to be a mixed-type inhibitor on electric eel AChE by enzyme kinetic study. Molecular docking revealed that two "water bridges" located at the two wings of Bis-Mep stabilized its interaction with both catalytic and peripheral anionic sites of AChE. Furthermore, subcutaneous administration of Bis-Mep (10, 100 or 1000 ng/kg) significantly reversed the scopolamine-induced memory deficits in a typical bell-shaped dose-response manner. The maximal cognitive amelioration of Bis-Mep was achieved at 100 ng/kg, comparable with the effect of a reference drug Huperzine A at 1 mg/kg and also the relevant AChE inhibition in brain. These findings suggested that Bis-Mep might be a promising dual-binding AChE inhibitor for potential AD therapeutics. PMID:23262302

Liu, Ting; Xia, Zheng; Zhang, Wei-Wei; Xu, Jian-rong; Ge, Xin-Xing; Li, Juan; Cui, Yongyao; Qiu, Zhui-Bai; Xu, Jun; Xie, Qiong; Wang, Hao; Chen, Hong-Zhuan

2012-12-19

72

Continuous colorimetric assay for acetylcholinesterase and inhibitor screening with gold nanoparticles.  

PubMed

We report herein a new colorimetric assay method for acetylcholinesterase (AChE) activity and its inhibitor screening by making use of the following facts: (1) the aggregation of gold nanoparticles (Au-NPs) results in the red-shift of the plasmon absorption due to interparticle plasmon interactions and (2) AChE can catalyze the hydrolysis of acetylthiocholine into thiocholine which can induce the aggregation of Au-NPs. With this convenient method, the activity of AChE with a concentration as low as 0.6 mU/mL can be assayed. Moreover, this assay method is also useful for screening inhibitors of AChE. Given its simplicity and easy-operation, this method may extend to high-throughput screening of AChE inhibitors and relevant drug discovery. PMID:19154124

Wang, Ming; Gu, Xinggui; Zhang, Guanxin; Zhang, Deqing; Zhu, Daoben

2009-02-17

73

Failure of Toxogonin to Reactivate Soman-Inhibited Brain AChE in Monkeys and Regeneration of the Enzyme.  

National Technical Information Service (NTIS)

Administration of Toxogonin to monkeys intoxicated with pinacolyl methylphosphonofluoridate (Soman) did not result in significant reactivation (P = 0.05) of inhibited acetylcholinesterase (AChE). 'Aging,' i.e., refractoriness of reactivation due to rapid ...

M. G. Filbert M. A. Lochner J. H. Fleisher

1972-01-01

74

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study.  

PubMed

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. PMID:23959117

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

2013-08-16

75

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

Microsoft Academic Search

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)

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

2005-01-01

76

Second Quaternary dating workshop.  

National Technical Information Service (NTIS)

The second Quaternary dating methods workshop was held at Lucas Heights and sponsored by ANSTO and AINSE. Topics covered include, isotope and thermoluminescence dating, usage of accelerator and thermal ionisation mass spectrometry in environmental studies...

1999-01-01

77

In vitro and in vivo interactions of aluminum on NTPDase and AChE activities in lymphocytes of rats.  

PubMed

Al adjuvants are used in vaccines to increase the immune response. NTPDase and AChE play a pivotal role and act in the regulation of the immune system. The effect of Al exposure in vitro and in vivo on NTPDase and AChE activities in the lymphocytes of rats was determined. In vitro, ATP hydrolysis was decreased by 20.4% and 17.3% and ADP hydrolysis was decreased by 36.5% and 34.8%, in groups D and E, respectively, when compared to the control. AChE activity was increased by 157.3%, 152.5%, 74.7% and 90.8% in groups B, C, D, and E, respectively, when compared to the control. In vivo, ATP hydrolysis was increased by 85% and 86% and ADP hydrolysis was increased by 104.2% and 74%, in Al plus citrate and Al groups, respectively, when compared to the control. AChE activity was increased by 50.7% in Al plus citrate and by 28.6% in Al groups, when compared to the control. Our results show that Al exposure both in vitro and in vivo altered NTPDase and AChE activities in lymphocytes. These results may demonstrate the ability of Al to elicit the immune system, where NTPDase and AChE activities can act as purinergic and cholinergic markers in lymphocytes. PMID:20832780

Kaizer, Rosilene R; Gutierres, Jessié M; Schmatz, Roberta; Spanevello, Rosélia M; Morsch, Vera M; Schetinger, Maria R C; Rocha, João B T

2010-08-13

78

Baculovirus expression, biochemical characterization and organophosphate sensitivity of rBmAChE1, rBmAChE2, and rBmAChE3 of Rhipicephalus (Boophilus) microplus  

Technology Transfer Automated Retrieval System (TEKTRAN)

Rhipicephalus (Boophilus) microplus cDNAs, BmAChE1, BmAChE2, and BmAChE3,were previously identified as presumptively encoding acetylcholinesterases, but biochemical identity was confirmed only for recombinant BmAChE3. In the present study, four recombinant BmAChE1 constructs and single recombinant c...

79

Generation of Recombinant Human AChE OP-Scavengers with Extended Circulatory Longevity.  

National Technical Information Service (NTIS)

We demonstrate that chemical conjugation of polyethylene glycol (PEG) moieties to recombinant human acetylcholinesterase (rHuAChE) gives rise to OP bioscavenger species which reside for very long periods of time in the circulation of mice, regardless of t...

A. Shafferman

2006-01-01

80

Generation of Recombinant Human AChE Op-Scavengers With Extended Circulatory Longevity.  

National Technical Information Service (NTIS)

We demonstrated in the past that chemical conjugation of polyethylene glycol (PEG) moieties to recombinant human acetylcholinesterase (rHuAChE) gives rise to OP bioscavenger species which reside for very long period of time in the circulation of mice, reg...

A. Shafferman C. Kronman A. Ordentlich B. Velan D. Kaplan

2005-01-01

81

Inhibitors  

MedlinePLUS

... message, please visit this page: About CDC.gov . Hemophilia Share Compartir Add this to... Añadir en... Favorites Delicious Digg Google Bookmarks Inhibitors People with hemophilia have a higher quality of life today than ...

82

Divergent structure-activity relationships of structurally similar acetylcholinesterase inhibitors.  

PubMed

The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure-activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE. PMID:23984975

Andersson, C David; Forsgren, Nina; Akfur, Christine; Allgardsson, Anders; Berg, Lotta; Engdahl, Cecilia; Qian, Weixing; Ekström, Fredrik; Linusson, Anna

2013-09-19

83

Biogenesis, trafficking and up-regulation of nicotinic ACh receptors.  

PubMed

Chronic nicotine exposure gives rise to neural adaptations that change whole cell physiology and behaviour mainly by interacting with neuronal nicotinic acetylcholine receptors (nAChRs). The major nicotine-induced neuroadaptation is the up-regulation of brain nAChRs by means of cell-delimited post-translational mechanisms. We review what is known of the processes regulating nAChR assembly, degradation and trafficking, and how nicotine-induced modulation of these processes leads to nAChR up-regulation and changes in downstream neuronal plasticity at molecular, cellular and circuit level. PMID:23830821

Colombo, Sara Francesca; Mazzo, Francesca; Pistillo, Fancesco; Gotti, Cecilia

2013-07-03

84

Acetylcholinesterase inhibitors from Corydalis yanhusuo.  

PubMed

In a bioassay-guided search for acetylcholinesterase (AChE) inhibitors from Chinese natural resources, eight isoquinoline alkaloids, tetrahydropalmatine (1), corydaline (2), protopine (3), berberine (4), palmatine (5), jatrorrhizine (6), coptisine (7) and dehydrocorydaline (8), were isolated from the methanolic extract of the tubers of Corydalis yanhusuo. Structures of these compounds were identified by spectroscopic techniques. Compounds 4-8 inhibited AChE activity in a dose-dependent manner, and the IC?? values were 0.47 ± 0.01, 0.74 ± 0.06, 2.08 ± 0.09, 1.01 ± 0.03 and 0.62 ± 0.05 µM, respectively. Structure-activity relationship analysis suggested that aromatisation at ring C, as well as substitutions at C-2, C-3, C-9, C-10 and C-13 affect the AChE activity of protoberberine alkaloids. PMID:20234973

Xiao, Hai-Tao; Peng, Jiao; Liang, Yan; Yang, Jie; Bai, Xue; Hao, Xiao-Yan; Yang, Fu-Mei; Sun, Qian-Yun

2011-07-08

85

ACH-806, an NS4A antagonist, inhibits hepatitis C virus replication by altering the composition of viral replication complexes.  

PubMed

Treatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH-806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication. PMID:23629709

Yang, Wengang; Sun, Yongnian; Hou, Xiaohong; Zhao, Yongsen; Fabrycki, Joanne; Chen, Dawei; Wang, Xiangzhu; Agarwal, Atul; Phadke, Avinash; Deshpande, Milind; Huang, Mingjun

2013-04-29

86

AChE deficiency or inhibition decreases apoptosis and p53 expression and protects renal function after ischemia\\/reperfusion  

Microsoft Academic Search

We recently reported that the expression of the synaptic form of acetylcholinesterase (AChE) is induced during apoptosis in\\u000a various cell types in vitro. Here, we provide evidence to confirm that AChE is expressed during ischemia–reperfusion (I\\/R)-induced\\u000a apoptosis in vivo. Renal I\\/R is a major cause of acute renal failure (ARF), resulting in injury and the eventual death of\\u000a renal cells due to

Weiyuan YeXiaowen; Xiaowen Gong; Jing Xie; Jun Wu; Xuejin Zhang; Qi Ouyang; Xiaolin Zhao; Yufang Shi; Xuejun Zhang

2010-01-01

87

Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors.  

PubMed

Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer's disease. Heterodimers comprised of dimethoxyindanone (from donepezil), hupyridone (from HupA), and connected with a multimethylene linker, were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers (RS,S)-17b (with a tetramethylene linker) exhibited the highest potency of inhibition towards AChE with an IC(50) value of 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM. PMID:23273608

Hu, Yueqing; Zhang, Jun; Chandrashankra, Oormila; Ip, Fanny C F; Ip, Nancy Y

2012-12-06

88

A therapeutic approach to cerebrovascular diseases based on indole substituted hydrazides and hydrazines able to interact with human vascular adhesion protein-1, monoamine oxidases (A and B), AChE and BuChE.  

PubMed

Herein, we report the biological evaluation of a series of indole substituted hydrazides and hydrazines throughout the assessment of their multipotent inhibitory potency towards monoamine oxidase (MAO) A and B, semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), and the cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Hydrazine JL72 (3-(3-hydrazinylpropyl)-1H-indole) showed a potent, reversible and non-time-dependent inhibition of MAO-A, which suggests its capacity in restoring serotoninergic neurotransmission being devoid of the side effects observed for classic MAO-A inhibitors. In addition, JL72 behaved as a moderate BuChE inhibitor. Finally, both hydrazines and hydrazides derivatives showed high affinity towards SSAO/VAP-1. Among them, JL72 behaved as a noncompetitive and the most potent inhibitor (IC50 = 0.19 ± 0.04 ?M), possessing also a significant anti-inflammatory activity. The combined inhibition of SSAO/VAP-1, MAO (A and B), AChE and BuChE appear as an important therapeutic target to be considered in the treatment of cerebrovascular and neurological disorders such as Alzheimer's disease. PMID:23263540

Esteban, Gerard; Bolea, Irene; Sun, Ping; Solé, Montse; Samadi, Abdelouahid; Marco-Contelles, José; Unzeta, Mercedes

2012-12-21

89

Infant Development Among the Ache of Eastern Paraguay  

Microsoft Academic Search

This study reports the results of research into infant development among the Ache of eastern Paraguay. The Ache were full time hunter-gatherers until the mid-1970s and now practice a mixed economy of settled agriculture and mobile foraging in the forest. Data on infant development and infant care in foraging societies are critical to an understanding of the factors that have

Hillard Kaplan; Heather Dove

1987-01-01

90

Role of nAChRs in Lung Cancer  

Center for Drug Evaluation (CDER)

Text Version... GPCRs GABARs Functions of nAChRs in the Brain Page 7. ... Nicotine Addiction Page 8. In analogy to its function in the brain, the ?7nAChR ... More results from www.fda.gov/downloads/drugs/newsevents

91

Enzyme inhibitor screening by electrospray mass spectrometry with immobilized enzyme on magnetic silica microspheres.  

PubMed

In this study, a novel technique for screening inhibitors by electrospray mass spectrometry (ESI-MS) with immobilized enzyme on magnetic microspheres has been demonstrated. First, the model enzyme acetylcholinesterase (AChE) is immobilized onto the 3-glycidoxypropyltrimethoxysilane (GLYMO)-modified magnetic silica microspheres. AChE activity was monitored by biochemical assay that is based on mixing of AChE immobilized microspheres and model substrate acetylcholine, separating and detecting the product through ESI-MS. Stability of the enzyme-immobilized microspheres was investigated. No apparent loss of enzyme activity was observed after fivefold reuse of AChE-immobilized microspheres. The enzyme-immobilized bioassay was used to effectively identify AChE inhibitors among two standard samples, huperzine A and huperzine B, and their source herbal Huperzia serrata, all of which were spiked into the substrate. The inhibition was determined by measuring a decrease of product formation using ESI-MS. PMID:18396060

Hu, Fengli; Zhang, Huiying; Lin, Huaqing; Deng, Chunhui; Zhang, Xiangmin

2008-03-18

92

Quaternary dichotomous voting rules  

Microsoft Academic Search

In this article, we provide a general model of “quaternary” dichotomous voting rules (QVRs), namely, voting rules for making\\u000a collective dichotomous decisions (to accept or reject a proposal), based on vote profiles in which four options are available\\u000a to each voter: voting (“yes”, “no”, or “abstaining”) or staying home and not turning out. The model covers most of actual\\u000a real-world

Annick Laruelle; Federico Valenciano

2010-01-01

93

Design, synthesis and evaluation of isaindigotone derivatives as dual inhibitors for acetylcholinesterase and amyloid beta aggregation.  

PubMed

A series of isaindigotone derivatives and analogues were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced ?-amyloid (A?) aggregation. The synthetic compounds had IC(50) values at micro or nano molar range for cholinesterase inhibition, and some compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE, which were much better than the isaindigotone derivatives previously reported by our group. Most of these compounds showed higher self-induced A? aggregation inhibitory activity than a reference compound curcumin. The structure-activity relationship studies revealed that the derivatives with higher inhibition activity on AChE also showed higher selectivity for AChE over BuChE. Compound 6c exhibiting excellent inhibition for both AChE and self-induced A? aggregation was further studied using CD, EM, molecular docking and kinetics. PMID:22444876

Yan, Jin-Wu; Li, Yan-Ping; Ye, Wen-Jie; Chen, Shuo-Bin; Hou, Jin-Qiang; Tan, Jia-Heng; Ou, Tian-Miao; Li, Ding; Gu, Lian-Quan; Huang, Zhi-Shu

2012-03-07

94

Synthesis and biological evaluation of phosphorylated flavonoids as potent and selective inhibitors of cholesterol esterase.  

PubMed

A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE). The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids. Furthermore, these phosphorylated flavonoids demonstrated good to high selectivity for CEase over AChE, which only showed micromolar potency inhibition of AChE. The most selective and potent inhibitor of CEase (3e) had IC50 value of 0.72 nM and 11800-fold selectivity for CEase over AChE. The structure-activity relationships revealed that the free hydroxyl group at position 5 and phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CEase. The inhibition mechanism and kinetic characterization studies indicated that they are irreversible competitive inhibitors of CEase. PMID:23601990

Wei, Yingling; Peng, Ai-Yun; Wang, Bo; Ma, Lin; Peng, Guoping; Du, Yidan; Tang, Jingming

2013-03-21

95

Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant, inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-? aggregation.  

PubMed

A series of 9-N-substituted berberine derivatives were synthesized and biologically evaluated as antioxidant and inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase and amyloid-? aggregation. Most of these compounds exhibited very good antioxidant activities, inhibitive activities of AChE and amyloid-? aggregation. Among them, compound 8d, (o-methylphenethyl)amino linked at the 9-position of berberine, was found to be a good antioxidant (with 4.05 ?M of Trolox equivalents), potent inhibitor of AChE (an IC(50) value of 0.027 ?M), and high active inhibitor of amyloid-? aggregation (an IC(50) value of 2.73 ?M). PMID:22019228

Shan, Wen-Jun; Huang, Ling; Zhou, Qi; Meng, Fan-Chao; Li, Xing-Shu

2011-10-05

96

Serotonin syndrome: pills, thrills and shoulder aches.  

PubMed

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

Proudfoot, Malcolm; Gormley, Joe

2013-02-20

97

Reservation food sharing among the Ache of Paraguay  

Microsoft Academic Search

We describe food transfer patterns among Ache Indians living on a permanent reservation. The social atmosphere at the reservation\\u000a is characterized by a larger group size, a more predictable diet, and more privacy than the Ache typically experience in the\\u000a forest while on temporary foraging treks. Although sharing patterns vary by resource type and package size, much of the food

Michael Gurven; Wesley Allen-Arave; Kim Hill; A. Magdalena Hurtado

2001-01-01

98

Variation of the butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) genes in coronary artery disease.  

PubMed

Butyrylcholinesterase (BChE) and acetylcholinesterase (AchE) are two enzymes of the cholinergic system putatively involved in coronary artery disease (CAD). We investigated two single nucleotide polymorphisms (SNPs) of the genes encoding these enzymes to determine whether some allele or genotype might represent a factor of risk or protection for CAD onset. AChE rs2571598 and BChE rs1803274 (the so-called K-variant) SNPs were investigated in a sample of 199 patients and 199 healthy subjects. No significant results were obtained for BChE, whereas for AChE the A allele was found significantly more frequent in patients than in controls (0.437 vs. 0.332; p=0.002). The crude Odds Ratio (OR) for CAD conferred by carrying the A allele was 1.76 (95% confidence interval [CI] 1.17-2.65). Stratification of the sample by gender revealed that the statistical significance was limited to female, where the crude OR associated with the A allele was 3.26 (95% CI 1.58-6.73). The lipidic pattern was also tested and related to variation of the two SNPs. In this case, an at limits significant result (p=0.03) was obtained for BChE, whose A allele (the K variant) in patients was found associated with higher plasma concentrations of high density lipoprotein-cholesterol. PMID:21473860

Scacchi, Renato; Ruggeri, Maria; Corbo, Rosa Maria

2011-04-05

99

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

PubMed

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 ?M 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. PMID:22339669

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

2012-02-29

100

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

PubMed

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. PMID:20558224

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

2010-06-15

101

Berberine derivatives, with substituted amino groups linked at the 9-position, as inhibitors of acetylcholinesterase/butyrylcholinesterase.  

PubMed

Berberine derivatives with substituted amino groups linked at the 9-position using different carbon spacers were designed, synthesized, and biologically evaluated as inhibitors of acetylcholinesterase. Compound 10b, with a cyclohexylamino group linked to berberine by a three carbon spacer, gave the most potent inhibitor activity with an IC(50) of 0.020 ?M for AChE. Kinetic studies revealed mixed inhibition of AChE, and molecular modeling simulations of the AChE-inhibitor complex confirmed that compounds bound to both the catalytic active site and the peripheral anionic site. PMID:20880702

Huang, Ling; Luo, Zonghua; He, Feng; Shi, Anding; Qin, Fangfei; Li, Xingshu

2010-09-15

102

New Acetylcholinesterase Inhibitors for Alzheimer's Disease  

PubMed Central

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

Mehta, Mona; Adem, Abdu; Sabbagh, Marwan

2012-01-01

103

Synthesis, biological activity and molecular modeling studies on 1H-benzimidazole derivatives as acetylcholinesterase inhibitors.  

PubMed

A series of N-{2-[4-(1H-benzimidazole-2-yl)phenoxy]ethyl}substituted amine derivatives were designed to assess cholinesterase inhibitor activities. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor activities were evaluated in vitro by using Ellman's method. It was discovered that most of the compounds displayed AChE and/or BuChE inhibitor activity and few compounds were selective against AChE/BuChE. Compound 3c and 3e were the most active compounds in the series against eeAChE and hAChE, respectively. Molecular docking studies and molecular dynamics simulations were also carried out. PMID:23891231

Alpan, Ay?e Selcen; Parlar, Sülünay; Carlino, Luca; Tarikogullari, Ayse Hande; Alptüzün, Vildan; Güne?, Hasan Semih

2013-07-10

104

Characterization by NMR and Fluorescence Spectroscopy of Differences in the Conformation of Non-Aged and Aged Organophosphoryl Conjugates of AChE (Acetylcholinesterase).  

National Technical Information Service (NTIS)

The objective of this project is to detect and characterize, by NMR and fluoressence spectroscopy, differences in the conformation of non-aged and aged organophosphoryl (OP) conjugates of acetylcholinesterase (AChE) and chymotrypsin (Cht). During the peri...

I. Silman Y. Ashani

1989-01-01

105

Comparative study of oxime-induced reactivation of erythrocyte and muscle AChE from different animal species following inhibition by sarin or paraoxon  

Microsoft Academic Search

Standard treatment of acute poisoning by organophosphorus compounds (OP) includes administration of an antimuscarinic (e.g. atropine) and of an oxime-based reactivator of OP-inhibited acetylcholinesterase (AChE). A recently introduced dynamically working in vitro model with real-time determination of membrane-bound AChE activity was shown to be a very versatile and promising model to investigate oxime-induced reactivation kinetics of OP-inhibited enzyme. In this

Nadja M. Herkert; Nadine Aurbek; Peter Eyer; Horst Thiermann; Franz Worek

2010-01-01

106

Low concentrations of methamidophos do not alter AChE activity but modulate neurotransmitters uptake in hippocampus and striatum in vitro  

Microsoft Academic Search

AimsMethamidophos (Meth) is a toxic organophosphorus compound (OP) that inhibits acetylcholinesterase enzyme (AChE) and induces neurotoxicity. As the mechanism of its neurotoxic effects is not well understood, the aim of the present study was to evaluate the effects of Meth on glutamate and gamma aminobutyric acid (GABA) uptake and correlate with cell viability and AChE and Na+\\/K+-ATPase enzyme activities in

Priscila Gubert; Daiana Silva Ávila; Jessika Cristina Bridi; Sara Saurin; Thiago Henrique Lugokenski; Jardel Gomes Villarinho; Roselei Fachinetto; Maria Ester Pereira; Juliano Ferreira; João Batista Teixeira da Rocha; Félix Alexandre Antunes Soares

2011-01-01

107

[Quaternary prevention in the elderly].  

PubMed

Quaternary prevention is a group of measures taken to prevent, decrease and/or alleviate the harm caused by health activities. Health activities not only generally produce benefits, but also harm. That is to say, although medical intervention is mainly favourable, there is a dynamic balance that requires continuous assessment of the clinical situation as naturally only those health activities that achieve more benefit than harm at the end are justified. Quaternary prevention is the avoidance of unnecessary medical activity, such as "check-ups". In another example, quaternary prevention is the recommendation of preventive measures of proven efficacy. As regards diagnosis, quaternary prevention is, for example, the avoidance of screening without foundation, such as in prostate cancer. The appropriate use of antibiotics in upper respiratory tract infections serves as an example of quaternary prevention in the field of treatment. Another example is the application of the correct rehabilitation techniques in non-specific low back pain, such as swimming and maintaining an active life as much as possible. Not to forget other important "non-classic" aspects in the elderly, such as to limit the harm that can be caused by physical movement restriction devices. These and other examples in daily practice are considered in this article to encourage the continual assessment of quaternary prevention, the classic primum non nocere "first, do no harm". PMID:23062686

Gérvas, Juan

2012-10-11

108

Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors.  

PubMed

Nicotinic acetylcholine receptors (nAChR) are pentameric ligand-gated ion channels composed of subunits that consist of an extracellular domain that carries the ligand-binding site and a distinct ion-pore domain. Signal transduction results from the allosteric coupling between the two domains: the distance from the binding site to the gate of the pore domain is 50 A. Normal mode analysis with a C(alpha) Gaussian network of a new structural model of the neuronal alpha7 nAChR showed that the lowest mode involves a global quaternary twist motion that opens the ion pore. A molecular probe analysis, in which the network is modified at each individual amino acid residue, demonstrated that the major effect is to change the frequency, but not the form, of the twist mode. The largest effects were observed for the ligand-binding site and the Cys-loop. Most (24/27) of spontaneous mutations known to cause congenital myasthenia and autosomal dominant nocturnal frontal lobe epilepsy are located either at the interface between subunits or, within a given subunit, at the interface between rigid blocks. These interfaces are modified significantly by the twist mode. The present analysis, thus, supports the quaternary twist model of the nAChR allosteric transition and provides a qualitative interpretation of the effect of the mutations responsible for several receptor pathologies. PMID:17077146

Taly, Antoine; Corringer, Pierre-Jean; Grutter, Thomas; Prado de Carvalho, Lia; Karplus, Martin; Changeux, Jean-Pierre

2006-10-31

109

NO decreases evoked quantal ACh release at a synapse of Aplysia by a mechanism independent of Ca2+ influx and protein kinase G.  

PubMed Central

1. The exogenous nitric oxide (NO) donor, SIN-1, decreased the postsynaptic response evoked by a presynaptic spike at an identified cholinergic neuro-neuronal synapse in the buccal ganglion of Aplysia californica. 2. The statistical analysis of long duration postsynaptic responses evoked by square depolarizations of the voltage-clamped presynaptic neurone showed that the number of evoked acetylcholine (ACh) quanta released was decreased by SIN-1, pointing to a presynaptic action of the drug. 3. Vitamin E, a scavenger of free radicals, prevented the effects of SIN-1 on ACh release. SIN-1 still decreased ACh release in the presence of superoxide dismutase, whereas haemoglobin suppressed the effects of SIN-1. These results showed that NO is the active compound. 4. 8-Bromoguanosine 3', 5' cyclic monophosphate (8-Br-cGMP) mimicked the inhibitory effect of NO on ACh release suggesting the involvement of a NO-sensitive guanylate cyclase. This was reinforced by the reversibility of the effects of SIN-1 by inhibitors of guanylate cyclase, Methylene Blue, cystamine or LY83583. Methylene Blue partially reduced the inhibitory effect of NO. In addition, in the presence of superoxide dismutase, Methylene Blue blocked and cystamine significantly reduced the NO-induced inhibition of ACh release. 5. In the presence of KT5823 or R-p-8-pCPT-cGMPS, two inhibitors of protein kinase G, the reduction of ACh release by SIN-1 still took place indicating that the effects of NO most probably did not involve protein kinase G-dependent phosphorylation. 6. Presynaptic voltage-dependent Ca2+ (L-, N- and P-types) and K+ (IA and late outward rectifier) currents were unmodified by SIN-1. 7. The modulation of ACh release in opposite ways by L-arginine and N omega-nitro-L-arginine points to the involvement of an endogenous NO synthase-dependent regulation of transmitter release.

Mothet, J P; Fossier, P; Tauc, L; Baux, G

1996-01-01

110

Lycopodiaceae from Panama: a new source of acetylcholinesterase inhibitors.  

PubMed

Acetylcholinesterase (AChE) inhibitors have been used for the symptomatic treatment of Alzheimer's disease. Eleven whole plants from Panama belonging to the Lycopodiaceae family have been screened for their anticholinesterase inhibitory and antioxidant activities by a thin-layer chromatography (TLC) bioautography method. Of these, only Lycopodium clavatum subsp. clavatum showed strong AChE inhibition. Seven plant extracts showed moderate inhibition, two of them, Huperzia cf chamaeleon and Huperzia reflexa, also possessed an antioxidant activity. This is the first report of anticholinesterase and antioxidant activities in these two native plants. Additionally, alkaloid extracts of the Lycopodiaceae plants were also analysed by TLC and LC-MS to identify the well-known AchE inhibitor, huperzine A. Two plants, H. cf chamaeleon and H. reflexa var. minor, showed the presence of huperzine. PMID:22746970

Calderón, Angela I; Simithy-Williams, Johayra; Sanchez, Rocío; Espinosa, Alex; Valdespino, Iván; Gupta, Mahabir P

2012-07-02

111

Bivalent ligands derived from Huperzine A as acetylcholinesterase inhibitors.  

PubMed

The naturally occurring alkaloid Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor that has been used for centuries as a Chinese folk medicine in the context of its source plant Huperzia Serrata. The potency and relative safety of HupA rendered it a promising drug for the ameliorative treatment of Alzheimer's disease (AD) vis-à-vis the "cholinergic hypothesis" that attributes the cognitive decrements associated with AD to acetylcholine deficiency in the brain. However, recent evidence supports a neuroprotective role for HupA, suggesting that it could act as more than a mere palliative. Biochemical and crystallographic studies of AChE revealed two potential binding sites in the active-site gorge of AChE, one of which, the "peripheral anionic site" at the mouth of the gorge, was implicated in promoting aggregation of the beta amyloid (Abeta) peptide responsible for the neurodegenerative process in AD. This feature of AChE facilitated the development of dual-site binding HupA-based bivalent ligands, in hopes of concomitantly increasing AChE inhibition potency by utilizing the "chelate effect", and protecting neurons from Abeta toxicity. Crystal structures of AChE allowed detailed modeling and docking studies that were instrumental in enhancing the understanding of underlying principles of bivalent inhibitor-enzyme dynamics. This monograph reviews two categories of HupA-based bivalent ligands, in which HupA and HupA fragments serve as building blocks, with a focus on the recently solved crystallographic structures of Torpedo californica AChE in complex with such bifunctional agents. The advantages and drawbacks of such structured-based drug design, as well as species differences, are highlighted and discussed. PMID:17305579

Haviv, H; Wong, D M; Silman, I; Sussman, J L

2007-01-01

112

Nicotine Promotes Proliferation of Human Nasopharyngeal Carcinoma Cells by Regulating ?7AChR, ERK, HIF-1? and VEGF/PEDF Signaling  

PubMed Central

Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis, but the precise mechanisms involved remain largely unknown. Here, we investigated the mechanism of action of nicotine in human nasopharyngeal carcinoma (NPC) cells. Nicotine significantly promoted cell proliferation in a dose and time-dependent manner in human NPC cells. The mechanism studies showed that the observed stimulation of proliferation was accompanied by the nicotine-mediated simultaneous modulation of ?7AChR, HIF-1?, ERK and VEGF/PEDF signaling. Treatment of NPC cells with nicotine markedly upregulated the expression of ?7AChR and HIF-1? proteins. Transfection with a ?7AChR or HIF-1?-specific siRNA or a ?7AChR-selective inhibitor significantly attenuated the nicotine-mediated promotion of NPC cell proliferation. Nicotine also promoted the phosphorylation of ERK1/2 but not JNK and p38 proteins, thereby induced the activation of ERK/MAPK signaling pathway. Pretreatment with an ERK-selective inhibitor effectively reduced the nicotine-induced proliferation of NPC cells. Moreover, nicotine upregulated the expression of VEGF but suppressed the expression of PEDF at mRNA and protein levels, leading to a significant increase of the ratio of VEGF/PEDF in NPC cells. Pretreatment with a ?7AChR or ERK-selective inhibitor or transfection with a HIF-1?-specific siRNA in NPC cells significantly inhibited the nicotine-induced HIF-1? expression and VEGF/PEDF ratio. These results therefore indicate that nicotine promotes proliferation of human NPC cells in vitro through simultaneous modulation of ?7AChR, HIF-1?, ERK and VEGF/PEDF signaling and suggest that the related molecules such as HIF-1? might be the potential therapeutic targets for tobacco-associated diseases such as nasopharyngeal carcinomas.

Chen, Wangbin; Fu, Lingyi; Wang, Jingshu; Tian, Yung; Xiao, Xiangsheng; Kang, Tiebang; Huang, Wenlin; Deng, Wuguo

2012-01-01

113

Acetylcholinesterase Inhibitors Promote Angiogenesis in Chick Chorioallantoic Membrane and Inhibit Apoptosis of Endothelial Cells  

PubMed Central

Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. Recently, a great attention has been paid to the possible role of vascular changes in the pathogenesis of AD. Reduced microvascular density and degeneration of the endothelium are of structural cerebrovascular changes in AD. Acetylcholinesterase (AChE) inhibitors are widely used for the improvement of AD symptoms. Until now, however, the effects of AChE inhibitors on vascular changes including angiogenesis and endothelial cell apoptosis are not fully understood. In the present work, the effects of three AChE inhibitors (donepezil, rivastigmine, and galantamine) were tested on H2O2-induced apoptosis in human umbilical vein endothelial cells (HUVECs) and on angiogenesis in chicken chorioallantoic membrane model. Incubation of HUVEC with H2O2 led to a significant decrease in cell viability and an increase in the percentage of apoptotic cells. The tested drugs, at concentrations of 1–100??M, significantly inhibited the H2O2-induced toxicity. Also, all donepezil, rivastigmine and galantamine significantly increased the number of vessels in the chorioallantoic membrane when injected into fertilized eggs. In conclusion, AChE inhibitors possess angiogenesis-accelerating properties and have antiapoptotic effects on endothelial cells. These effects of AChE inhibitors may be involved in their beneficial effects on AD.

Mortazavian, Seyed Mohsen; Parsaee, Heydar; Mousavi, Seyed Hadi; Tayarani-Najaran, Zahra; Sadeghnia, Hamid Reza

2013-01-01

114

Distribution of NADPH-diaphorase and AChE activity in the anterior leaflet of rat mitral valve.  

PubMed

The mitral valve, as an active flap, forms the major part of the left ventricular inflow tract and therefore plays an important function in many aspects of left ventricular performance. The anterior leaflet of this valve is the largest and most ventrally placed of two leaflets that come together during ventricular systole to close the left atrioventricular orifice. Various neurotransmitters are responsible for different functions including controlling valve movement, inhibiting or causing the failure of impulse conduction in the valve and the sensation of pain. Nitric oxide acts as a gaseous free radical neurotransmitter, neuromediator and effective cardiovascular modulator. Acetyl-choline is known to function as a typical neurotransmitter. Histochemical methods for detection of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), as an indirect nitric oxide-synthase marker, and method for detection of acetylcholinesterase (AChE) were used. Both methods were performed on the same valve sample. A widespread distribution of nerve fibres was observed in the anterior leaflet of the mitral valve. The fine NADPH-d positive (nitrergic) nerve fibres were identified in all zones of valve leaflet. AChE positive (cholinergic) nerve fibres were identified forming dense network and fibres organized in stripes. Endocardial cells and vessels manifested heavy NADPH-d activity. Our observations suggest a different arrangement of nitrergic and cholinergic nerve fibres in the anterior leaflet of the mitral valve. The presence of nitrergic and cholinergic activity confirms the involvement of both neurotransmitters in nerve plexuses and other structures of mitral valve. PMID:20353912

Lovasova, K; Kluchova, D; Bolekova, A; Dorko, F; Spakovska, T

2010-02-04

115

Distribution of NADPH-diaphorase and AChE activity in the anterior leaflet of rat mitral valve  

PubMed Central

The mitral valve, as an active flap, forms the major part of the left ventricular inflow tract and therefore plays an important function in many aspects of left ventricular performance. The anterior leaflet of this valve is the largest and most ventrally placed of two leaflets that come together during ventricular systole to close the left atrioventricular orifice. Various neurotransmitters are responsible for different functions including controlling valve movement, inhibiting or causing the failure of impulse conduction in the valve and the sensation of pain. Nitric oxide acts as a gaseous free radical neurotransmitter, neuromediator and effective cardiovascular modulator. Acetyl-choline is known to function as a typical neurotransmitter. Histochemical methods for detection of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), as an indirect nitric oxide-synthase marker, and method for detection of acetylcholinesterase (AChE) were used. Both methods were performed on the same valve sample. A widespread distribution of nerve fibres was observed in the anterior leaflet of the mitral valve. The fine NADPH-d positive (nitrergic) nerve fibres were identified in all zones of valve leaflet. AChE positive (cholinergic) nerve fibres were identified forming dense network and fibres organized in stripes. Endocardial cells and vessels manifested heavy NADPH-d activity. Our observations suggest a different arrangement of nitrergic and cholinergic nerve fibres in the anterior leaflet of the mitral valve. The presence of nitrergic and cholinergic activity confirms the involvement of both neurotransmitters in nerve plexuses and other structures of mitral valve.

Lovasova, K.; Kluchova, D.; Bolekova, A.; Dorko, F.; Spakovska, T.

2010-01-01

116

Molecular basis of interactions of cholinesterases with tight binding inhibitors.  

PubMed

Among the large variety of reversible inhibitors that bind to cholinesterases (ChE), only a few exhibit exquisitely strong binding reflected in low femtomolar to picomolar equilibrium dissociation constants. These tight binding inhibitors owe their high affinity to distinctive modes of interaction with the enzyme: naturally occurring snake toxins, the fasciculins, share a large 1000 angstroms2 complementary surface for its complex with acetylcholinesterases (AChE; EC 3.1.1.7); transition state analogs trifluoroacetophenones form a covalent bond with the active serine; disubstituted 1,2,3-triazole inhibitors formed in situ are selected by AChE for optimal interaction surface over the length of the active center gorge. All these inhibitors bind with higher affinity to AChEs than to the closely related butyrylcholinesterases (BuChE; EC 3.1.1.8). Selectivity of individual inhibitors towards BuChE increases with increasing their molecular size. Interaction kinetics for all three classes of compounds reveal very slow rates of dissociation of the AChE-inhibitor complexes or conjugates combined with very fast association rates. The influence of conformational flexibility of the active center gorge on the affinity of inhibitor binding was demonstrated by comparing binding properties of a series of disubstituted 1,2,3-triazoles having systematically varied structures. Analysis of the linear free energy relationships of binding to both mouse and Electrophorus AChE reveals independent contributions of individual structural elements of inhibitors to their binding with the triazole ring emerging as an independently contributing pharmacophore. These tight binding inhibitor interactions reveal useful information not only on the conformational flexibility of ChEs, but also on the diversity of modes of interaction that achieve inhibition. PMID:16289416

Radi?, Zoran; Manetsch, Roman; Krasi?ski, Antoni; Raushel, Jessica; Yamauchi, John; Garcia, Cindy; Kolb, Hartmuth; Sharpless, K Barry; Taylor, Palmer

2005-11-11

117

Beyond the Cholinergic Hypothesis: The Effect of Metrifonate and Other Cholinesterase Inhibitors on Neuropsychiatric Symptoms in Alzheimer’s Disease  

Microsoft Academic Search

Preliminary studies suggest that non-cognitive behavioural and personality alterations in Alzheimer’s disease may benefit from agents which inhibit central acetylcholinesterase (AChE). A double-blind, placebo-controlled, 26-week study of the AChE inhibitor metrifonate using the NeuroPsychiatric Inventory (NPI) to assess the effects of treatment on neuropsychiatric symptoms observed statistically significant mean change differences favouring treatment in the total NPI score and in

Daniel Kaufer

1998-01-01

118

Freshwater microcrustacean Daphnia magna Straus as an early screen model to compare toxicity of acetylcholinesterase inhibitors  

Microsoft Academic Search

Summary Daphnia magna is a freshwater microcrustacean which is often used for acute and chronic toxicity testing in aquatic ecotoxicology. Recently, tests with daphnids have been used to prescreen the toxicity of newly synthesized acetylcholinesterase reactivators (oximes), which appear as weak inhibitors of acetylcholinesterase (AChE). In our study we investigated and compared the toxicity of five reversible acetylcholinesterase inhibitors, two

Kamil Ku?a

119

Pharmacology and toxicology of cholinesterase inhibitors: uses and misuses of a common mechanism of action  

Microsoft Academic Search

Cholinesterase inhibitors have been used in the treatment of human diseases, the control of insect pests, and more notoriously as chemical warfare agents and weapons of terrorism. Most uses of cholinesterase inhibitors are based on a common mechanism of action initiated by inhibition of acetylcholinesterase (AChE). Extensive inhibition of this enzyme leads to accumulation of the neurotransmitter acetylcholine and enhanced

Carey Pope; Subramanya Karanth; Jing Liu

2005-01-01

120

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

PubMed

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 ?-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

Kaladhar, Dowluru Svgk; Yarla, Nagendra Sastry; Anusha, N

2013-06-20

121

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

PubMed Central

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 ?-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.

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

2013-01-01

122

Acetylcholinesterase Inhibitor, Pyridostigmine Bromide, Reduces Skin Blood Flow in Humans.  

National Technical Information Service (NTIS)

Five subjects exercised on a cycle ergometer for 30 min at 55% peak VO2 on two occasions in a slightly warm environment. Pyridostigmine bromide (PYR), an acetylcholinesterase (AChE) inhibitor, was ingested (30 mg) approximately 150 min before one experime...

L. A. Stephenson M. A. Kolka

1989-01-01

123

Bivalent Ligands Derived from Huperzine A as Acetylcholinesterase Inhibitors  

Microsoft Academic Search

The naturally occurring alkaloid Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor that has been used for centuries as a Chinese folk medicine in the context of its source plant Huperzia Serrata. The potency and relative safety of HupA rendered it a promising drug for the ameliorative treatment of Alzheimer's disease (AD) vis-à-vis the \\

H. Haviv; D. M. Wong; I. Silman; J. L. Sussman

2007-01-01

124

Selective cholinesterase inhibitors from Buxus sempervirens L. and their molecular docking studies.  

PubMed

In this work, two alkaloids namely (+)-buxabenzamidienine (1) and (+)-buxamidine (2) were isolated from Buxus sempervirens, using bioassay-guided fractionation and isolation method. Their acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitory activities were studied and the compounds were found to be quite selective inhibitors of AChE. IC50 values of compound 1 for electric eel AChE and horse BChE were 0.787 and 7.68 mM, respectively; while the corresponding IC50 of compound 2 were 1.70 and 549.98 mM, respectively. Theoretical (quantum mechanical, homology modelling and docking) calculations were performed in order to explain their interactions with different AChE (electric eel and human) and BChE (horse and human). The x-ray crystal structures of electric eel AChE, human AChE, human BChE and a model of horse BChE constructed by homology with human BChE were used for docking of compounds 1 and 2. Density functional theory (DFT) calculations of the compounds were performed at the B3LYP/6- 31G** level using the program Spartan™, and their HOMO and LUMO energy levels were calculated. Docking studies exhibited that compound 1 interacts with the acyl-binding pocket of the active site gorge of huAChE, and including several other hydrophobic interactions. PMID:22050684

Orhan, Ilkay E; Khan, Mahmud T H; Erdem, Sinem A; Kartal, Murat; Sener, Bilge

2011-12-01

125

Identification of Novel ?4?2-Nicotinic Acetylcholine Receptor (nAChR) Agonists Based on an Isoxazole Ether Scaffold that Demonstrate Antidepressant-like Activity  

PubMed Central

There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening towards other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.

Yu, Li-Fang; Tuckmantel, Werner; Eaton, J. Brek; Caldarone, Barbara; Fedolak, Allison; Hanania, Taleen; Brunner, Dani; Lukas, Ronald J.; Kozikowski, Alan P.

2012-01-01

126

Comparative study on the changes in AChE and ATPase activities in neonate and adult rat brains under thiobencarb stress.  

PubMed

Thiobencarb (S-(4-chlorobenzyl)-N,N-diethyl thiol carbamate), a dithiocarbamate herbicide, was found to cause neuronal dysfunction in adult and neonate albino rats. In general, organocarbamates exert their action by inhibiting acetylcholinesterase (AChE) activity. Thiobencarb inhibited both acetylcholinesterase and adenosine triphosphatase (ATPase) activities in rat brain. Withdrawal of thiobencarb treatment resulted in the recovery of AChE activity to a normal level, whereas there was no recovery of Na(+)-K(+)-ATPase activity in either neonate or adult rat brains. The results suggest that neuronal dysfunction caused by thiobencarb is mainly due to the inhibition of ATPase activity rather than to the inhibition of AChE activity. PMID:8440873

Pentyala, S N; Chetty, C S

127

Lead finding for acetyl cholinesterase inhibitors from natural origin: structure activity relationship and scope.  

PubMed

Acetylcholinesterase (AChE) inhibitors are considered as promising therapeutic agents for the treatment of several neurological disorders such as Alzheimer's disease (AD), senile dementia, ataxia and myasthenia gravis. There are only few synthetic medicines with adverse effects, available for treatment of cognitive dysfunction and memory loss associated with these diseases. A variety of plants has been reported to possess AChE inhibitory activity and so may be relevant to the treatment of neurodegenerative disorders such as AD. Hence, developing potential AChE inhibitors from botanicals is the need of the day. This review will cover some of the promising acetylcholinesterase inhibitors isolated from plants with proven in vitro and in vivo activities with concern to their structure activity relationship. PMID:21222577

Mukherjee, P K; Satheeshkumar, N; Venkatesh, P; Venkatesh, M

2011-03-01

128

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

PubMed

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 microscopy, circular dichroism spectroscopy, X-ray crystallography, time-resolved fluorescence spectroscopy, and liquid chromatography triple quadrupole mass spectrometry. These results support our view that the mosquito-specific Cys is a viable target for developing new mosquitocides to control disease vectors and to alleviate resistance problems with reduced toxicity toward non-target species. PMID:19714254

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

2009-08-28

129

Quaternary uplift of southern Italy  

Microsoft Academic Search

Dramatic coastline changes demonstrate rapid Quaternary uplift of Calabria in southern Italy. Because most of the west (Tyrrhenian Sea) coast is normal fault bounded, previous work has asserted that its uplift is local footwall uplift related to extension. However, the east (Ionian Sea) coast is also uplifting but is not normal fault bounded. This reanalysis, based on original field work

Rob Westaway

1993-01-01

130

Quaternary Studies: An Interdisciplinary Program  

NSDL National Science Digital Library

Rutgers University promotes its Graduate Certificate in Quaternary Studies where students take part in geology, geography, meteorology, and other disciplines interested in the last couple of million years of Earth's history. Students and educators can find information on the researchers involved with the program and the necessary course work.

1969-12-31

131

Quaternary alkaloids of Argemone mexicana.  

PubMed

Four quaternary isoquinoline alkaloids, dehydrocorydalmine, jatrorrhizine, columbamine, and oxyberberine, have been isolated from the whole plant of Argemone mexicana Linn. (Papaveraceae) and their structures established by spectral evidence. This is the first report of these alkaloids (dehydrocorydalmine, jatrorrhizine, columbamine, and oxyberberine) from Argemone mexicana and the Argemone genus. PMID:20645832

Singh, Sarita; Singh, Tryambak Deo; Singh, Virendra Pratap; Pandey, Vidya Bhushan

2010-02-01

132

Identification of potential bivalent inhibitors from natural compounds for acetylcholinesterase through in silico screening using multiple pharmacophores.  

PubMed

The symptomatic cure observed in the treatment of Alzheimer's disease (AD) by FDA approved drugs could possibly be due to their specificity against the active site of acetylcholinesterase (AChE) and not by targeting its pathogenicity. The AD pathogenicity involved in AChE protein is mainly due to amyloid beta peptide aggregation, which is triggered specifically by peripheral anionic site (PAS) of AChE. In the present study, a workflow has been developed for the identification and prioritization of potential compounds that could interact not only with the catalytic site but also with the PAS of AChE. To elucidate the essential structural elements of such inhibitors, pharmacophore models were constructed using PHASE, based on a set of fifteen best known AChE inhibitors. All these models on validation were further restricted to the best seven. These were transferred to PHASE database screening platform for screening 89,425 molecules deposited at the "ZINC natural product database". Novel lead molecules retrieved were subsequently subjected to molecular docking and ADME profiling. A set of 12 compounds were identified with high pharmacophore fit values and good predicted biological activity scores. These compounds not only showed higher affinity for catalytic residues, but also for Trp86 and Trp286, which are important, at PAS of AChE. The knowledge gained from this study, could lead to the discovery of potential AChE inhibitors that are highly specific for AD treatment as they are bivalent lead molecules endowed with dual binding ability for both catalytic site and PAS of AChE. PMID:23353586

Lakshmi, V; Kannan, V Santhosh; Boopathy, R

2013-01-04

133

Regulation of PRiMA-linked G(4) AChE by a cAMP-dependent signaling pathway in cultured rat pheochromocyoma PC12 cells.  

PubMed

The catalytic subunit of acetylcholinesterase (AChE(T)) interacts with proline-rich membrane anchor (PRiMA) to form PRiMA-linked G(4) AChE on membrane surface for its cholinergic function. Cultured PC12 cells expressed the transcripts encoding AChE(T) and PRiMA I, but the expression of PRiMA II transcript was below detection. Upon the treatment of dibutyryl-cAMP (Bt(2)-cAMP) and forskolin in cultured cells to stimulate the cAMP-dependent signaling pathway, the mRNA expressions of both AChE(T) and PRiMA I, as well as the enzymatic activity were up-regulated. More importantly, sucrose density gradient analysis revealed that both G(1) and G(4) AChE isoforms were increased in the Bt(2)-cAMP-treated cultures. These results suggest that the regulation of PRiMA-linked G(4) AChE in terms of gene transcription and molecular assembly in the cultured PC12 cells could be mediated by a cAMP-dependent signaling mechanism. PMID:18514641

Choi, Roy C Y; Mok, Mokka K W; Cheung, Anna W H; Siow, Nina L; Xie, Heidi Q; Tsim, Karl W K

2008-06-02

134

Non-cholinergic afferents determine the distribution of the cholinergic septohippocampal projection: a study of the AChE staining pattern in the rat fascia dentata and hippocampus after lesions, X-irradiation, and intracerebral grafting  

Microsoft Academic Search

The acetylcholinesterase (AChE) activity of the rat hippocampus and fascia dentata depends on an intact septohippocampal connection, and histochemical staining for AChE is commonly used to monitor the distribution of the cholinergic septohippocampal projection. It is also characteristic that the laminae of low or moderate to dense AChE staining in the hippocampus and fascia dentata coincide with the terminal fields

J. Zimmer; S. Laurberg; N. Sunde

1986-01-01

135

Development and validation of a sample stabilization strategy and a UPLC-MS/MS method for the simultaneous quantitation of acetylcholine (ACh), histamine (HA), and its metabolites in rat cerebrospinal fluid (CSF).  

PubMed

A UPLC-MS/MS assay was developed and validated for simultaneous quantification of acetylcholine (ACh), histamine (HA), tele-methylhistamine (t-mHA), and tele-methylimidazolacetic acid (t-MIAA) in rat cerebrospinal fluid (CSF). The biological stability of ACh in rat CSF was investigated. Following fit-for-purpose validation, the method was applied to monitor the drug-induced changes in ACh, HA, t-mHA, and t-MIAA in rat CSF following administration of donepezil or prucalopride. The quantitative method utilizes hydrophilic interaction chromatography (HILIC) Core-Shell HPLC column technology and a UPLC system to achieve separation with detection by positive ESI LC-MS/MS. This UPLC-MS/MS method does not require extraction or derivatization, utilizes a stable isotopically labeled internal standard (IS) for each analyte, and allows for rapid throughput with a 4 min run time. Without an acetylcholinesterase (AChE) inhibitor present, ACh was found to have 1.9±0.4 min in vitro half life in rat CSF. Stability studies and processing modification, including the use of AChE inhibitor eserine, extended this half life to more than 60 min. The UPLC-MS/MS method, including stabilization procedure, was validated over a linear concentration range of 0.025-5 ng/mL for ACh and 0.05-10 ng/mL for HA, t-mHA, and t-MIAA. The intra-run precision and accuracy for all analytes were 1.9-12.3% CV and -10.2 to 9.4% RE, respectively, while inter-run precision and accuracy were 4.0-16.0% CV and -5.3 to 13.4% RE, respectively. By using this developed and validated method, donepezil caused increases in ACh levels at 0.5, 1, 2, and 4h post dose as compared to the corresponding vehicle group, while prucalopride produced approximately 1.6- and 3.1-fold increases in the concentrations of ACh and t-mHA at 1h post dose, respectively, compared to the vehicle control. Overall, this methodology enables investigations into the use of CSF ACh and HA as biomarkers in the study of these neurotransmitter systems and related drug discovery efforts. PMID:21684223

Zhang, Yanhua; Tingley, F David; Tseng, Elaine; Tella, Max; Yang, Xin; Groeber, Elizabeth; Liu, Jianhua; Li, Wenlin; Schmidt, Christopher J; Steenwyk, Rick

2011-05-27

136

Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade  

Microsoft Academic Search

We show here that donepezil, galanathamine and tacrine, therapeutic acetylcholinesterase inhibitors currently being used for treatment of Alzheimer's disease, protect neuronal cells in a time- and concentration-dependent manner from glutamate neurotoxicity that involves apoptosis. The neuroprotective effects were antagonized by mecamylamine, an inhibitor of nicotinic acetylcholine receptors (nAChRs). Dihydro-?-erythroidine and methyllycaconitine, antagonists for ?4-nAChR and ?7-nAChR, respectively, antagonized the protective

Yuki Takada-Takatori; Toshiaki Kume; Mitsuhiro Sugimoto; Hiroshi Katsuki; Hachiro Sugimoto; Akinori Akaike

2006-01-01

137

Isolation, Identification and Characterization of a Antidementia Acetylcholinesterase Inhibitor-Producing Yarrowia lipolytica S-3  

PubMed Central

This report describes the isolation and identification of a potent acetylcholinesterase (AChE) inhibitor-producing yeasts. Of 731 species of yeast strain, the S-3 strain was selected as a potent producer of AChE inhibitor. The selected S-3 strain was investigated for its microbiological characteristics. The S-3 strain was found to be short-oval yeast that did not form an ascospore. The strain formed a pseudomycelium and grew in yeast malt medium containing 50% glucose and 10% ethanol. Finally, the S-3 strain was identified by its physiological characteristics and 26S ribosomal DNA sequences as Yarrowia lipolytica S-3.

Kang, Min-Gu; Yoon, Min-Ho; Choi, Young-Jun

2012-01-01

138

Modulation of acetylcholine release from rat cortical slices by inhibitors of acetylcholine biosynthesis and vesicular packaging  

SciTech Connect

Acetylcholine (ACh) release is thought to be linked to choline (Ch) uptake and vesicular packaging in peripheral mammalian systems. Several compounds, having various inhibitory effects on isolated cholinergic systems, were tested for their ability to modulate the release of Ch and ACh from rat cortex slices. Release experiments were conducted at 37/sup 0/C by 4 successive incubations; (1) 15 min prestimulation with 30 mM K/sup +/ to increase ACh turnover, (2) 20 min incubation with /sup 3/H-Ch and Ch to radiolabel a portion of the ACh pool, (3) 15 min washout incubation, and (4) 10 min stimulation with 20 mM K/sup +/ to release ACh and/sup 3/ACh. When present during /sup 3/H-Ch uptake, acetylsecohemicholinium (AcSecoHC) and N-allyl-3-quinuclidinol (NAQ), inhibitors of high-affinity Ch uptake (HAChU), reduced the subsequent release of ACh and /sup 3/H-ACh with a decrease in ACh specific activity. Both compounds reduced the efflux of /sup 3/H-Ch while only AcSecoHC affected Ch efflux. These compounds were ineffective when added during the 30 mM K/sup +/ stimulation. Tissue levels of /sup 3/H-ACh and ACh were markedly reduced when analyzed before or after stimulated release. This suggested that modulation of ACh release occurred through depletion of /sup 3/H-ACh and ACh in AcSecoHC and NAQ-treated tissues. 2-(4-phenyl-piperidino) cyclohexanol (AH5183), a potent inhibitor of ACh transport into synaptic vesicles, reduced the subsequent release of ACh with out a change in specific activity, when tissues were pretreated during /sup 3/H-Ch uptake. When added at the time of release, AH5183 reduced but did not completely inhibit both /sup 3/H-ACh and ACh release, demonstrating the presence of an AH5183-insensitive ACh pool of high specific activity. Analysis of AH5183-treated tissues before or after K/sup +/ stimulation, revealed adequate levels of /sup 3/H-ACh and ACh.

Sheldon, R.J.

1987-01-01

139

The toxicity of four native Indian plants: Effect on AChE and acid\\/alkaline phosphatase level in fish Channa marulius  

Microsoft Academic Search

The latex of four plants viz. Euphorbia royleana, Jatropha gossypifolia (Euphorbiaceae), Nerium indicum and Thevetia peruviana (Apocynaceae) caused significant reduction in acid\\/alkaline phosphatase activity and anti-acetylcholinesterase activity in nervous tissue of freshwater air breathing fish Channa marulius. The reduction in the activity of both phosphatases and AChE were time as well as dose dependent.

Digvijay Singh; Ajay Singh

2005-01-01

140

The toxicity of four native Indian plants: effect on AChE and acid/alkaline phosphatase level in fish Channa marulius.  

PubMed

The latex of four plants viz. Euphorbia royleana, Jatropha gossypifolia (Euphorbiaceae), Nerium indicum and Thevetia peruviana (Apocynaceae) caused significant reduction in acid/alkaline phosphatase activity and anti-acetylcholinesterase activity in nervous tissue of freshwater air breathing fish Channa marulius. The reduction in the activity of both phosphatases and AChE were time as well as dose dependent. PMID:15910912

Singh, Digvijay; Singh, Ajay

2005-04-13

141

Seasonal screening of AChE, GSH and gonad histology, in European sea bass Dicentrarchus labrax L. reared in three different fish farms  

Microsoft Academic Search

The aim of this work was to do a preliminary seasonal screening of ecotoxicological biomarkers in European sea bass Dicentrarchus labrax in three different fish farms, to know if the different location and typology can discriminate them. A set of selected biomarkers of xenobiotic exposure, such as acetylcholinesterase (AChE) activity, Glutathione (GSH) and gonad morphology were investigated seasonally in male

Maria Vittoria Cangialosi; Ilaria Corsi; Stefano Bonacci; Cristiana Sensini; Nicola Cicero; Silvano Focardi; Antonio Mazzola

2012-01-01

142

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

PubMed Central

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??M 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.

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

2013-01-01

143

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

PubMed

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??M 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

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

2013-02-05

144

Andrei Sher and Quaternary science  

NASA Astrophysics Data System (ADS)

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.

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

2011-08-01

145

Oil dispersions of nAChR binding neonicotinoids  

US Patent & Trademark Office Database

Selective insect neonicotinoids is a class of pesticide active ingredients that share some characteristics in their chemical structures and bind to the nAChR acetylcholine receptors. Formulation of such compounds in oil suspension or oil dispersion is challenging due to their electrostatic interactions of the heteroatoms in oily media, that lead to irreversible flocculation or diminished homogeneicity and bleeding of such oil dispersions. Imidacloprid, Thiamethoxam, Thiachloprid, Nitenpyram, Acetamiprid, Clothianidin and Dinetofuran and derivatives thereof with nAChR binding ability are successfully formulated in oil suspension with the use of certain copolymeric anionic fatty-acid based dispersants, sorbitan derivatives, ionic surfactants, other non-ionic surfactants and inorganic polyvalent cationic salt dispersed in the oil. The formulations this way produced show excellent storage stability properties regarding physiochemical parameters, including stability of the neonicotinoid active ingredient, reduced bleeding, and complete redispersibility. Further, they show excellent biological efficacy due to the reduced and homogeneous particle size below 2 .mu.m when diluted--emulsified--in water.

2012-10-23

146

Quaternary ecology: A paleoecological perspective  

SciTech Connect

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.

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

1991-01-01

147

Synthesis and evaluation of substituted 4-methyl-2-oxo-2H-chromen-7-yl phenyl carbamates as potent acetylcholinesterase inhibitors and anti- amnestic agents.  

PubMed

The study aimed to synthesize and evaluate substituted 4-methyl-2-oxo-2H-chromen-7-yl phenylcarbamates as potent acetylcholinesterase (AChE) inhibitors and anti-amnestic agents. The compounds were evaluated for AChE and butyrylcholinesterase (BuChE) inhibitory activity in rat brain homogenate and plasma, respectively. The most potent test compound 4d was evaluated for memory testing in scopolamine-induced amnesia. The phenylcarbamate substituted coumarins (4a-4h) demonstrated more potent AChE inhibitory as compared to parent 7-hydroxy-4-methylcoumarin. The introduction of phenylcarbamate moiety to coumarin template also significantly increased BuChE inhibitory activity, albeit less than AChE inhibitory activity with approximate BuChE/AChE selectivity ratio of 20. The compound 4d displayed the most potent AChE inhibitory activity with IC50 = 13.5 ± 1.7 nM, along with amelioration of amnesia in mice in terms of restoration of time spent in target quadrant and escap latency time. It is concluded that carbamate derivatives of coumarin may be employed as potential AChE inhibitors and anti-amnestic agents. PMID:23072555

Anand, Preet; Singh, Baldev

2013-08-01

148

Increased ratio of rapsyn to ACh receptor stabilizes postsynaptic receptors at the mouse neuromuscular synapse  

PubMed Central

The metabolic turnover of nicotinic ACh receptors (AChR) at the neuromuscular synapse is regulated over a tenfold range by innervation status, muscle electrical activity and neural agrin, but the downstream effector of such changes has not been defined. The AChR-associated protein rapsyn is essential for forming AChR clusters during development. Here, rapsyn was tagged with enhanced green fluorescent protein (EGFP) to begin to probe its influence at the adult synapse. In C2 myotubes, rapsyn–EGFP participated with AChR in agrin-induced AChR cluster formation. When electroporated into the tibialis anterior muscle of young adult mice, rapsyn–EGFP accumulated in discrete subcellular structures, many of which colocalized with Golgi markers, consistent with the idea that rapsyn assembles with AChR in the exocytic pathway. Rapsyn–EGFP also targeted directly to the postsynaptic membrane where it occupied previously vacant rapsyn binding sites, thereby increasing the rapsyn to AChR ratio. At endplates displaying rapsyn–EGFP, the metabolic turnover of AChR (labelled with rhodamine-?-bungarotoxin) was slowed. Thus, the metabolic half-life of receptors at the synapse may be modulated by local changes in the subsynaptic ratio of rapsyn to AChR.

Gervasio, Othon L; Phillips, William D

2005-01-01

149

Structural determinants of selective ?-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP  

PubMed Central

The nicotinic acetylcholine receptor (nAChR) is the prototype member of the superfamily of pentameric ligand-gated ion channels. How the extracellular ligand-binding domain coordinates selective binding of ligand molecules to different subtypes of the receptor is unknown at the structural level. Here, we present the 2.2-Å crystal structure of a homolog of the ligand-binding domain of the nAChR, Aplysia californica AChBP (Ac-AChBP), in complex with ?-conotoxin ImI. This conotoxin is unique in its selectivity toward the neuronal ?3?2 and ?7 nAChR, a feature that is reflected in its selective binding to Ac-AChBP compared with other AChBP homologs. We observe a network of interactions between the residues of the ligand-binding site and the toxin, in which ImI Arg-7 and Trp-10 play a key role. The toxin also forms interactions in the ligand-binding site that were not seen in the complex of Ac-AChBP with PnIA(A10L D14K), a conotoxin variant that lacks binding selectivity to AChBP homologs. In combination with electrophysiological recordings obtained by using the wild-type ?7 nAChR and L247T mutant, we show that conotoxin ImI inhibits ion conduction by stabilizing the receptor in a desensitized conformation. Comparison of the Ac-AChBP–ImI crystal structure with existing AChBP structures offers structural insight into the extent of flexibility of the interface loops and how their movement may couple ligand binding to channel gating in the context of a nAChR.

Ulens, Chris; Hogg, Ronald C.; Celie, Patrick H.; Bertrand, Daniel; Tsetlin, Victor; Smit, August B.; Sixma, Titia K.

2006-01-01

150

An electrochemical platform for acetylcholinesterase activity assay and inhibitors screening based on Michael addition reaction between thiocholine and catechol-terminated SAMs.  

PubMed

An electrochemical platform for acetylcholinesterase (AChE) activity assay and its inhibitors screening is developed based on the Michael addition reaction of thiocholine, the hydrolysis product of acetylthiocholine (AsCh) in the presence of AChE, with the electrogenerated o-quinone of catechol-terminated SAMs on a gold electrode. For understanding and confirming the mechanism of the reaction, the electrochemical behaviors of Michael addition reaction of two model compounds, cysteine (CYS) and glutathione (GSH), towards the catechol-terminated SAMs have been studied. The enzyme kinetics and the inhibition effects of three types of AChE inhibitors, which are tacrine, carbofuran and parathion-methyl, have been investigated using an amperometric method. Among these three inhibitors, tacrine exhibits the strongest inhibiting effect, which is reinforced by the resulting data of kinetic studies on each inhibitor's influence upon the enzyme activity. PMID:21994917

Tian, Yuan; Ye, Siqiu; Shi, Xinhao; Jing, Li; Liang, Cong; Xian, Yuezhong

2011-10-13

151

Ion pair recognition of quaternary ammonium and iminium salts by uranyl-salophen compounds in solution and in the solid state.  

PubMed

Efficient ditopic receptors for quaternary ammonium and iminium salts have been obtained upon functionalization of the uranyl-salophen unit with conformationally flexible side arms bearing phenyl or beta-naphthyl substituents. Binding affinities in chloroform solution have been measured for a large number of quaternary salts comprising tetramethylammonium (TMA), tetrabutylammonium (TBA), acetylcholine (ACh), N-methylpyridinium (NMP), and N-methylisoquinolinium (NmiQ) cations. Recognition of the anion partner is ensured by coordination to the hard Lewis acidic uranyl center, whereas cation-pi/CH-pi interactions of the quaternary ions are established with the aromatic pendants. The role of the cation-anion interactions on the dynamics of exchange between the free and complexed species is discussed. Solid-state structures have been obtained for a few salt-receptor combinations. In the solid state, side-armed receptor molecules form assemblies that enclose ion pair aggregates of varying composition and structure, including AChCl dimers, two different kinds of tetrameric (TMA)Cl clusters, and unidimentional salt strips of (NMP)Br. The lack of side arms as preferential binding sites for the polar quaternary cations prevents association patterns of the kinds formed with the side-armed receptors, as shown by the crystal structure of the complex of (TMA)Cl with the parent uranyl-salophen receptor. PMID:17338524

Cametti, Massimo; Nissinen, Maija; Cort, Antonella Dalla; Mandolini, Luigi; Rissanen, Kari

2007-03-06

152

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

PubMed

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

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

2013-10-09

153

21 CFR 172.165 - Quaternary ammonium chloride combination.  

Code of Federal Regulations, 2013 CFR

...FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride...

2013-04-01

154

Blind array channel division multiple access (AChDMA) for mobile communications  

Microsoft Academic Search

The paper introduces array channel division multiple access (AChDMA), which is a new blind algorithm for advanced SDMA in mobile communications systems. As an SDMA technique, AChDMA increases the system capacity by improving its time and frequency reuse. Being a blind algorithm, it requires no training sequences, previously known directions of arrival, or user codes, AChDMA separates the moving sources

Victor A. N. Barroso; J. M. F. Moura; J. Xavier

1998-01-01

155

Investigation into the characteristics of aC:H films irradiated by electron beam  

Microsoft Academic Search

The characteristics of a-C:H films irradiated by different doses of electron beam have been studied by x-ray diffraction. IR absorption, Raman scattering, and resonant nuclear reaction. Such irradiation can lead the structure of a-C:H films to change in a different degree. The proportions of diamond crystalline and graphite structures in a-C:H films have a proper change simultaneously. The experimental results

Shu L. Gu; Yuliang L. He; Zhi C. Wang

1991-01-01

156

The First Total Synthesis of (?) Cyclophostin and (?) Cyclipostin P: Inhibitors of the Serine Hydrolases Acetyl Cholinesterase and Hormone Sensitive Lipase  

PubMed Central

Cyclophostin, a structurally unique and potent naturally occurring acetyl cholinesterase (AChE) inhibitor, and its unnatural diastereomer were prepared in 6 steps and 15% overall yield from hydroxymethyl butyrolactone. The unnatural diastereomer of cyclophostin was converted into cyclipostin P, a potent naturally occurring hormone sensitive lipase (HSL) inhibitor, using a one pot dealkylation-alkylation process. The inhibition [IC50] of human AChE by cyclophostin and its diastereomer are reported, as well as constituent binding (KI) and reactivity (k2) constants.

Malla, Raj K.; Bandyopadhyay, Saibal; Spilling, Christopher D.; Dutta, Supratik; Dupureur, Cynthia M.

2011-01-01

157

Quaternary glaciation of the Himalayan-Tibetan  

Microsoft Academic Search

Glacial geological evidence from throughout the Himalayan-Tibetan orogen is examined to determine the timing and extent of late Quaternary glaciation in this region and its relation to similar changes on a global scale. The evidence summarised here supports the existence of expanded ice caps and extensive valley glacier systems throughout the region during the late Quaternary. However, it cannot yet

LEWIS A. OWEN; MARC W. CAFFEE; ROBERT C. FINKEL; YEONG BAE SEONG

158

Stereoselective Synthesis of Quaternary Proline Analogues  

PubMed Central

This review describes available methods for the diastereoselective and asymmetric synthesis of quaternary prolines. The focus is on the preparation of ?-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.

Calaza, M. Isabel

2009-01-01

159

Structural determinants in phycotoxins and AChBP conferring high affinity binding and nicotinic AChR antagonism.  

PubMed

Spirolide and gymnodimine macrocyclic imine phycotoxins belong to an emerging class of chemical agents associated with marine algal blooms and shellfish toxicity. Analysis of 13-desmethyl spirolide C and gymnodimine A by binding and voltage-clamp recordings on muscle-type alpha1(2)betagammadelta and neuronal alpha3beta2 and alpha4beta2 nicotinic acetylcholine receptors reveals subnanomolar affinities, potent antagonism, and limited subtype selectivity. Their binding to acetylcholine-binding proteins (AChBP), as soluble receptor surrogates, exhibits picomolar affinities governed by diffusion-limited association and slow dissociation, accounting for apparent irreversibility. Crystal structures of the phycotoxins bound to Aplysia-AChBP ( approximately 2.4A) show toxins neatly imbedded within the nest of ar-omatic side chains contributed by loops C and F on opposing faces of the subunit interface, and which in physiological conditions accommodates acetylcholine. The structures also point to three major features: (i) the sequence-conserved loop C envelops the bound toxins to maximize surface complementarity; (ii) hydrogen bonding of the protonated imine nitrogen in the toxins with the carbonyl oxygen of loop C Trp147 tethers the toxin core centered within the pocket; and (iii) the spirolide bis-spiroacetal or gymnodimine tetrahydrofuran and their common cyclohexene-butyrolactone further anchor the toxins in apical and membrane directions, along the subunit interface. In contrast, the se-quence-variable loop F only sparingly contributes contact points to preserve the broad receptor subtype recognition unique to phycotoxins compared with other nicotinic antagonists. These data offer unique means for detecting spiroimine toxins in shellfish and identify distinctive ligands, functional determinants and binding regions for the design of new drugs able to target several receptor subtypes with high affinity. PMID:20224036

Bourne, Yves; Radic, Zoran; Aráoz, Rómulo; Talley, Todd T; Benoit, Evelyne; Servent, Denis; Taylor, Palmer; Molgó, Jordi; Marchot, Pascale

2010-03-11

160

Structural determinants in phycotoxins and AChBP conferring high affinity binding and nicotinic AChR antagonism  

PubMed Central

Spirolide and gymnodimine macrocyclic imine phycotoxins belong to an emerging class of chemical agents associated with marine algal blooms and shellfish toxicity. Analysis of 13-desmethyl spirolide C and gymnodimine A by binding and voltage-clamp recordings on muscle-type ?12??? and neuronal ?3?2 and ?4?2 nicotinic acetylcholine receptors reveals subnanomolar affinities, potent antagonism, and limited subtype selectivity. Their binding to acetylcholine-binding proteins (AChBP), as soluble receptor surrogates, exhibits picomolar affinities governed by diffusion-limited association and slow dissociation, accounting for apparent irreversibility. Crystal structures of the phycotoxins bound to Aplysia-AChBP (?2.4Å) show toxins neatly imbedded within the nest of ar-omatic side chains contributed by loops C and F on opposing faces of the subunit interface, and which in physiological conditions accommodates acetylcholine. The structures also point to three major features: (i) the sequence-conserved loop C envelops the bound toxins to maximize surface complementarity; (ii) hydrogen bonding of the protonated imine nitrogen in the toxins with the carbonyl oxygen of loop C Trp147 tethers the toxin core centered within the pocket; and (iii) the spirolide bis-spiroacetal or gymnodimine tetrahydrofuran and their common cyclohexene-butyrolactone further anchor the toxins in apical and membrane directions, along the subunit interface. In contrast, the se-quence-variable loop F only sparingly contributes contact points to preserve the broad receptor subtype recognition unique to phycotoxins compared with other nicotinic antagonists. These data offer unique means for detecting spiroimine toxins in shellfish and identify distinctive ligands, functional determinants and binding regions for the design of new drugs able to target several receptor subtypes with high affinity.

Bourne, Yves; Radic, Zoran; Araoz, Romulo; Talley, Todd T.; Benoit, Evelyne; Servent, Denis; Taylor, Palmer; Molgo, Jordi; Marchot, Pascale

2010-01-01

161

Synthesis and biological evaluation of 3,6-diaryl-7H-thiazolo[3,2-b] [1,2,4]triazin-7-one derivatives as acetylcholinesterase inhibitors.  

PubMed

Acetylcholinesterase (AChE) inhibitors played an important role in developing a cure for Alzheimer' s disease. In order to study on the influence of modifications at different groups and side chains on the AChE inhibitory ability and the active sites of 7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives, fourteen 3,6-diaryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives were designed and synthesized. The study of AChE inhibitory activity was carried out using the Ellman colorimetric assay with huperzine-A as the positive control drug. Most of the target compounds exhibited more than 50% inhibition at 10 ?M. Some target compounds showed strong inhibition against AChE. The molecular fields analysis and preliminary structure-activity relationships are discussed. PMID:21052939

Jin, Zhe; Yang, Liu; Liu, Si-Jie; Wang, Jian; Li, Shuo; Lin, Huang-Quan; Wan, David Chi Cheong; Hu, Chun

2010-10-30

162

Chronic (?) deprenyl administration increases dendritic arborization in CA3 neurons of hippocampus and AChE activity in specific regions of the primate brain  

Microsoft Academic Search

The mechanism by which (?) deprenyl enhances cognitive function in Alzheimer's disease (AD) is not yet understood. (?)Deprenyl (0.2 mg\\/kg\\/day) was administered intramuscularly to adult male monkeys (n=6) for 25 days. Control monkeys (n=6) received physiological saline by the same route. The activity of acetylcholinesterase (AChE) in different brain regions and the dendritic arborization in CA3 pyramidal neurons of hippocampus

Madepalli K Lakshmana; B. S Shankaranarayana Rao; Narender K Dhingra; R Ravikumar; Govindaiah; Ramachandra; B. L Meti; T. R Raju

1998-01-01

163

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

PubMed Central

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.

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

2012-01-01

164

On-line immobilized acetylcholinesterase microreactor for screening of inhibitors from natural extracts by capillary electrophoresis.  

PubMed

In this study we developed a simple capillary electrophoresis (CE) method with an on-line acetylcholinesterase (AChE) microreactor at the inlet of capillary for inhibitor screening. The fused-silica capillary surface was modified with a polycationic polyethylenimine coating. Solutions of the enzyme and chitosan were then injected to immobilize the enzyme in approximately 2.9 cm of the capillary inlet (total length of capillary 60.2 cm) by electrostatic interaction and the film overlay technique. Separation of enzyme reaction product (thiocholine, ThCh) and unreacted substrate (acetylthiocholine, AThCh) was achieved within 3.0 min. The conditions affecting the efficiency of reaction of the enzyme were optimized by measuring the peak area of ThCh. Under the optimum conditions, using Huperzine-A as model inhibitor, K (i) and IC (50) were 0.551 ?mol L(-1) and 1.52 ?mol L(-1), respectively, for immobilized AChE. Finally, screening of a small compound library containing two known AChE inhibitors and 30 natural extracts was conducted, and species with inhibition activity were directly identified. Compared with previous publications on screening for AChE inhibitors in natural products based on CE methods, the method developed in this work has the advantages of lower cost per analysis, less leakage, and better bioaffinity for the immobilized enzyme because of the unique properties of sodium alginate and chitosan. PMID:22932810

Min, Wenao; Wang, Weiping; Chen, Jianrong; Wang, Aijun; Hu, Zhide

2012-08-30

165

Oh, my aching laptop: expanding the boundaries of campus computing ergonomics  

Microsoft Academic Search

Feeling pins-and-needles in your fingers, having a sore back, blurry vision or aching wrists are common symptoms for many employees in the technology field. Such aches and pains are often warning signs that significant injuries are just one more mouse click away. Until recently, such ailments have not traditionally been considered common symptoms for students. Yet, with the rapid growth

Patricia Wyatt; Kim Todd; Tabatha Verbick

2006-01-01

166

Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and ?-amyloid aggregation inhibitors.  

PubMed

A series of novel triazole-containing berberine derivatives were synthesized via the azide-alkyne cycloaddition reaction. Their biological activity as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. Among them, compound 16d, which featured a diisopropylamino substitution at the 4-position of triazole ring, was found to be a potent inhibitor of AChE, with IC(50) value of 0.044 ?M. Compound 18d, which beares a butyl at the 4-position of the triazole ring, showed the highest potency of ?-amyloid aggregation inhibition (77.9% at 20 ?M). Molecular modeling studies indicated that the triazole moiety of berberine derivatives displayed a face-to-face ?-? stacking interaction in a 'sandwich' form with the Trp84 (4.09 Å) and Phe330 (4.33 Å) in catalytic sites of AChE. PMID:21397508

Shi, Anding; Huang, Ling; Lu, Chuanjun; He, Feng; Li, Xingshu

2011-02-18

167

From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimer's disease: acetylcholinesterase inhibitors.  

PubMed

The leading Alzheimer's disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation. In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants. Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example. The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory. Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD. PMID:23210783

Russo, P; Frustaci, A; Del Bufalo, A; Fini, M; Cesario, A

2013-01-01

168

Synthesis and Kinetic Analysis of Some Phosphonate Analogs of Cyclophostin as Inhibitors of Human Acetylcholinesterase  

PubMed Central

Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC50 of 3 ?M. Potency is only preserved when the cyclic enol phosphonate is intact and conjugated to an ester. Kinetic analysis indicates both a binding and a slow inactivation step for all active compounds. Mass spectrometric analysis indicates that the active site Ser is indeed phosphorylated by the bicyclic phosphonate.

Dutta, Supratik; Malla, Raj K.; Bandyopadhyay, Saibal; Spilling, Christopher D.; Dupureur, Cynthia M.

2010-01-01

169

Reagent-less detection of a competitive inhibitor of immobilized acetylcholinesterase.  

PubMed

The interaction of monosulfonate tetraphenyl porphine (TPPS(1)) with immobilized acetylcholinesterase (AChE) yields a characteristic absorbance peak at 446 nm. Addition of acetylcholine iodide or the competitive inhibitor tetracaine to the immobilized TPPS(1)-AChE complex results in a decrease in absorbance intensity at 446 nm due to displacement of the porphyrin from the active site. The loss in intensity at 446 nm is linearly dependent on tetracaine concentration at levels below 100 ppb. Tetracaine concentrations as low as 300 ppt have been detected. PMID:11888725

White, Brandy J; Legako, J Andrew; Harmon, H James

2002-05-01

170

Synthesis and kinetic analysis of some phosphonate analogs of cyclophostin as inhibitors of human acetylcholinesterase.  

PubMed

Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC(50) of 3 microM. Potency is only preserved when the cyclic enol phosphonate is intact and conjugated to an ester. Kinetic analysis indicates both a binding and a slow inactivation step for all active compounds. Mass spectrometric analysis indicates that the active site Ser is indeed phosphorylated by the bicyclic phosphonate. PMID:20189400

Dutta, Supratik; Malla, Raj K; Bandyopadhyay, Saibal; Spilling, Christopher D; Dupureur, Cynthia M

2010-02-04

171

A Speculative Model of AChR Gating at the Frog Neuromuscular Junction  

NSDL National Science Digital Library

The animation depicts a speculative model of nicotinic acetylcholine receptor (AChR) gating at the frog neuromuscular junction. Following a nerve impulse, the neurotransmitter acetylcholine (ACh) is released from synaptic vesicles docked at the active zone of the presynaptic nerve terminal. ACh diffuses across the synaptic cleft to bind to AChRs, ligand-gated channels found at the lips of the postjunctional folds of the muscle, initiating gating, a conformational change that allows ions to flow through the channel and thereby elicit an electrical response in the muscle (the end-plate potential). In the AChR, gating involves a series of small conformational changes that propagate throughout the channel as it moves from "closed" to "open," rather than a synchronous switch in protein configuration. [Resource Details

Anthony Auerbach (State University of New York at Buffalo;Center for Single Molecule Biophysics REV)

2003-09-02

172

Additive Effects of Numbness and Muscle Aches on Fatigue Occurrence in Individuals with HIV/AIDS Who are Taking Antiretroviral Medications  

PubMed Central

Context Muscle aches, numbness in the feet/toes (neuropathy), and fatigue are often reported concurrently and are among the symptoms most frequently reported by individuals with HIV/AIDS, whether or not they are taking antiretroviral medications (ARVs). Objectives This study used a longitudinal analytical methodology to analyze these symptoms together to determine whether symptom clusters are maintained over time and to determine whether there is a temporal relationship between fatigue and reports of neuropathic pain and muscle aches. Methods This was a secondary analysis of a subset of data from a six-month, longitudinal, randomized, controlled trial of 243 HIV-positive individuals taking ARVs. Self-reported symptom frequency and intensity were recorded using the Revised Sign and Symptom Checklist for Persons with HIV Disease at baseline (month 0), one month, three months, and six months. Multilevel, logistic regression models were used to analyze time-lagged effects of muscle aches, numbness of the feet/toes, and fatigue to estimate any predictive and interactive effects that the symptoms have upon one another. Results A significant relationship between muscle aches and fatigue intercepts was noted (odds ratio [OR] =1.80, P ? 0.05). Significant relationships between numbness and fatigue were also noted for the entire measurement period (OR=2.70, P ? 0.05). Time-lagged models showed persons reporting neuropathic-related numbness in one period were nearly twice as likely to report fatigue in subsequent periods (OR=1.89, P ? 0.05). The final model revealed that the addition of muscle aches and numbness explained 28% of the random variance in the occurrence of fatigue. Between-person descriptive variables including years living with HIV, age, having an AIDS diagnosis, ethnicity, and nucleoside reverse transcriptase inhibitor (NRTI) treatment regimens with stavudine, zalactabine, or didanosine did not significantly explain any additional model variation. Conclusion These findings are consistent with physiological research and provide evidence that analyzing multiple symptom change over time can provide a more accurate representation of an individual’s symptom experience. When evaluating patients with muscle aches or numbness, particularly when both symptoms are present, an evaluation of fatigue should be considered. Similarly, if fatigue is reported, underlying physiological assessments for neuropathic symptoms and muscle aches may be considered.

Wantland, Dean J.; Mullan, Joseph P.; Holzemer, William L.; Portillo, Carmen J.; McGhee, Eva M.

2011-01-01

173

The AChE membrane-binding tail PRiMA is down-regulated in muscle and nerve of mice with muscular dystrophy by merosin deficiency.  

PubMed

Since Duchenne muscular dystrophy was attributed to mutations in the dystrophin gene, more than 30 genes have been found to be causally related with muscular dystrophies, about half of them encoding proteins of the dystrophin-glycoprotein complex (DGC). Through laminin-2, the DGC bridges the muscle cytoskeleton and the extracellular matrix. Decreased levels of PRiMA-linked acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) have been observed in dystrophic muscle and nerve of dystrophin-deficient (mdx) and laminin-2 deficient (Lama2dy) mice. To help explain these observations, the relative content of AChE, BuChE and PRiMA mRNAs were compared in normal and Lama2dy mouse muscle and sciatic nerve. The 17-fold lower level of PRiMA mRNA in Lama2dy muscle explained the deficit in PRiMA-linked ChEs. This would increase acetylcholine availability and, eventually, the desensitization of nicotinic receptors. Abnormal development of the Schwann cells led to peripheral neuropathy in the Lama2dy mouse. Compared with normal nerve, dystrophic nerve displayed 4-fold less AChE-T mRNA, 3-fold more BuChE mRNA and 2.5-fold less PRiMA mRNA, which agreed with the lower AChE activity in dystrophic nerve, its increased BuChE activity and the specific drop in PRiMA-linked BuChE. The widely accepted role of glial cells as the source of BuChE, the observed dysmyelination of Lama2dy nerve and its increased BuChE activity support the idea that BuChE up-regulation is related with the aberrant differentiation of the Schwann cells. PMID:22906800

Vidal, C J; Montenegro, M F; Muñoz-Delgado, E; Campoy, F J; Cabezas-Herrera, J; Moral-Naranjo, M T

2012-08-10

174

Two Distinct Channels Mediated by m2mAChR and ?9nAChR Co-Exist in Type II Vestibular Hair Cells of Guinea Pig.  

PubMed

Acetylcholine (ACh) is the principal vestibular efferent neurotransmitter among mammalians. Pharmacologic studies prove that ACh activates a small conductance Ca2+-activated K+ channels (KCa) current (SK2), mediated by ?9-containing nicotinic ACh receptor (?9nAChR) in mammalian type II vestibular hair cells (VHCs II). However, our studies demonstrate that the m2 muscarinic ACh receptor (m2mAChR) mediates a big conductance KCa current (BK) in VHCs II. To better elucidate the correlation between these two distinct channels in VHCs II of guinea pig, this study was designed to verify whether these two channels and their corresponding AChR subtypes co-exist in the same VHCs II by whole-cell patch clamp recordings. We found that m2mAChR sensitive BK currents were activated in VHCs II isolated by collagenase IA, while ?9nAChR sensitive SK2 currents were activated in VHCs II isolated by trypsin. Interestingly, after exposing the patched cells isolated by trypsin to collagenase IA for 3 min, the ?9nAChR sensitive SK2 current was abolished, while m2mAChR-sensitive BK current was activated. Therefore, our findings provide evidence that the two distinct channels and their corresponding AChR subtypes may co-exist in the same VHCs II, and the alternative presence of these two ACh receptors-sensitive currents depended on isolating preparation with different enzymes. PMID:23615472

Zhou, Tao; Wang, Yi; Guo, Chang-Kai; Zhang, Wen-Juan; Yu, Hong; Zhang, Kun; Kong, Wei-Jia

2013-04-24

175

1H NMR relaxation investigation of acetylcholinesterase inhibitors from huperzine A and derivative.  

PubMed

The binding properties of huperzine A (1) with Torpediniforms Nacline acetylcholinesterase (TnAChE) were investigated by (1)H NMR methods. The noselective, selective and double-selective spin-lattice relaxation rates were acquired in absent and present of TnAChE at a ratio [ligand]/[protein]=1:0.005. The selective relaxation rates shown protons of 1 had dipole-dipole interaction with protein active site protons. The motional correlation time of bound ligand was calculated by double-selective relaxation rate at 1 tau(2,3)=40.5 ns at 298 K, which showed 1 had high affinity with TnAChE. The experiments give a possible method to use TnAChE to locate the new huperzine A derivatives as AChE inhibitors. PMID:15006409

Li, Yiming; Li, Qian; Sun, Manchi; Song, Guoqiang; Jiang, Shanhao; Zhu, Dayuan

2004-03-22

176

Synthesis, characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors.  

PubMed

Two series of novel acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors containing benzimidazole core structure were synthesized by a four-step reaction pathway starting from 4-fluoro-3-nitrobenzoic acid as the basic compound. The structure of the novel benzimidazoles was characterized and confirmed by the elemental and mass spectral analyses as well as (1)H NMR spectroscopic data. Of the 34 novel synthesized compounds, three benzimidazoles revealed AChE inhibition with IC50<10?M. The highest inhibitory activity (IC50=5.12?M for AChE and IC50=8.63?M for BChE) corresponds to the compound 5IIc (ethyl 1-(3-(1H-imidazol-1-yl)propyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate). The relationship between lipophilicity and the chemical structures as well as their limited structure-activity relationship was discussed. PMID:23886696

Yoon, Yeong Keng; Ali, Mohamed Ashraf; Wei, Ang Chee; Choon, Tan Soo; Khaw, Kooi-Yeong; Murugaiyah, Vikneswaran; Osman, Hasnah; Masand, Vijay H

2013-07-04

177

Novel selective and irreversible mosquito acetylcholinesterase inhibitors for controlling malaria and other mosquito-borne diseases.  

PubMed

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 (k(inact)/K(I)) of 3,604-458,597 M(-1)sec(-1) but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with k(inact)/K(I) values of 1,915 and 1,507 M(-1)sec(-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. PMID:23323211

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

2013-01-15

178

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

PubMed Central

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.

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

2013-01-01

179

Myasthenic syndrome AChR? C-loop mutant disrupts initiation of channel gating  

PubMed Central

Congenital myasthenic syndromes (CMSs) are neuromuscular disorders that can be caused by defects in ace­tylcholine receptor (AChR) function. Disease-associated point mutants can reveal the unsuspected functional significance of mutated residues. We identified two pathogenic mutations in the extracellular domain of the AChR ? subunit (AChR?) in a patient with myasthenic symptoms since birth: a V188M mutation in the C-loop and a heteroallelic G74C mutation in the main immunogenic region. The G74C mutation markedly reduced surface AChR expression in cultured cells, whereas the V188M mutant was expressed robustly but had severely impaired kinetics. Single-channel patch-clamp analysis indicated that V188M markedly decreased the apparent AChR channel opening rate and gating efficiency. Mutant cycle analysis of energetic coupling among conserved residues within or dispersed around the AChR? C-loop revealed that V188 is functionally linked to Y190 in the C-loop and to D200 in ?-strand 10, which connects to the M1 transmembrane domain. Furthermore, V188M weakens inter-residue coupling of K145 in ?-strand 7 with Y190 and with D200. Cumulatively, these results indicate that V188 of AChR? is part of an interdependent tetrad that contributes to rearrangement of the C-loop during the initial coupling of agonist binding to channel gating.

Shen, Xin-Ming; Brengman, Joan M.; Sine, Steven M.; Engel, Andrew G.

2012-01-01

180

Liquid-crystal alignment on a-C:H films by nitrogen plasma beam scanning  

NASA Astrophysics Data System (ADS)

A plasma beam scanning treatment has been developed to modify the surface of the hydrogenated amorphous carbon (a-C:H) film on the indium tin oxide glass. The plasma beam scanning treatment makes the a-C:H film an excellent layer for liquid-crystal alignment. The qualities of a-C:H films were characterized by using atomic force microscope, micro-Raman spectroscopy, and field-emission scanning electron microscope. The ultrathin a-C:H films were deposited at 50% CH4/(H2+CH4) gas ratio, 100 W radio-frequency power, and a gas pressure of 10 mtorr for 15 min by capacitive-coupled plasma chemical-vapor deposition method. The twist nematic cells were filled with liquid crystal (ZLI-2293) on the a-C:H film treated with different nitrogen plasma beam scanning time. The grooving mechanism is considered not responsible for the liquid-crystal (LC) alignment. Raman spectra suggest that a bond-breaking process of aromatic rings occurs in the a-C:H film. The O1s, C1s, and N1s core-level spectra support that the nitrogen plasma beam scanning treatment induces a bond-breaking process of aromatic rings to create available carbon dangling bonds for the formation of C-O bonds. The newly formed C-O bonds are ``directional,'' which favor the LC alignment on the a-C:H film.

Wu, K. Y.; Chen, C.-H.; Yeh, C.-M.; Hwang, J.; Liu, P.-C.; Lee, C.-Y.; Chen, C.-W.; Wei, H. K.; Kou, C. S.; Lee, C.-D.

2005-10-01

181

Crystal structures of Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides imidacloprid and clothianidin  

PubMed Central

Neonicotinoid insecticides, which act on nicotinic acetylcholine receptors (nAChRs) in a variety of ways, have extremely low mammalian toxicity, yet the molecular basis of such actions is poorly understood. To elucidate the molecular basis for nAChR–neonicotinoid interactions, a surrogate protein, acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) was crystallized in complex with neonicotinoid insecticides imidacloprid (IMI) or clothianidin (CTD). The crystal structures suggested that the guanidine moiety of IMI and CTD stacks with Tyr185, while the nitro group of IMI but not of CTD makes a hydrogen bond with Gln55. IMI showed higher binding affinity for Ls-AChBP than that of CTD, consistent with weaker CH–? interactions in the Ls-AChBP–CTD complex than in the Ls-AChBP–IMI complex and the lack of the nitro group-Gln55 hydrogen bond in CTD. Yet, the NH at position 1 of CTD makes a hydrogen bond with the backbone carbonyl of Trp143, offering an explanation for the diverse actions of neonicotinoids on nAChRs.

Ihara, Makoto; Okajima, Toshihide; Yamashita, Atsuko; Oda, Takuma; Hirata, Koichi; Nishiwaki, Hisashi; Morimoto, Takako; Akamatsu, Miki; Ashikawa, Yuji; Kuroda, Shun'ichi; Mega, Ryosuke; Kuramitsu, Seiki; Sattelle, David B.

2008-01-01

182

Synergy of a Hepatitis C Virus (HCV) NS4A Antagonist in Combination with HCV Protease and Polymerase Inhibitors?  

PubMed Central

Rapid emergence of resistance to monotherapy with virus-specific inhibitors necessitates combination therapy. ACH-806 is a hepatitis C virus NS4A inhibitor with a novel mechanism of action and resistance pathway. This compound was synergistic with NS3 protease inhibitors and NS5B nucleoside and nonnucleoside polymerase inhibitors.

Wyles, David L.; Kaihara, Kelly A.; Schooley, Robert T.

2008-01-01

183

Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors.  

PubMed

A new series of 2-(diethylaminoalkyl)-isoindoline-1,3-dione derivatives intended as dual binding site cholinesterase inhibitors were designed using molecular modeling and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and the formation of the ?-amyloid (A?) plaques. For AChE inhibitory activity, the spectrophotometric method of Ellman and the electrophoretically mediated microanalysis assay were used, giving good results. Most of the synthesized compounds had AChE inhibitory activity with IC(50) values ranging from IC(50) = 0.9 to 19.5 µM and weak A? anti-aggregation inhibitory activity. These results support the outcome of docking studies which tested compounds targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The most promising selective AChE inhibitors are compounds 10 (IC(50) = 1.2 µM) and 11 (IC(50) = 1.1 µM), with 6-7 methylene chains, which also inhibit A? fibril formation. PMID:22467516

Ignasik, Michalina; Bajda, Marek; Guzior, Natalia; Prinz, Michaela; Holzgrabe, Ulrike; Malawska, Barbara

2012-03-30

184

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis  

PubMed Central

Purpose. A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED. Methods. DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b+ and conjunctival CD3+ T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA. Results. Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3+ T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. Conclusions. In vivo inhibition of mAChRs variably affects CD4+ T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms.

Chen, Yihe; Chauhan, Sunil K.; Lee, Hyun Soo; Stevenson, William; Schaumburg, Chris S.; Sadrai, Zahra; Saban, Daniel R.; Kodati, Shilpa; Stern, Michael E.; Dana, Reza

2013-01-01

185

Screening of new huprines--inhibitors of acetylcholinesterases by electrospray ionization ion trap mass spectrometry.  

PubMed

Acetylcholinesterase inhibitors (AChEI) are one of the drugs families validated for clinical use in the treatment of Alzheimer's disease (AD). For this reason, finding new more potent and more selective AChEIs is always of interest. Since 1961, the inhibitory activity of AChEI is evaluated through the Ellman's method. Herein, we reported a MS-based evaluation of potential new AChEI with the determination of their inhibitory activity (IC(50) and K(I)). Compared to the Ellman's method, that uses the substrate analog acetylthiocholine, the electrospray ionization ion trap mass spectrometry (ESI-IT-MS) consists in monitoring the conversion ratio of a low concentration of the natural substrate - acetylcholine to choline. We present here the inhibition activity of huprine X and six of its derivates (bearing different functional groups at position 9) towards the recombinant human (rhAChE) and Electrophorus electricus acetylcholinesterase (EelAChE). Mechanisms of action of selected inhibitors were evaluated by means of Lineweaver-Burk plot analysis. The Michaelis-Menten constants (K(M)), inhibitory constants (K(I)) were examined as well as the IC(50) to allow classifying a series of huprine derivatives by inhibition potency by a comparison with a reference (huprine X). Our results demonstrate that these drugs are very potent AChE inhibitors, especially (±)-huprine 6 with an inhibitory activity on recombinant human AChE (rhAChE) in the picomolar range. This study reveals the interest of huprine compounds in the treatment of AD. PMID:22677656

Ziemianin, Anna; Ronco, Cyril; Dolé, Romain; Jean, Ludovic; Renard, Pierre-Yves; Lange, Catherine M

2012-02-17

186

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

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

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

2010-01-28

187

Brain-selective stimulation of nicotinic receptors by TC1734 enhances ACh transmission from frontoparietal cortex and memory in rodents  

Microsoft Academic Search

The authors have described the effect of TC-1734, a brain-selective nicotinic acetylcholine receptor (nAChR) agonist, on acetylcholine (ACh) release in the frontoparietal cortex of rats and on cognitive function in mice. Oral administration of TC-1734 (5, 10 and 20 mg\\/kg) stimulated ACh release in a dose-dependent manner, as measured by transversal microdialysis. The maximal effect on the amplitude of ACh

Maria Carmen Obinu; Michel Reibaud; Jean Marie Miquet; Martine Pasquet; Thomas Rooney

2002-01-01

188

Quaternary tectonics of the southeastern coastal area, Korea: subsidence of marine terrace and late Quaternary faults  

Microsoft Academic Search

Strong earthquake has rarely occurred in Korean peninsula and a few events were recorded since 27 A.D. Historical and recent earthquakes are concentrated in the southeastern area of Korean peninsula, where more than 30 Quaternary fault exposures have recently been founded. The southern tip of the southeastern coastal area has been known as a stable block: quaternary fault and micro-earthquakes

S.-J. Choi; Y. Ota; U. Chwae

2003-01-01

189

An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission  

Microsoft Academic Search

Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor

Jana K Shirey; Zixiu Xiang; Darren Orton; Ashley E Brady; Kari A Johnson; Richard Williams; Jennifer E Ayala; Alice L Rodriguez; Jürgen Wess; David Weaver; Colleen M Niswender; P Jeffrey Conn

2007-01-01

190

AChE-rich magnopyramidal neurons have a left–right size asymmetry in Broca's area  

Microsoft Academic Search

Acetylcholinesterase-rich neurons (AChERN) are a particular group of pyramidal neurons, displaying a specific laminar and ontogenetic pattern in the cerebral cortex of human and nonhuman primates. Using histochemistry and morphometrical methods, we have found a layer 3 magnopyramidal AChERN left–right size asymmetry restricted to Brodmann's area 45, a component of Broca's language area. This structural feature could be related to

Ricardo R. García; Juan F. Montiel; Aldo U. Villalón; Mario A. Gatica; Francisco Aboitiz

2004-01-01

191

Sequence polymorphism in acetylcholinesterase transcripts and genotyping survey of BmAChE1 in laboratory and Mexican strains of Rhipicephalus (Boophilus) microplus  

Technology Transfer Automated Retrieval System (TEKTRAN)

BmAChE1, BmAChE2, and BmAChE3 cDNAs of Rhipicephalus (Boophilus) microplus were sequenced and found to exhibit significant polymorphism. A portion of the predicted amino acid substitutions in BmAChE1, BmAChE2 and BmAChE3 were found predominantly in organophosphate-resistant (OP-R) strains, but most ...

192

Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain.  

PubMed

A high throughput screening was carried out in order to search for inhibitors of acetylcholinesterase (AChE) from microorganism metabolites. An actinomycete strain was found to produce active compounds named N98-1272 A, B and C with IC50 of 15.0, 11.5, 12.5 microM, respectively. Structural studies revealed that the three compounds are identical to the known antibiotics, Manumycin C, B and A. Kinetic analyses showed that N98-1272 C (Manumycin A) acted as a reversible noncompetitive inhibitor of acetylcholinesterase, with a Ki value of 7.2 microM. The cyclohexenone epoxide part of the structure plays a crucial role in the inhibitory activity against AChE. Compared with Tacrine, N98-1272 A, B, and C exhibit much better selectivity toward AChE over BuChE. PMID:17373546

Zheng, Zhi-Hui; Dong, Yue-Sheng; Zhang, Hua; Lu, Xin-Hua; Ren, Xiao; Zhao, Guiyu; He, Jian-Gong; Si, Shu-Yi

2007-02-01

193

The use of zebrafish mutants to identify secondary target effects of acetylcholine esterase inhibitors.  

PubMed

We are confronted with a large and steadily growing number of bioactive compounds, including drugs, pesticides, and industrial by-products. The assessment of target specificity and potential toxic effect on human health and the environment generates a strong demand for robust and cost-effective models with high predictive power. We investigated the potential of the zebrafish embryo as a whole organism, vertebrate model to assess the specificity of compounds that are known to inhibit acetylcholinesterase (AChE). Inhibitors of AChE are widely used as drugs and pesticides. By application of simple assays and comparison with the phenotype of embryos with genetic lesions in the ache gene, we demonstrate that only one of the AChE inhibitors (galanthamine) reproduces the phenotype of ache mutant embryos. The other compounds produced additional effects indicating secondary targets. Our work demonstrates the power of a genetic system for toxicological evaluations. The combination of genetics and transgenesis with the other experimental virtues of the zebrafish embryo, such as small size and low cost, offers a whole organism platform for medium to high throughput compound testing. PMID:14657522

Behra, Martine; Etard, Christelle; Cousin, Xavier; Strähle, Uwe

2003-12-02

194

Kinetic inhibitor of hydrate crystallization.  

PubMed

We present the results of a combined theoretical/experimental study into a new class of kinetic inhibitor of gas hydrate formation. The inhibitors are based on quaternary ammonium zwitterions, and were identified from a computational screen. Molecular dynamics simulations were used to characterize the effect of the inhibitor on the interface between a type II hydrate and natural gas. These simulations show that the inhibitor is bifunctional, with the hydrophobic end being compatible with the water structure present at the hydrate interface, while the negatively charged functional group promotes a long ranged water structure that is inconsistent with the hydrate phase; the sulfonate-induced structure was found to propagate strongly over several solvation shells. The compound was subsequently synthesized and used in an experimental study of both THF and ethane hydrate formation, and was shown to have an activity that was comparable with an existing commercial kinetic inhibitor: PVP. PMID:14759217

Storr, Mark T; Taylor, Paul C; Monfort, Jean-Pierre; Rodger, P Mark

2004-02-11

195

Bioassay- and liquid chromatography/mass spectrometry-guided acetylcholinesterase inhibitors from Picriafel-terrae  

PubMed Central

Background: Picria fel-terrae is a traditional Chinese medicine. Materials and Methods: A new approach to the search for acetylcholinesterase (AChE) inhibitors from Picria fel-terrae is presented. Results: Bioassay- and LC-MS-guided fractionation of the ethyl acetate extract was from traditional Chinese medicine P.fel-terrae. Following primary extraction, the ethyl acetate extracts fraction of P.fel-terrae showed strong AChE inhibitory activities. So the sample was separated using highperformance liquid chromatography (HPLC). The effluent was split towards two identical 96-well fraction collectors, and the presence of the biologically interesting portion and chromatographic fractions could be readily detected by analyzing selected ion chromatograms through an electrophoresis-electrospray ionization mass spectrometry (ESIMS) system for accurate mass measurement. One 96-well plate was used for a bioassay (AChE-inhibitory assay) and detected the bioactivity and position of the relevant peak in the chromatogram. The positive well in the second 96-well plate was used for identification by LC-(+) ESIMS. Conclusion: As abovementioned, the AChE inhibitory constituents from P.fel-terrae by LC-bioassay-ESIMS were rapid identified. Liquid chromatography/ mass spectrometry (LC-MS) screening detected the presence of six active compounds, identified as picfeltarraenin IA (1), picfeltarraenin IB (2), picfeltarraenin IV (3), picfeltarraenin X (4), picfeltarraenin XI (5), and one unknown compound. The structures were further determined by 13C NMR. The six compounds expressed stronger AChE inhibition than the known AChE inhibitorTacrine. Above all, the value of this LC-bioassay-ESIMS methodology is highlighted by the finding and structure elucidation of the active constituents from many other structural families of natural products.

Wen, Lu; Wei, Qiqiu; Chen, Gang; Liu, Fan; Zhang, Shichang; You, Tinghuo

2013-01-01

196

Agonist mediated internalization of M2 mAChR is ?-arrestin-dependent  

PubMed Central

Background Muscarinic acetylcholine receptors (mAChRs) undergo agonist-promoted internalization, but evidence suggesting that the mechanism of internalization is ?-arrestin dependent has been contradictory and unclear. Previous studies using heterologous over-expression of wild type or dominant-negative forms of ?-arrestins have reported that agonist-promoted internalization of M2 mAChRs is a ?-arrestin- and clathrin-independent phenomenon. In order to circumvent the complications associated with the presence of endogenous ?-arrestin that may have existed in these earlier studies, we examined agonist-promoted internalization of the M2 mAChR in mouse embryonic fibroblasts (MEFs) derived from ?-arrestin knockout mice that lack expression of either one or both isoforms of ?-arrestin (?-arrestin 1 and 2). Results In wild type MEF cells transiently expressing M2 mAChRs, 40% of surface M2 mAChRs underwent internalization and sorted into intracellular compartments following agonist stimulation. In contrast, M2 mAChRs failed to undergo internalization and sorting into intracellular compartments in MEF ?-arrestin double knockout cells following agonist stimulation. In double knockout cells, expression of either ?-arrestin 1 or 2 isoforms resulted in rescue of agonist-promoted internalization. Stimulation of M2 mAChRs led to a stable co-localization with GFP-tagged ?-arrestin within endocytic structures in multiple cell lines; the compartment to which ?-arrestin localized was determined to be the early endosome. Agonist-promoted internalization of M2 mAChRs was moderately rescued in MEF ?-arrestin 1 and 2 double knockout cells expressing exogenous arrestin mutants that were selectively defective in interactions with clathrin (?-arrestin 2 ?LIELD), AP-2 (?-arrestin 2-F391A), or both clathrin/AP-2. Expression of a truncated carboxy-terminal region of ?-arrestin 1 (319–418) completely abrogated agonist-promoted internalization of M2 mAChRs in wild type MEF cells. Conclusion In summary, this study demonstrates that agonist-promoted internalization of M2 mAChRs is ?-arrestin- and clathrin-dependent, and that the receptor stably co-localizes with ?-arrestin in early endosomal vesicles.

Jones, Kymry T; Echeverry, Maria; Mosser, Valerie A; Gates, Alicia; Jackson, Darrell A

2006-01-01

197

A Toxicological Evaluation of Certain Heparin-Quaternary Ammonium Complexes.  

National Technical Information Service (NTIS)

Physical and chemical characterizations show that the heparin-quaternary ammonium salt complexes can be reproducibly prepared from a given lot of a quaternary ammonium salt. Local toxicity studies also indicate that both the tridodecyl methyl ammonium chl...

G. A. Grode J. P. Crowley R. D. Falb R. I. Leininger

1974-01-01

198

Bacterial metabolism of quaternary ammonium compounds.  

PubMed Central

Of 10 quaternary ammonium compounds tested for biodegradation by the biological oxygen demand technique, only decyl- and hexadecyltrimethylammonium bromides were decomposed by organisms derived from sewage and soil. A mixture consisting of individual strains of Pseudomonas and Xanthomonas grew in solutions containing decyltrimethylammonium bromide as sole carbon source. The xanthomonad metabolized this quaternary ammonium compound in the presence of other organic molecules. The products of this activity included 9-carboxynomyl- and 7-carboxyheptyltrimethylammonium, suggesting that the terminal carbon of the decyl moiety is oxidized and the resulting carboxylic acid is subject to beta-oxidation.

Dean-Raymond, D; Alexander, M

1977-01-01

199

Quaternary Marine Sulfur Cycle Dynamics  

NASA Astrophysics Data System (ADS)

Published data show a -0.8% change in marine sulfate ?34S ratios in the past 2 Ma. Prior to this period it was stable at ~ 22% for ~ 50Ma since the Eocene. Compared to the residence time of sulfate (>10 Ma) the observed change is large and implies a major disturbance of the marine sulfur cycle. However, the cause of the disturbance, as well as the timing of its onset are poorly constrained. Here we present a new set of ?34S ratios of marine sulfate for the last 3 Ma with a temporal resolution of ~300ka, which shows a linear decline from 22 to ~21% in the past 1.75Ma. This may represent a change in volcanic and hydrothermal activity, pyrite burial or erosion and weathering of exposed evaporites and sulfides, which are the main processes affecting sulfate ?34S. However, during this period there is no geological evidence for exceptional volcanic and hydrothermal activity and consequently, the observed negative shift reflects either a change in isotopic composition and volume of erosional input of sulfate to the ocean, or a decrease in pyrite burial. The isotopic composition of the input flux depends on the relative proportion of sulfide vs. sulfate weathering. Sedimentary sulfides are mostly concentrated in organic rich sediments on continental shelves. Existing sea level records suggest periodic sea level drops during glacial stages related to the formation of ice sheets. This could affect sulfur cycling in two ways: a) exposure to surface weathering and erosion agents of large parts of continental shelves increased global sulfide oxidation and thus the input flux of sulfate to the ocean and/or b) the reduction of shelf areas resulted in decreased pyrite burial. We explore the effects of these changes with a simple box model. The modeling results indicate that the observed isotopic shift requires a 150% increase of pyrite weathering or a 90% reduction of pyrite burial over the past 1.75Ma. When both of these processes change in concert the same effect is produced with the doubling of pyrite weathering and 50% decrease of pyrite burial. As pyrite burial and organic matter burial are intimately linked, a drastic decrease in pyrite burial should leave its mark in the carbon isotopic record which shows no evidence of a major change in carbon cycling. We thus propose that increased sulfide weathering, either from subaerial exposure, or as a result of increased winnowing might be the principal cause of the negative ?34S shift in the Quaternary.

Markovic, S.; Paytan, A.; Wortmann, U. G.

2011-12-01

200

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

Code of Federal Regulations, 2013 CFR

...2013-07-01 false Tricyclic quaternary amine salt (generic). 721.10569 Section 721...721.10569 Tricyclic quaternary amine salt (generic). (a) Chemical substance...generically as tricyclic quaternary amine salt (PMN P-08-471) is subject to...

2013-07-01

201

Porphyrin derivatives as inhibitors for acetylcholinesterase from Drosophila melanogaster.  

PubMed

The cure for Alzheimer's disease (AD) is still unknown. According to Cholinergic hypothesis, Alzheimer's disease is caused by the reduced synthesis of the neurotransmitter, Acetylcholine. Regional cerebral blood flow can be increased in patients with Alzheimer's disease by Acetylcholinesterase (AChE) inhibitors. In this regard, Tetraphenylporphinesulfonate (TPPS), 5,10,15,20- Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) Chloride (FeTPPS) and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinatoIron(III) nitrosyl Chloride (FeNOTPPS) were investigated as candidate compounds for inhibition of Acteylcholinesterase of Drosophila melanogaster (DmAChE) by use of Molecular Docking. The results show that FeNOTPPS forms the most stable complex with DmAChE. PMID:23904743

Hai, Abdul; Kizilbash, Nadeem A; Zaidi, Syedahuma H; Alruwaili, Jamal

2013-07-12

202

Bis(12)-hupyridone, a novel multifunctional dimer, promotes neuronal differentiation more potently than its monomeric natural analog huperzine A possibly through ?7 nAChR.  

PubMed

The cause of many neurodegenerative disorders can be ascribed to the loss of functional neurons, and thus agents capable of promoting neuronal differentiation may have therapeutic benefits to patients of these disorders. In this study, the effects and underlying mechanisms of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase inhibitor modified from huperzine A (HA), on neuronal differentiation were investigated using both the rat PC12 pheochromocytoma cell line and adult rat hippocampus neural stem cells. B12H (3-30 ?M), characterized by morphological changes and expression of GAP-43, induced neurite outgrowth in a concentration- and time-dependent manner, with almost 3-fold higher efficacy than that of HA in PC12 cells. Furthermore, B12H (2.5-10 ?M), but not HA, promoted neuronal differentiation as shown by the percentage increase of ?III-tubulin positive neurons in neural stem cells. The activities of extracellular signal-regulated kinase (ERK), as well as its downstream transcription factors Elk-1 and cAMP response element-binding protein (CREB) were elevated in the B12H-treated PC12 cells. Mitogen-activated protein kinase kinase inhibitors and alpha7-nicotinic acetylcholine receptor (?7nAChR) antagonist blocked the neurite outgrowth and the activation of ERK induced by B12H. All these findings suggest that B12H potently induces pro-neuronal cells into differentiated neurons by activating the ERK pathway possibly via regulating ?7nAChR. These findings support the recent proposition that ?7nAChR is required for the neuronal dendritic arborization and differentiation in the adult mice hippocampus, and provide insights into the possible therapeutic potential of B12H in treating neurodegenerative disorders. PMID:21665194

Cui, Wei; Cui, Guo-Zhen; Li, Wenming; Zhang, Zaijun; Hu, Shengquan; Mak, Shinghung; Zhang, Huan; Carlier, Paul R; Choi, Chung-Lit; Wong, Yi-Tao; Lee, Simon Ming-Yuen; Han, Yifan

2011-05-25

203

High Throughput Enzyme Inhibitor Screening by Functionalized Magnetic Carbonaceous Microspheres and Graphene Oxide-Based MALDI-TOF-MS  

NASA Astrophysics Data System (ADS)

In this work, a high throughput methodology for screening enzyme inhibitors has been demonstrated by combining enzyme immobilized magnetic carbonaceous microspheres and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with grapheme oxide as matrix. First, model enzyme acetylcholinesterase (AChE) was immobilized onto the 3-glycidoxypropyltrimethoxysilane (GLYMO)-modified magnetic carbonaceous (MC) microspheres, displaying a high enzyme activity and stability, and also facilitating the separation of enzyme from substrate and product. The efficiency of immobilized AChE was monitored by biochemical assay, which was carried out by mixing enzyme-immobilized MC microspheres with model substrate acetylcholine (ACh), and subsequent quantitative determination of substrate ACh and product choline using graphene oxide-based MALDI-TOF-MS with no background inference. The limit of detection (LOD) for ACh was 0.25 fmol/?L, and excellent linearity (R2 = 0.9998) was maintained over the range of 0.5 and 250 fmol/?L. Choline was quantified over the range of 0.05 and 15 pmol/?L, also with excellent linearity (R2 = 0.9994) and low LOD (0.15 fmol/?L). Good accuracy and precision were obtained for all concentrations within the range of the standard curves. All together, eight compounds (four known AChE inhibitors and four control chemical compounds with no AChE inhibit effect) were tested with our promoted methodology, and the obtained results demonstrated that our high throughput screening methodology could be a great help to the routine enzyme inhibitor screening.

Liu, Yang; Li, Yan; Liu, Junyan; Deng, Chunhui; Zhang, Xiangmin

2011-12-01

204

Chemical Chaperones Exceed the Chaperone Effects of RIC-3 in Promoting Assembly of Functional ?7 AChRs  

PubMed Central

Functional ?7 nicotinic acetylcholine receptors (AChRs) do not assemble efficiently in cells transfected with ?7 subunits unless the cells are also transfected with the chaperone protein RIC-3. Despite the presence of RIC-3, large amounts of these subunits remain improperly assembled. Thus, additional chaperone proteins are probably required for efficient assembly of ?7 AChRs. Cholinergic ligands can act as pharmacological chaperones to promote assembly of mature AChRs and upregulate the amount of functional AChRs. In addition, we have found that the chemical chaperones 4-phenylbutyric acid (PBA) and valproic acid (VPA) greatly increase the amount of functional ?7 AChRs produced in a cell line expressing both ?7 and RIC-3. Increased ?7 AChR expression allows assay of drug action using a membrane potential-sensitive fluorescent indicator. Both PBA and VPA also increase ?7 expression in the SH-SY5Y neuroblastoma cell line that endogenously expresses ?7 AChRs. VPA increases expression of endogenous ?7 AChRs in hippocampal neurons but PBA does not. RIC-3 is insufficient for optimal assembly of ?7 AChRs, but provides assay conditions for detecting additional chaperones. Chemical chaperones are a useful pragmatic approach to express high levels of human ?7 AChRs for drug selection and characterization and possibly to increase ?7 expression in vivo.

Kuryatov, Alexander; Mukherjee, Jayanta; Lindstrom, Jon

2013-01-01

205

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

PubMed Central

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 ? 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.

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

2008-01-01

206

Hippocampal nAChRs Mediate Nicotine Withdrawal-Related Learning Deficits  

PubMed Central

Nicotine modulation of learning may contribute to its abuse liability. The role of hippocampal nicotinic acetylcholine receptors (nAChRs) in the effects of acute, chronic and withdrawal from chronic nicotine on learning was assessed via intrahippocampal drug infusion in mice. Acute dorsal hippocampal nicotine infusion enhanced contextual fear conditioning. Conversely, chronic intrahippocampal infusion of a matched dose had no effect, and withdrawal from chronic infusion impaired learning. Thus, hippocampal functional adaptation, evidenced by learning deficits during abstinence, occurs with the transition from acute to chronic nicotine exposure. To investigate which hippocampal nAChRs mediate these adaptations, C57BL/6, ?2 nAChR subunit knockout (KO), and wildtype (WT) mice treated chronically with systemic nicotine received intrahippocampal dihydro-?-erythroidine (a high affinity nAChR antagonist). Intrahippocampal dihydro-?-erythroidine precipitated learning deficits in all but the KO mice. Therefore, the action of nicotine at hippocampal ?2* nAChRs mediates adaptations in hippocampal function that underlie withdrawal deficits in contextual fear conditioning.

Davis, Jennifer A.; Gould, Thomas J.

2009-01-01

207

Further studies on the control of ACh sensitivity by muscle activity in the rat.  

PubMed Central

1. Denervated rat soleus muscles were stimulated directly through chronically implanted electrodes and the influence of different amounts and patterns of stimuli on the acetylcholine (ACh) sensitivity of the muscle was studied. The number of stimuli was varied by giving similar trains of stimuli (10 Hz for 10 sec) at different intervals (0 to 12 hr). The pattern of stimulation was varied by giving different trains of stimuli (100 Hz for 1 sec, 10 Hz for 10 sec and 1 Hz continuously) as the same average frequency of stimulation (1 Hz). 2. Stimulation usually started 5 days after the denervation when ACh hypersensitivity was fully developed. Most stimulation procedures reduced extrajunctional ACh sensitivity to normal or below normal values within 5-21 days, and these levels were maintained on prolonged stimulation. 3. The rate at which ACh hypersensitivity disappeared increased with increasing amount and frequency of stimulation. However, as few as 100 stimuli given every 5-5 hr for 3 weeks caused a tenfold reduction of sensitivity. 4. The stimulation had little or no effect on the ACh sensitivity at the end plate. Along the rest of the fibre the sensitivity was reduced at approximately the same rate except near the tendons where it appeared to fall more slowly in some fibres. 5. The stimulation restored the resting membrane potential of the denervated fibres to normal.

Lomo, T; Westgaard, R H

1975-01-01

208

Quaternary cave levels in peninsular Florida  

Microsoft Academic Search

The hypothesis that caves in the Florida Peninsula are tied to Quaternary sea levels was proposed by hydrogeologists, without data, some 40 years ago. The hypothesis is a version of glacial control of cave levels, which is the logical combination of the water-table theory of speleogenesis and the concept that base level positions the water table. At the USA type

Lee J. Florea; H. L. Vacher; Brian Donahue; David Naar

2007-01-01

209

Quaternary glaciation of the Himalaya and Tibet  

Microsoft Academic Search

Glacial geological evidence from throughout the Himalaya-Tibet shows the existence of expanded ice caps and extensive valley glacier systems during the late Quaternary. Whether the timing of the extent of maximum glaciation was synchronous throughout the entire region or whether the response was more varied is a topic of much contention. This is mainly because the lack of organic material

L. A. Owen

2008-01-01

210

Differential Densities of Muscarinic Acetylcholine Receptor and IK,ACh in Canine Supraventricular Tissues and the Effect of Amiodarone on Cholinergic Atrial Fibrillation and IK,ACh  

Microsoft Academic Search

Background: Vagal nerve plays an important role in the induction and maintenance of atrial fibrillation (AF). This study investigated the differential densities of M2 receptor and acetylcholine-induced inward rectifier K+ current (IK,ACh) in atrial appendage, atrium, pulmonary vein (PV) and super vena cava (SVC) to discuss the role of atrial appendage and PV in cholinergic AF. Methods and Results: In

Cong-Xin Huang; Qing-Yan Zhao; Jin-Jun Liang; Hui Chen; Bo Yang; Hong Jiang; Geng-Shan Li

2006-01-01

211

Discrimination of agonists versus antagonists of nicotinic ligands based on docking onto AChBP structures.  

PubMed

Numerous high-resolution crystallographic structures of the acetylcholine binding protein (AChBP), a molluscan cholinergic protein, homologous to the extracellular domain of nicotinic acetylcholine receptors, are available. This offers opportunities to model the interaction between various ligands and the acetylcholine binding site. Herein we present a study of the interplay between ligand binding and motions of the C-loop capping the binding site. Nicotinic agonists and antagonists were docked on AChBP X-ray structures. It is shown that the studied agonists and antagonists can be discriminated according to their higher affinities for structures respectively obtained in the presence of agonists or antagonists, highlighting the fact that AChBP structures retain a pharmacological footprint of the compound used in crystallography experiments. A detailed analysis of the binding site cavities suggests that this property is mainly related to the shape of the cavities. PMID:21764343

Taly, Antoine; Colas, Claire; Malliavin, Thérèse; Blondel, Arnaud; Nilges, Michael; Corringer, Pierre-Jean; Joseph, Delphine

2011-06-29

212

Tumor necrosis factor reduces the ACh-induced outward current in identified Aplysia neurons.  

PubMed

Effects of extracellularly applied recombinant human tumor necrosis factor (rhTNF) on the acetylcholine (ACh)-induced K+ current recorded from identified neurons (R9 and R10) of Aplysia kurodai were investigated with conventional voltage-clamp and pressure ejection techniques. Bath-applied rhTNF (200-500 U/ml) reduced the ACh-induced current in the neurons without affecting the holding current and resting membrane conductance. The suppressing effect of rhTNF on the current was completely reversible. Inhibition by rhTNF was non-competitive. Heat-inactivated rhTNF was without effect. Our results suggest that the immunomodulator TNF can act on the ACh receptor in the nervous system. PMID:1722298

Sawada, M; Hara, N; Maeno, T

1991-10-14

213

Impairment of endothelium-dependent ACh-induced relaxation in aorta of diabetic db/db mice--possible dysfunction of receptor and/or receptor-G protein coupling.  

PubMed

Diabetes is a risk factor of ischemic heart disease, cerebral ischemia, and atherosclerosis, in which endothelial dysfunction plays a role in the pathogenesis. We examined vascular responses in the aorta of pre-diabetic db/db mice with normoglycemia, hyperlipidemia, and hyperinsulinemia (6 weeks old), and diabetic db/db mice with hyperglycemia, hyperlipidemia, and hyperinsulinemia (11 weeks old) in comparison with age-matched non-diabetic db/+ mice. Prostaglandin F2alpha (PGF2alpha)-induced contraction was significantly enhanced in the aorta of diabetic but not pre-diabetic db/db mice compared to age-matched non-diabetic db/+ mice. Acetylcholine (ACh), adenosine-5'-diphosphate (ADP), NaF, a G protein activator and A-23187, a Ca-ionophore, caused endothelium-dependent and nitric oxide (NO)-mediated relaxation, and sodium nitroprusside (SNP), an NO donor, caused endothelium-independent relaxation in the pre-contracted aorta of db/db mice. Maximal endothelium-dependent ACh-induced relaxation was reduced in diabetic but not pre-diabetic db/db mice compared to age-matched db/+ mice, while maximal SNP-induced relaxation was not different between diabetic and non-diabetic mice. ACh-induced relaxation in diabetic db/db mice was not affected by ozagrel, a thromboxane A2 (TXA2) synthetase inhibitor, or acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor, suggesting no involvement of endogenous TXA2 or prostanoids in the reduction of relaxation. Maximal endothelium-dependent ADP-, A-23187-, and NaF-induced relaxation was not reduced in diabetic db/db mice. EC50 values for ACh- and SNP-induced relaxation were increased in diabetic but not pre-diabetic db/db mice, suggesting decreases in sensitivity to NO in diabetic mice. Two-week treatment with KV-5070, a PPARgamma agonist, lowered plasma glucose, triglyceride (TG), and insulin but not cholesterol, and reversed the reduced ACh-induced relaxation. In conclusion, ACh-induced endothelium-dependent relaxation is impaired in diabetic db/db mice, probably due to the dysfunction of ACh receptors and/or receptor-G protein coupling. Endothelial dysfunction was not genetic and was considered to be initiated primarily by hyperglycemia, and was improved by anti-diabetic treatment with a PPARgamma agonist. PMID:18228001

Miike, Tomohiro; Kunishiro, Kazuyoshi; Kanda, Mamoru; Azukizawa, Satoru; Kurahashi, Kazuyoshi; Shirahase, Hiroaki

2008-01-29

214

Prefrontal ?2 subunit-containing and ?7 nAChRs differentially control glutamatergic and cholinergic signaling  

PubMed Central

Second-long increases in prefrontal cholinergic activity (“transients”) were previously demonstrated to be necessary for the incorporation of cues into ongoing cognitive processes ("cue detection"). Nicotine and, more robustly, selective agonists at ?4?2* nicotinic acetylcholine receptors (nAChRs), enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of ?2-containing and ?7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the ?4?2* nAChR agonist ABT-089 or the ?7 nAChR agonist A-582941. Transients were recorded in mice lacking ?2 or ?7 nAChRs and in rats following removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of ?4?2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking ?2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by ?2* knockout. Conversely, in mice lacking the ?7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of ?7 nAChR in controlling the duration of release events, stimulation of ?7 nAChR produced cholinergic transients that lasted 10–15 fold longer than those evoked by nicotine. ?7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal ?4?2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance.

Parikh, Vinay; Ji, Jinzhao; Decker, Michael W.; Sarter, Martin

2010-01-01

215

Design, synthesis, biological evaluation and docking study of 5-oxo-4,5-dihydropyrano[3,2-c]chromene derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors.  

PubMed

A series of fused coumarins namely 5-oxo-4,5-dihydropyrano[3,2-c]chromenes linked to N-benzylpyridinium scaffold were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The 1-(4-fluorobenzyl)pyridinium derivative 6g showed the most potent anti-AChE activity (IC50 value = 0.038 ?M) and the highest AChE/BuChE selectivity (SI > 48). The docking study permitted us to rationalize the observed structure-affinity relationships and to detect possible binding modes. PMID:23988409

Khoobi, Mehdi; Alipour, Masoumeh; Sakhteman, Amirhossein; Nadri, Hamid; Moradi, Alireza; Ghandi, Mehdi; Emami, Saeed; Foroumadi, Alireza; Shafiee, Abbas

2013-08-11

216

Age-dependency in hunting ability among the Ache of Eastern Paraguay  

Microsoft Academic Search

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

Robert Walker; Kim Hill; Hillard Kaplan; Garnett McMillan

2002-01-01

217

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

PubMed Central

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 ?4?2* 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 ?4?2* 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.

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

2009-01-01

218

Optogenetic Release of ACh Induces Rhythmic Bursts of Perisomatic IPSCs in Hippocampus  

Microsoft Academic Search

Acetylcholine (ACh) influences a vast array of phenomena in cortical systems. It alters many ionic conductances and neuronal firing behavior, often by regulating membrane potential oscillations in populations of cells. Synaptic inhibition has crucial roles in many forms of oscillation, and cholinergic mechanisms regulate both oscillations and synaptic inhibition. In vitro investigations using bath-application of cholinergic receptor agonists, or bulk

Daniel A. Nagode; Ai-Hui Tang; Miranda A. Karson; Matthias Klugmann; Bradley E. Alger

2011-01-01

219

Efficient cellulose solvent: quaternary ammonium chlorides.  

PubMed

Pure quaternary tetraalkylammonium chlorides with one long alkyl chain dissolved in various organic solvents constitute a new class of cellulose solvents. The electrolytes are prepared in high yields and purity by Menshutkin quaternization, an inexpensive and easy synthesis route. The pure molten tetraalkylammonium chlorides dissolve up to 15 wt% of cellulose. Cosolvents, including N,N-dimethylacetamide (DMA), may be added in large excess, leading to a system of decreased viscosity. Contrary to the well-established solvent DMA/LiCl, cellulose dissolves in DMA/quaternary ammonium chlorides without any pretreatment. Thus, the use of the new solvent avoids some disadvantages of DMA/LiCl and ionic liquids, the most extensively employed solvents for homogeneous cellulose chemistry. PMID:24014114

Kostag, Marc; Liebert, Tim; El Seoud, Omar A; Heinze, Thomas

2013-09-09

220

Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating agents.  

PubMed

A series of novel indanone derivatives was designed, synthesised and evaluated as potential agents for Alzheimer's disease. Among them, compound 6a, with a piperidine group linked to indone by a two-carbon spacer, exhibited the most potent inhibitor activity, with an IC(50) of 0.0018 ?M for AChE; the inhibitory activity of this compound was 14-fold more potent than that of donepezil. Furthermore, these compounds also exhibited good metal-chelating ability. PMID:22633691

Meng, Fan-Chao; Mao, Fei; Shan, Wen-Jun; Qin, Fangfei; Huang, Ling; Li, Xing-Shu

2012-04-13

221

Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis  

Microsoft Academic Search

Synaptic loss, particularly related to the forebrain cholinergic system, is considered to be an early event that leads to\\u000a Alzheimer’s disease (AD) and has led to the development of acetylcholinesterase inhibitors (AChE-Is) as the mainstay of treatment\\u000a for several degenerative disorders that culminate in dementia. The primary dose-limiting toxicities of all clinically available\\u000a AChE-Is are, similar to useful actions on

Mohammad A. Kamal; Xianqin Qu; Qian-sheng Yu; David Tweedie; Harold W. Holloway; Yazhou Li; Yi Tan; Nigel H. Greig

2008-01-01

222

Quaternary glaciations in the Northern Hemisphere  

SciTech Connect

This volume presents the final report of Project 24 of the International Geological Correlation Programme. The publication is drawn from the contributions of leading individual scientist as well as from scientific research teams. It reflects the present state of knowledge of the Quaternary Glaciations in the Northern Hemisphere and their correlation in space and time, as well as providing a unique summary of climatic change.

Sibrava, V.; Bowen, D.Q.; Richmond, G.M.

1987-01-01

223

Quaternary phylogeography: the roots of hybrid zones  

Microsoft Academic Search

The older history of hybrid zones is explored through consideration of recent advances in climatology, paleontology and phylogeography\\u000a in the Late Cenozoic, particularly the Quaternary Period with its major climatic cycles. The fossil record shows that these\\u000a ice ages and their nested millennial oscillations caused substantial changes in species distributions and with genetic evidence\\u000a allows deduction of refugia and colonization

Godfrey M. Hewitt

2011-01-01

224

Hydration effects in quaternary amine extraction systems  

Microsoft Academic Search

The extraction of Al+++, Cd++, Co++, Cu+, Cu++, Fe++, Fe+++, In+++, Ni++, and Zn++ with quaternary amine was studied using chloride and sulfate as ligands. On the basis of loading experiments and slope analyses, the species extracted were: CdCl{4\\/=}, CoCl{4\\/=}, CuCl{2\\/-}, CuCl{4\\/=}, FeCl{4\\/-}, and ZnCl{4\\/=}. Water content of the organic phase was analyzed as a function of loading by Karl

J. D. Miller; M. C. Fuerstenau

1970-01-01

225

Hydration effects in quaternary amine extraction systems  

Microsoft Academic Search

The extraction of Al+++, Cd++, Co++, Cu+, Cu++, Fe++, Fe+++, In+++, Ni++, and Zn++ with quaternary amine was studied using chloride and sulfate as ligands. On the basis of loading experiments and slope analyses,\\u000a the species extracted were: CdCl4=, CoCl4=, CuCl2?, CuCl4=, FeCl4?, and ZnCl4=. Water content of the organic phase was analyzed as a function of loading by Karl

J. D. Miller; M. C. Fuerstenau

1970-01-01

226

In situ formation of metal coordination polymer: a strategy for fluorescence turn-on assay of acetylcholinesterase activity and inhibitor screening.  

PubMed

A novel method for the sensing of acetylcholinesterase (AChE) activity and inhibitor screening based on the formation of metal coordination polymer has been developed. Acetylthiocholine (ATCh) was selected as the substrate. In the presence of AChE, ATCh was hydrolyzed to thiocholine and acetate. Thiocholine interacted with Ag(I) to form a metal coordination polymer. A positively charged perylene probe (probe 1) was employed. The fluorescence of probe 1 was very efficiently quenched by a polyanion [PVS, poly(vinyl sulfonate)]. In the presence of acetylcholinesterase, the positively charged metal coordination polymer newly formed in situ would interact with PVS, probe 1 monomer molecules were released, and a turn on fluorescence signal was detected. The assay is highly sensitive, a limit of detection of 0.04 mU/mL AChE was obtained. The assay is also highly selective, a number of potential interference proteins (enzymes) were tested, and none of them show noticeable interference. Sensing of AChE inhibitor was also demonstrated. Our assay is fairly simple and inexpensive. We envision that it could be used for the sensitive detection of other hydrolytic enzyme activities with properly selected substrates and for the screening of potential inhibitor drugs. PMID:23379662

Liao, Dongli; Chen, Jian; Zhou, Huipeng; Wang, Yan; Li, Yongxin; Yu, Cong

2013-02-18

227

Corrosion inhibition of iron in acidic solutions by alkyl quaternary ammonium halides: Correlation between inhibition efficiency and molecular structure  

Microsoft Academic Search

The corrosion inhibition of iron in 0.5M H2SO4 solutions by alkyl quaternary ammonium halides (AQAH) inhibitors has been studied by potentiodynamic polarization curves and electrochemical impedance spectroscopy (EIS) measurements. The correlation between inhibition efficiency and molecular structure of the AQAH compounds is investigated. The results show that besides the concentration, the structure of alkyl groups and the type of halide

Lin Niu; Hu Zhang; Fenghua Wei; Suxiang Wu; Xiaoli Cao; Pengpeng Liu

2005-01-01

228

Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR.  

PubMed

2,5-disubstituted tetrahydrofuran derivatives display a dual functionality: they are PAF antagonists and acetylcholinesterase (AChE) inhibitors. In vitro anti-AChE activity and in vivo trials are presented herein. These compounds are competitive and potent AChE inhibitors. Structure-activity relationships are described and compared with PAF-antagonist results. The presence of an onium group, a suitable distance supplied by a chain of 7 or 10 carbon atoms separating the function from the polar head and an appreciable chain hydrophobicity (4 < sigma f < 7) are the main features required for a dual activity. The derivatives are evaluated in a mouse passive avoidance model. Only compounds with both activities are able to reverse scopolamine-induced amnesia. In addition, they display a very weak toxicity. PMID:8816985

Le Texier, L; Favre, E; Ronzani, N; Massicot, F; Blavet, N; Pirotzky, E; Godfroid, J J

1996-05-01

229

Mycorrhiza helper bacterium Streptomyces AcH 505 induces differential gene expression in the ectomycorrhizal fungus Amanita muscaria  

Microsoft Academic Search

Summary • The interaction between the mycorrhiza helper bacteria Streptomyces nov. sp. 505 (AcH 505) and Streptomyces annulatus 1003 (AcH 1003) with fly agaric ( Amanita muscaria ) and spruce ( Picea abies ) was investigated. • The effects of both bacteria on the mycelial growth of different ectomycorrhizal fungi, on ectomycorrhiza formation, and on fungal gene expression in dual

Silvia D. Schrey; Michael Schellhammer; Margret Ecke; Rüdiger Hampp; Mika T. Tarkka

2005-01-01

230

In situ click chemistry: enzyme inhibitors made to their own specifications.  

PubMed

The in situ click chemistry approach to lead discovery employs the biological target itself for assembling inhibitors from complementary building block reagents via irreversible connection chemistry. The present publication discusses the optimization of this target-guided strategy using acetylcholinesterase (AChE) as a test system. The application of liquid chromatography with mass spectroscopic detection in the selected ion mode for product identification greatly enhanced the sensitivity and reliability of this method. It enabled the testing of multicomponent mixtures, which may dramatically increase the in situ screening throughput. In addition to the previously reported in situ product syn-TZ2PA6, we discovered three new inhibitors, syn-TZ2PA5, syn-TA2PZ6, and syn-TA2PZ5, derived from tacrine and phenylphenanthridinium azides and acetylenes, in the reactions with Electrophorus electricus and mouse AChE. All in situ-generated compounds were extremely potent AChE inhibitors, because of the presence of multiple sites of interaction, which include the newly formed triazole nexus as a significant pharmacophore. PMID:15469276

Manetsch, Roman; Krasi?ski, Antoni; Radi?, Zoran; Raushel, Jessica; Taylor, Palmer; Sharpless, K Barry; Kolb, Hartmuth C

2004-10-13

231

Design, synthesis and pharmacological evaluation of hybrid molecules out of quinazolinimines and lipoic acid lead to highly potent and selective butyrylcholinesterase inhibitors with antioxidant properties  

Microsoft Academic Search

A set of hybrid molecules were synthesized out of lipoic acid, ?,?-diamines of different lengths serving as spacers, and cholinesterase (ChE) inhibiting [2,1-b]quinazolinimines. Depending on the length of the alkylene spacer the amide hybrids are inhibitors of acetylcholinesterase (AChE) with inhibitory activities of 0.5–4.6?M and inhibitors of butyrylcholinesterase (BChE) with activities down to 5.7nM, therefore greatly exceeding the inhibitory activities

Michael Decker; Birgit Kraus; Jörg Heilmann

2008-01-01

232

QUATERNARY GEOLOGICAL FRAMEWORK OF NORTH-HOLLAND AND THE MARKERMEER  

Microsoft Academic Search

Quaternary geological data are presented as a basis for the extensive geohydrological and geotechnical studies performed to investigate possible harmful effects of the Markerwaard reclamation project.

W. E. Westerhoff

233

Muscle aches  

MedlinePLUS

... Other blood tests to look at muscle enzymes (creatine kinase) and possibly a test for Lyme disease ... Jr, Miller MD, eds. DeLee and Drez’s Orthopaedic Sports Medicine. 3rd ed. Philadelphia, Pa: Saunders Elsevier; 2009: ...

234

Corrosion inhibition of iron in acidic solutions by alkyl quaternary ammonium halides: Correlation between inhibition efficiency and molecular structure  

NASA Astrophysics Data System (ADS)

The corrosion inhibition of iron in 0.5 M H2SO4 solutions by alkyl quaternary ammonium halides (AQAH) inhibitors has been studied by potentiodynamic polarization curves and electrochemical impedance spectroscopy (EIS) measurements. The correlation between inhibition efficiency and molecular structure of the AQAH compounds is investigated. The results show that besides the concentration, the structure of alkyl groups and the type of halide ions of these AQAH inhibitors greatly influence the inhibition efficiency. Data obtained from EIS measurements are analyzed to model the corrosion inhibition process through appropriate equivalent circuit models.

Niu, Lin; Zhang, Hu; Wei, Fenghua; Wu, Suxiang; Cao, Xiaoli; Liu, Pengpeng

2005-12-01

235

Blood pro-inflammatory cytokines in Alzheimer's disease in relation to the use of acetylcholinesterase inhibitors.  

PubMed

OBJECTIVE: A potential anti-inflammatory role for acetylcholinesterase inhibitors (AChEIs) has been supported by animal studies. As very limited data exist from individuals with Alzheimer's disease (AD), the aim of this study was to assess the potential influence of AChEIs on blood pro-inflammatory cytokines. We hypothesized that pro-inflammatory cytokine concentrations were lower in individuals with AD stabilized on AChEIs. METHODS: Blood interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha concentrations were assessed using specific enzyme-linked immunosorbent assays in three groups of participants: patients with AD stabilized on a therapeutic dose of an AChEI (n?=?42); AChEIs drug naïve patients (n?=?24); and a cognitively unimpaired control group (n?=?35). Patients in the AChEIs group had received medication for an average of one year. RESULTS: Patients stabilized on an AChEI did not differ significantly from drug naïve patients in relation to the concentrations of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p?=?0.874, 0.225, and 0.978, respectively). Within the group taking AChEIs, the levels of cytokines did not differ between those taking donepezil, rivastigmine, or galantamine (p?=?0.368, 0.851, and 0.299, respectively). CONCLUSIONS: Results from animal studies suggesting a modulatory anti-inflammatory role for AChEIs was not advanced in this study. In individuals with AD, very limited evidence currently exists to support the hypothesis that AChEIs may influence inflammatory blood markers and function beyond the enhancement of neuronal transmission. However, further studies assessing a wider range of inflammatory markers and processes are still needed before this hypothesis can be ruled out. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23585364

Richardson, Cassandra; Gard, Paul R; Klugman, Anthony; Isaac, Mokhtar; Tabet, Naji

2013-04-14

236

Miniaturized electrochemical system for cholinesterase inhibitor detection.  

PubMed

The utility of a simple, low-cost detection platform for label-free electrochemical characterization of acetylcholinesterase (AChE) inhibition is demonstrated as a potential tool for screening of small-molecule therapeutic agents for Alzheimer's disease (AD). Technique validation was performed against the standard Ellman's colorimetric assay using the clinically established cholinesterase inhibitor (ChEI), Donepezil (Aricept(®)). Electrochemical measurements were obtained by differential pulse voltammetry (DPV) performed using a portable potentiostat system for detection of the enzymatic product, thiocholine (TCh), by direct oxidation on unmodified gold screen-printed electrodes. The IC50 profiles for Donepezil measured in vitro were found to be comparable between both colorimetric and electrochemical detection methods for the analysis of purified human erythrocyte-derived AChE (28±7 nM by DPV; 26±8 nM by Ellman's method). The selectivity of this unmodified electrode system was compared to a range of biological sulfur-containing compounds including cysteine, homocysteine, glutathione and methionine as well as ascorbic acid. Preliminary studies also demonstrated the potential applicability of this electrochemical technique for the analysis of Donepezil in crude cholinesterase samples from anterior cortex homogenates of C57BL/6J mice. PMID:23567119

Veloso, Anthony J; Nagy, Paul M; Zhang, Biao; Dhar, Devjani; Liang, Anqi; Ibrahim, Tarek; Mikhaylichenko, Svetlana; Aubert, Isabelle; Kerman, Kagan

2013-03-13

237

Transient effects during sputtering of a-C:H surfaces by nitrogen ions  

NASA Astrophysics Data System (ADS)

Sputtering of polymer-like amorphous hydrogenated carbon (a-C:H) thin films by 0.5-1 keV N2+ molecular ions has been studied in situ and real-time using a highly sensitive quartz crystal microbalance technique. During bombardment of a fresh, plasma-deposited a-C:H layer with nitrogen ions the measured sputtering yield decreases exponentially with ion fluence until a steady state value is reached at a fluence of typically about 3.5 × 1015 N2+ ions per cm2. A chemical sputtering mechanism has to be considered in addition to physical sputtering to explain the observed steady state sputtering values. Simulations based on the code TRIDYN, which take into account a change of surface composition due to implantation and erosion, are performed to understand the transient development of sputtering yields.

Dobes, K.; Naderer, P.; Hopf, C.; Schwarz-Selinger, T.; Aumayr, F.

2012-09-01

238

Regulation of AChR Clustering by Dishevelled Interacting with MuSK and PAK1  

Microsoft Academic Search

An important aspect of synapse development is the clustering of neurotransmitter receptors in the postsynaptic membrane. Although MuSK is required for acetylcholine receptor (AChR) clustering at the neuromuscular junction (NMJ), the underlying molecular mechanisms remain unclear. We report here that in muscle cells, MuSK interacts with Dishevelled (Dvl), a signaling molecule important for planar cell polarity. Disruption of the MuSK-Dvl

Zhen G. Luo; Qiang Wang; Jian Z. Zhou; Jianbo Wang; Zhijun Luo; Mingyao Liu; Xi He; Anthony Wynshaw-Boris; Wen C. Xiong; Bai Lu; Lin Mei

2002-01-01

239

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

NASA Astrophysics Data System (ADS)

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 ?m. The nano-hardness of the UHMWPE coated with a-C:H films, measured at an applied load of 200 ?N, 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 ?m 2 of untreated UHMWPE to 26 ?m 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.

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

2009-10-01

240

Modeling nicotinic neuromodulation from global functional and network levels to nAChR based mechanisms.  

PubMed

Neuromodulator action has received increasing attention in theoretical neuroscience. Yet models involving both neuronal populations dynamics at the circuit level and detailed receptor properties are only now being developed. Here we review recent computational approaches to neuromodulation, focusing specifically on acetylcholine (ACh) and nicotine. We discuss illustrative examples of models ranging from functional top-down to neurodynamical bottom-up. In the top-down approach, a computational theory views ACh as encoding the uncertainty expected in an environment. A different line of models accounts for neural population dynamics treating ACh as toggling neuronal networks between read-in of information and recall of memory. Building on the neurodynamics idea we discuss two models of nicotine's action with increasing degree of biological realism. Both consider explicitly receptor-level mechanisms but with different scales of detail. The first is a large-scale model of nicotine-dependent modulation of dopaminergic signaling that is capable of simulating nicotine self-administration. The second is a novel approach where circuit-level neurodynamics of the ventral tegmental area (VTA) are combined with explicit models of the dynamics of specific nicotinic ACh receptor subtypes. We show how the model is constructed based on local anatomy, electrophysiology and receptor properties and provide an illustration of its potential. In particular, we show how the model can shed light on the specific mechanisms by which nicotine controls dopaminergic neurotransmission in the VTA. This model serves us to conclude that detailed accounts for neuromodulator action at the basis of behavioral and cognitive models are crucial to understand how neuromodulators mediate their functional properties. PMID:19498415

Graupner, Michael; Gutkin, Boris

2009-06-01

241

Phenyl pyrrolidine analogues as potent nicotinic acetylcholine receptor (nAChR) ligands  

Microsoft Academic Search

The synthesis and SAR of a series of 2-phenyl pyrrolidines as neuronal nAChR ligands are described. Substitution on the aryl ring had a dramatic effect on receptor binding affinity, with Ki values ranging from 46 nM to >10,000 nM. Analogues 8, 9, and 14 were the most potent ligands evaluated, having Ki values of 68 nM, 75 nM, and 46

Richard L. Elliott; Keith B. Ryther; David J. Anderson; Joanna L. Raszkiewicz; Jeffrey E. Campbell; James P. Sullivan; David S. Garvey

1995-01-01

242

2-(Aryloxymethyl) azacyclic analogues as novel nicotinic acetylcholine receptor (nAChR) ligands  

Microsoft Academic Search

A series of 2-(aryloxymethyl) azetidine and pyrrolidine nAChR ligands in which the 3-pyridyl moiety of a previously described series1 was replaced by a substituted phenyl group was explored. Aromatic substitution afforded analogues with Ki values ranging from 3 to >10,000 nM. Generally, substitution at the ortho- and para-position was unfavorable, whereas electron-withdrawing groups at the meta-position improved the Ki values.

Richard L. Elliott; Hana Kopecka; David E. Gunn; Nan-Horng Lin; David S. Garvey; Keith B. Ryther; Mark W. Holladay; David J. Anderson; Jeffrey E. Campbell; James P. Sullivan; Michael J. Buckley; Karen L. Gunther; Alyssa B. O'Neill; Michael W. Decker; Stephen P. Arneri?

1996-01-01

243

Late Quaternary history of southern Chesapeake Bay  

SciTech Connect

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.

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

1985-01-01

244

Quaternary structure, aggregation and cytotoxicity of transthyretin.  

PubMed

Transthyretin (TTR) with a Ser112-to-Ile mutation is known to cause amyloidosis with severe cardiomyopathy. We investigated the quaternary structure, aggregation and cytotoxicity of the S112I variant. This variant exists as a dimer at physiological pH, self-assembles into spherical aggregates and induces cell death in human neuroblastoma IMR-32 cells. In addition, we determined the neutron crystal structure of TTR at 2.0 Å resolution. The neutron structure revealed that the hydrogen-bond network involving His88 is important for the stabilization of the dimer-dimer and monomer-monomer interfaces. PMID:22439750

Mizuguchi, Mineyuki; Yokoyama, Takeshi; Nabeshima, Yuko; Kawano, Keiichi; Tanaka, Ichiro; Niimura, Nobuo

2012-03-23

245

Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies.  

PubMed

Patients with myasthenia gravis (MG) with antibodies to muscle-specific receptor tyrosine kinase (MuSK) differ from acetylcholine receptor (AChR)-positive MG patients, as they frequently present with severe oculobulbar muscle weakness or with neck, shoulder, and respiratory muscle involvement. The neuromuscular junction (NMJ) has been confirmed to be the main target of both AChR- and MuSK-MG. However, histopathological investigation disclosed that muscle fiber atrophy was prevalent in AChR-MG, whereas mild myopathic changes and mitochondrial abnormalities were more frequently observed in MuSK-MG. As the pathogenetic mechanism in MuSK-MG remains unclear, this study investigated the submicroscopic pattern of muscle histopathology to establish a possible correlation between clinical involvement and subcellular morphological findings. Muscle biopsies from seven MuSK-MG patients and from seven patients with AChR-MG were analyzed by transmission electron microscopy. Myopathic and mitochondrial abnormalities were more prominent in MuSK-MG and show giant, swollen, and degenerated mitochondria with fragmented cristae. The most common changes in AChR-MG muscles were fiber atrophy, myofibrillar disarray, and Z-line streaming, consistent with mild neurogenic abnormalities. A different pathogenetic mechanism is emerging in MuSK-MG compared to AChR-MG. Mitochondrial abnormalities seem to be more prominent in MuSK-MG, whereas neurogenic atrophy is observed in AChR-MG. PMID:21088848

Cenacchi, Giovanna; Papa, Valentina; Valentina, Papa; Fanin, Marina; Marina, Fanin; Pegoraro, Elena; Elena, Pegoraro; Angelini, Corrado; Corrado, Angelini

2010-11-19

246

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

PubMed

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. PMID:22421347

Buiculescu, Raluca; Chaniotakis, Nikos A

2012-02-23

247

Development and testing of a low toxicity acid corrosion inhibitor for industrial cleaning applications  

Microsoft Academic Search

A low toxicity corrosion inhibitor used in hydrochloric acid cleaning formulations has been developed. This formulation does not contain formaldehyde. It contains cinnamaldehyde, quaternary nitrogen salts, and a nonionic surfactant, none of which are currently known or suspected to be carcinogens. In laboratory tests, corrosion protection values were equivalent to those provided by current commercial acid inhibitors. Field tests using

Frenier

1997-01-01

248

Uplift of quaternary shorelines in eastern Patagonia: Darwin revisited  

Microsoft Academic Search

During his journey on the Beagle, Darwin observed the uniformity in the elevation of coastal Eastern Patagonia along more than 2000km. More than one century later, the sequences of Quaternary shorelines of eastern Patagonia have been described and their deposits dated but not yet interpreted in terms of geodynamics. Consequently, we i) mapped the repartition of the Quaternary coastal sequences

Kevin Pedoja; Vincent Regard; Laurent Husson; Joseph Martinod; Benjamin Guillaume; Enrique Fucks; Maximiliano Iglesias; Pierre Weill

2011-01-01

249

Ecostratigraphic datums and sequence stratigraphy: Application to the marine Quaternary  

Microsoft Academic Search

The marine Quaternary is characterized by few evolutionary appearances and extinctions of planktonic foraminifera. Because climatic fluctuations are a fundamental characteristic of Pleistocene, however, better stratigraphic resolution of the marine Quaternary can be gained by the establishment of biozones based on climatically controlled foraminiferal assemblages. Utilizing relative abundances of the warm-water Globorotalia menardii complex and temperature-water G. inflata, supplemented by

R. E. Martin; E. Neff; G. W. Johnson; D. Krantz

1991-01-01

250

Sorption and desorption of quaternary amine cations on clays  

Microsoft Academic Search

The authors have studied the sorption and desorption of three quaternary amines, namely, nonyltrimethylammonium, dodecyltrimethylammonium, and hexadecyltrimethylammonium, on homoionic Na- and K-montmorillonite using a titration procedure. More than 99% of all three of the quaternary amine cations studied were sorbed on the montmorillonite when the added amines were less than 70% of the cation-exchange capacity of the montmorillonite. Sorption of

Z. Zhong Zhang; Donald L. Sparks; Noel C. Scrivner

1993-01-01

251

In vitro antituberculosis activities of ACH-702, a novel isothiazoloquinolone, against quinolone-susceptible and quinolone-resistant isolates.  

PubMed

ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of ACH-702 had significantly improved inhibitory activity compared with fluoroquinolones. PMID:20516287

Pucci, Michael J; Ackerman, Maria; Thanassi, Jane A; Shoen, Carolyn M; Cynamon, Michael H

2010-06-01

252

In Vitro Antituberculosis Activities of ACH-702, a Novel Isothiazoloquinolone, against Quinolone-Susceptible and Quinolone-Resistant Isolates?  

PubMed Central

ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of ?1 ?g/ml, comparable to that of the fluoroquinolone moxifloxacin for quinolone-susceptible isolates but superior to that for quinolone-resistant isolates. Biochemical assays involving M. tuberculosis gyrase enzymes indicated that ACH-702 had significantly improved inhibitory activity compared with fluoroquinolones.

Pucci, Michael J.; Ackerman, Maria; Thanassi, Jane A.; Shoen, Carolyn M.; Cynamon, Michael H.

2010-01-01

253

Treatment of Visual Hallucinations in Schizophrenia by Acetylcholinesterase Inhibitors: a case report  

PubMed Central

Schizophrenia and various neurological disorders have some signs and symptoms. Visual hallucinations are one of such disorders. The related studies in some diseases for example Parkinson Disease and Lewy Body Dementia indicate that Acetylcholine (Ach) plays a significant role in neuropsychiatric manifestation and its association with visual hallucination; therefore, visual hallucinations occur due to the depletion of Ach. Drug therapies such as Cholinesterase inhibitors (ChEIs) for increasing Ach level may be beneficial in treating visual hallucination. AchEI's have been used in the treatment of visual hallucinations in Dementia and Parkinson's Disease. We thought that a similar Ach depletion may cause visual hallucinations in patients with schizophrenia and may provide a target for drug treatment. We had a patient with schizophrenia whose psychotic symptoms responded to the treatment plan, but her visual hallucination did not. However, the patient's visual hallucination successfully responded to Rivastigmine (AchEI). This case illustrates the use of an AchEI in the treatment of refractory visual hallucinations in a patient with schizophrenia.

Abad, Nazir Hashemi; Doulatabad, Najafi Shala; Mohammadi, Ali

2011-01-01

254

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

PubMed

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. PMID:23149565

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

2012-11-13

255

PET imaging of acetylcholinesterase inhibitor-induced effects on ?4?2 nicotinic acetylcholine receptor binding.  

PubMed

Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimer's disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo ?4?2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The ?4?2 nAChR-specific radioligand [(18) F]nifene was used to examine the effects of 0.1-0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60-min bolus-infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [(18) F]nifene. Significant [(18) F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [(18) F]nifene in detecting increases in synaptic ACh induced by AChEIs. Synapse 67:882-886, 2013. © 2013 Wiley Periodicals, Inc. PMID:23913347

Hillmer, Ansel T; Wooten, Dustin W; Farhoud, Mohammed; Higgins, Andrew T; Lao, Patrick J; Barnhart, Todd E; Mukherjee, Jogeshwar; Christian, Bradley T

2013-08-30

256

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

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.

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

257

Docking studies of benzylidene anabaseine interactions with ?7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): application to the design of related ?7 selective ligands.  

PubMed

AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and ?7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the ?7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH(2) functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the ?7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-? interactions. The use of AChBPs structure as a surrogate to predict binding affinity to ?7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a ?7 homology model, Bt or Ac crystal structure is used. PMID:21986237

Kombo, David C; Mazurov, Anatoly; Tallapragada, Kartik; Hammond, Philip S; Chewning, Joseph; Hauser, Terry A; Vasquez-Valdivieso, Montserrat; Yohannes, Daniel; Talley, Todd T; Taylor, Palmer; Caldwell, William S

2011-09-29

258

Conformational flexibility in the peripheral site of Torpedo californica acetylcholinesterase revealed by the complex structure with a bifunctional inhibitor.  

PubMed

The X-ray crystallographic structure of Torpedo californica acetylcholinesterase (TcAChE) in complex with the bifunctional inhibitor NF595, a potentially new anti-Alzheimer drug, has been solved. For the first time in TcAChE, a major conformational change in the peripheral-site tryptophan residue is observed upon complexation. The observed conformational flexibility highlights the dynamic nature of protein structures and is of importance for structure-based drug design. PMID:16594661

Colletier, Jacques Ph; Sanson, Benoît; Nachon, Florian; Gabellieri, Emanuele; Fattorusso, Caterina; Campiani, Giuseppe; Weik, Martin

2006-04-12

259

NIOSH Health Hazard Evaluation Report: HETA No. 2005-0243-3016, ACH Foam Technologies, Fond du Lac, Wisconsin, September 2006.  

National Technical Information Service (NTIS)

On May 17, 2005, the National Institute for Occupational Safety and Health (NIOSH) received a confidential request from three employees at ACH Foam Technologies in Fond du Lac, Wisconsin. The requestors expressed concerns about potential long-term effects...

M. Rodriguez C. Achutan

2006-01-01

260

Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies  

Microsoft Academic Search

Patients with myasthenia gravis (MG) with antibodies to muscle-specific receptor tyrosine kinase (MuSK) differ from acetylcholine\\u000a receptor (AChR)-positive MG patients, as they frequently present with severe oculobulbar muscle weakness or with neck, shoulder,\\u000a and respiratory muscle involvement. The neuromuscular junction (NMJ) has been confirmed to be the main target of both AChR-\\u000a and MuSK-MG. However, histopathological investigation disclosed that muscle

Giovanna Cenacchi; Papa Valentina; Fanin Marina; Pegoraro Elena; Angelini Corrado

2011-01-01

261

Physiological and pharmacological properties of responses to GABA and ACh by abdominal motor neurons in Manduca sexta  

Microsoft Academic Search

1.GABA, ACh, and other agents were applied by pressure ejection to the neuropil of the third abdominal ganglion in the isolated nerve cord of Manduca sexta. Intersegmental muscle motor neurons with dendritic arborizations in the same hemiganglion were inhibited by GABA (Fig. 2) and excited by ACh (Fig. 5).2.Picrotoxin was a potent antagonist of GABA (Fig. 4A). Bicuculline reduced GABA

B. Waldrop

1994-01-01

262

Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors  

Microsoft Academic Search

Pentameric ligand gated ion-channels, or Cys-loop receptors, mediate rapid chemical transmission of signals. This superfamily of allosteric transmembrane proteins includes the nicotinic acetylcholine (nAChR), serotonin 5-HT3, ?-aminobutyric-acid (GABAA and GABAC) and glycine receptors. Biochemical and electrophysiological information on the prototypic nAChRs is abundant but structural data at atomic resolution have been missing. Here we present the crystal structure of molluscan

Willem J. van Dijk; Remco V. Klaassen; Mascha Schuurmans; John van der Oost; August B. Smit; Titia K. Sixma

2001-01-01

263

The acetylcholinesterase inhibitors competitively inhibited an acetyl L-carnitine transport through the blood-brain barrier.  

PubMed

We investigated the interaction of acetylcholinesterase (AChE) inhibitors with acetyl-L-carnitine (ALCAR) transporter at the blood-brain barrier (BBB). ALCAR uptake by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB cells), as an in vitro model of BBB, were characterized by cellular uptake study using [(3)H]ALCAR. In vivo brain uptake of [(3)H]ALCAR was determined by brain uptake index after carotid artery injection in rats. In results, the transport properties for [(3)H]ALCAR by TR-BBB cell were consistent with those of ALCAR transport by the organic cation/carnitine transporter 2 (OCTN2). Also, OCTN2 was confirmed to be expressed in the cells. The uptake of [(3)H]ALCAR by TR-BBB cells was inhibited by AChE inhibitors such as donepezil, tacrine, galantamine and rivastigmine, which IC(50) values are 45.3, 74.0, 459 and 800 ?M, respectively. Especially, donepezil and galantamine inhibited the uptake of [(3)H]ALCAR competitively, but tacrine and rivastigmine inhibited noncompetitively. Furthermore, [(3)H]ALCAR uptake by the rat brain was found to be significantly decreased by quinidine, donepezil and galantamine. Our results suggest that transport of AChE inhibitors such as donepezil and galantamine through the BBB is at least partly mediated by OCTN2 which is involved in transport of ALCAR. PMID:22359054

Lee, Na-Young; Choi, Hyung-Ok; Kang, Young-Sook

2012-02-23

264

Re-characterisation of Saccharomyces cerevisiae Ach1p: fungal CoA-transferases are involved in acetic acid detoxification.  

PubMed

Saccharomyces cerevisiae and Neurospora crassa mutants defective in the so-called acetyl-CoA hydrolases Ach1p and Acu-8, respectively, display a severe growth defect on acetate, which is most strongly pronounced under acidic conditions. Acetyl-CoA hydrolysis is an energy wasting process and therefore denoted as a biochemical conundrum. Acetyl-CoA hydrolases show high sequence identity to the CoA-transferase CoaT from Aspergillus nidulans. Therefore, we extensively re-characterised the yeast enzyme. Ach1p showed highest specific activity for the CoASH transfer from succinyl-CoA to acetate and only a minor acetyl-CoA-hydrolase activity. Complementation of an ach1 mutant with the coaT gene reversed the growth defect on acetate confirming the in vivo function of Ach1p as a CoA-transferase. Our results imply that Ach1p is involved in mitochondrial acetate detoxification by a CoASH transfer from succinyl-CoA to acetate. Thereby, Ach1p does not perform the energy wasting hydrolysis of acetyl-CoA but conserves energy by the detoxification of mitochondrial acetate. PMID:19298859

Fleck, Christian B; Brock, Matthias

2009-03-17

265

The role of Quaternary environmental change in plant macroevolution: the exception or the rule?  

Microsoft Academic Search

The Quaternary has been described as an important time for genetic diversification and speciation. This is based on the premise that Quaternary climatic conditions fostered the isolation of populations and, in some instances, allopatric speciation. However, the 'Quaternary Ice-Age speciation model' rests on two key assumptions: (i) that biotic responses to climate change during the Quaternary were significantly different from

Katherine J. Willis; Karl J. Niklas

2004-01-01

266

Inhibitors of acetylcholine esterase in vitro--screening of steroidal alkaloids from Fritillaria species.  

PubMed

18 alkaloids were successfully isolated from five Fritillaria species and 5 derivatives were synthesized. Their effects on the bioactivity of human whole blood cholinesterase (ChE) were assessed. The results showed that N-demethylpuqietinone, hupeheninoside, ebeiedinone, yibeinoside A and chuanbeinone inhibited the bioactivity of human whole blood ChE at the concentration of 1.0 x 10 ( - 4) M, with the inhibitory effects of 55.5 +/- 2.7 %, 66.8 +/- 2.0 %, 69.0 +/- 1.7 %, 71.2 +/- 1.8 % and 70.7 +/- 3.3 %, respectively. The effects of the five alkaloids on human red blood cell (RBC) acetylcholinesterase (AChE) and human plasma butyrylcholinesterase (BChE) were further studied, and their IC (50) values for human RBC AChE were 6.4 +/- 0.003 microM, 16.9 +/- 0.018 microM, 5.7 +/- 0.004 microM, 6.5 +/- 0.013 microM and 7.7 +/- 0.001 microM, respectively, and the IC50 values for human plasma BChE were 12.5 +/- 0.026 microM, 2.1 +/- 0.005 microM, 5.2 +/- 0.002 microM, 7.3 +/- 0.005 microM and 0.7 +/- 0.001 microM, respectively. These data suggest, therefore, that N-demethylpuqietinone, hupeheninoside, ebeiedinone, yibeinoside A and chuanbeinone have both anti-RBC AChE and anti-plasma BChE activities, N-demethylpuqietinone is a selective inhibitor of AChE, whereas hupeheninoside and chuanbeinone are the selective inhibitors of BChE. PMID:16881015

Lin, Bao-Qin; Ji, Hui; Li, Ping; Fang, Wei; Jiang, Yan

2006-07-01

267

Isoflurane-Induced Spatial Memory Impairment in Mice is Prevented by the Acetylcholinesterase Inhibitor Donepezil  

PubMed Central

Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg) or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2%) for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE), choline acetylase (ChAT) and ?7 nicotinic receptor (?7-nAChR) were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or ?7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.

Wang, Beilei; Xu, Huan; Li, Wen; Chen, Jie; Wang, Xiangrui

2011-01-01

268

In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens?  

PubMed Central

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 ?g/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of ?0.5 ?g/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.

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

2011-01-01

269

In vitro and in vivo profiles of ACH-702, an isothiazoloquinolone, against bacterial pathogens.  

PubMed

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 ?g/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of ?0.5 ?g/ml) against staphylococcal strains with two mutations in both gyrA and grlA, and low frequencies for the selection of higher-level resistance (<10?¹?). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates. PMID:21464250

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

2011-04-04

270

In Vitro Activity of a New Isothiazoloquinolone, ACH-702, against Mycobacterium tuberculosis and Other Mycobacteria?  

PubMed Central

In this work, we describe the activity of ACH-702 against clinical isolates of Mycobacterium tuberculosis and six different nontuberculous mycobacteria. The MIC50 and MIC90 of both susceptible and drug-resistant M. tuberculosis strains tested were 0.0625 and 0.125 ?g/ml, respectively. The MIC50 and MIC90 values for Mycobacterium fortuitum isolates were 0.0625 ?g/ml in both cases; Mycobacterium avium complex isolates showed MIC50 and MIC90 values of 0.25 and 4 ?g/ml, respectively.

Molina-Torres, Carmen A.; Ocampo-Candiani, Jorge; Rendon, Adrian; Pucci, Michael J.; Vera-Cabrera, Lucio

2010-01-01

271

Antifungal activity of gemini quaternary ammonium salts.  

PubMed

A series of gemini quaternary ammonium chlorides and bromides with various alkyl chain and spacer lengths was synthesized. The most active compounds against fungi were chlorides with 10 carbon atoms within the hydrophobic chain. Among these compounds were few with no hemolytic activity at minimal inhibitory concentrations. None of the tested compounds were cytotoxic and mutagenic. Cationic gemini surfactants poorly reduced the adhesion of microorganisms to the polystyrene plate, but inhibited the filamentation of Candida albicans. One of the tested compounds eradicated C. albicans and Rodotorula mucilaginosa biofilm, what could be important in overcoming catheter-associated infections. It was also shown that gemini surfactants enhanced the sensitivity of C. albicans to azoles and polyenes, thus they might be potentially used in combined therapy against fungi. PMID:23827647

Ob??k, Ewa; Piecuch, Agata; Krasowska, Anna; Luczy?ski, Jacek

2013-07-01

272

Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.  

PubMed

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 ?M) and BuChE (IC50=0.46±0.06 ?M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A? aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. PMID:22023459

Bolea, Irene; Juárez-Jiménez, Jordi; de Los Ríos, Cristóbal; Chioua, Mourad; Pouplana, Ramón; Luque, F Javier; Unzeta, Mercedes; Marco-Contelles, José; Samadi, Abdelouahid

2011-11-15

273

A quaternary temperament model and defense cluster preferences.  

PubMed

A quaternary model of temperament constructed from orthogonal axes defined by Extraversion-Introversion and Thinking-Feeling resulted in four groups: Introverted Thinking, Introverted Feeling, Extraverted Thinking, and Extraverted Feeling. Hypothesized relationships between quaternary groups and defense cluster preferences were tested by giving 158 female college students the Myers-Briggs Type Indicator and the Defense Mechanisms Inventory. There was little support for hypothesized relationships between the quaternary model and defense preferences. The only hypothesized significant group difference showed the Extraverted Feeling group recording a greater preference for the Reversal defense cluster than the Introverted Feeling group. PMID:14650666

Kelly, Kathryn E; Tobacyk, Jerome J

2003-10-01

274

An expedient, ionic liquid mediated multi-component synthesis of novel piperidone grafted cholinesterase enzymes inhibitors and their molecular modeling study.  

PubMed

Series of hitherto unreported piperidone grafted pyridopyrimidines synthesized through ionic liquid mediated multi-component reaction. These compounds were evaluated for their inhibitory activities against AChE and BChE enzymes. All the compounds displayed considerable potency against AChE with IC50 values ranging from 0.92 to 9.11 ?M, therein compounds 6a, 6h and 6i displayed superior enzyme inhibitory activities compared to standard drug with IC50 values of 0.92, 1.29 and 2.07 ?M. Remarkably, all the compounds displayed higher BChE inhibitory activity compared to galantamine with IC50 values of 1.89-8.13 ?M. Molecular modeling, performed for the most active compounds using three dimensional crystal structures of TcAChE and hBChE, disclosed binding template of these inhibitors into the active site of their respective enzymes. PMID:23871902

Basiri, Alireza; Murugaiyah, Vikneswaran; Osman, Hasnah; Kumar, Raju Suresh; Kia, Yalda; Awang, Khalijah Binti; Ali, Mohamed Ashraf

2013-07-04

275

Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland.  

PubMed

A family of five subtypes of muscarinic acetylcholine receptors (mAChR) has been identified based on their molecular structures and second signal transduction pathways. In the present study, we examined the antagonist binding profiles of 9 muscarinic antagonists (atropine, 4-DAMP, pirenzepine, oxybutynin, tiquizium, timepidium, propiverine, darifenacin and zamifenacin) for human muscarinic acetylcholine receptor subtypes (m1, m2, m3, m4 and m5) produced by using a baculovirus infection system in Sf9 insect cells, and rat tissue membrane preparations (heart and submandibular gland). In a scopolamine methyl chloride [N-methyl-3H]- ([3H]NMS) binding assay, pirenzepine and timepidium displayed the highest affinities for the m1 and m2 subtypes, respectively, and both zamifenacin and darifenacin had the highest affinities for the m3 subtype, although the selectivities among the five subtypes were less than 10-fold. Propiverine showed a slightly higher affinity for the m5 subtype, whereas none of the drugs used in this study was uniquely selective for the m4 subtype. The binding affinities of muscarinic antagonists for rat heart and submandibular gland strong correlated with those for human cloned m2 and m3 subtypes, respectively. These data suggest that [3H]NMS binding studies using rat heart and submandibular gland might be useful methods which predict the affinities of test drugs for human muscarinic M2 and M3 receptor subtypes. PMID:10374898

Moriya, H; Takagi, Y; Nakanishi, T; Hayashi, M; Tani, T; Hirotsu, I

1999-01-01

276

Development and testing of a low toxicity acid corrosion inhibitor for industrial cleaning applications  

SciTech Connect

A low toxicity corrosion inhibitor used in hydrochloric acid cleaning formulations has been developed. This formulation does not contain formaldehyde. It contains cinnamaldehyde, quaternary nitrogen salts, and a nonionic surfactant, none of which are currently known or suspected to be carcinogens. In laboratory tests, corrosion protection values were equivalent to those provided by current commercial acid inhibitors. Field tests using the low toxicity inhibitor were conducted.

Frenier, W.W. [HydroChem Industrial Services Inc., Houston, TX (United States)

1997-02-01

277

Two mutations linked to nocturnal frontal lobe epilepsy cause use-dependent potentiation of the nicotinic ACh response.  

PubMed

1. We constructed rat homologues (S252F and +L264) of two human alpha4 nicotinic mutations - alpha4(S248F) and alpha4(777ins3) - that have been linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and co-expressed them with wild-type rat beta2 subunits in Xenopus oocytes. 2. The S252F and +L264 mutations had three common effects on the ACh response. First, they caused use-dependent potentiation of the response during a train of brief 100 nM ACh pulses. Second, they delayed the rise times of the 5-15 nM (+L264) and 30 nM (S252F) ACh responses. Third, they reduced extracellular Ca2+-induced increases in the 30 microM ACh response. 3. Beside these shared effects, the S252F mutation also reduced the channel burst duration measured from voltage-jump relaxations, enhanced steady-state desensitization and reduced the single-channel conductance. In contrast, the +L264 mutation prolonged the channel burst duration, did not affect desensitization and slightly increased single-channel conductance. Neither mutation affected the number of surface receptors measured by antibody binding but the S252F mutation reduced the maximum ACh response. 4. The ACh concentration dependence of use-dependent potentiation and the delay in the rising phase of the mutant ACh response suggest that these effects are caused by a slow unblocking of the closed mutant receptors. Use-dependent potentiation of the mutant response during a series of high-frequency cholinergic inputs to the presynaptic terminal could trigger ADNFLE seizures by suddenly increasing nicotinic-mediated transmitter release. PMID:9824708

Figl, A; Viseshakul, N; Shafaee, N; Forsayeth, J; Cohen, B N

1998-12-15

278

Blockade of neuronal ?7-nAChR by ?-conotoxin ImI explained by computational scanning and energy calculations.  

PubMed

?-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactions are still ambiguous in the absence of experimental structures of conotoxin-receptor complexes. In this study, the binding modes of ?-conotoxin ImI to the ?7-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent dielectric constant or explicit water, or molecular dynamics using five restraint strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of ?-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and chemically modified ?-conotoxins. PMID:21390272

Yu, Rilei; Craik, David J; Kaas, Quentin

2011-03-03

279

Quaternary Stratigraphy and Depositional Environments, Santa Monica Bay, Southern California.  

National Technical Information Service (NTIS)

High-resolution seismic-reflection profiles were used in conjunction with 51 vibracores to examine the Quaternary stratigraphy of the Santa Monica Shelf, southern California. Upper Pleistocene strata are confined to the central part of the shelf between t...

R. H. Osborne R. C. Scheidemann T. R. Nardin A. S. Harper

1980-01-01

280

Chemical Warfare Agent Decontaminant Solution Using Quaternary Ammonium Complexes.  

National Technical Information Service (NTIS)

A chemical warfare agent decontamination solution made up of about 20% of a quaternary ammonium complex containing benzyltrimethylammonium chloride and benzyltriethylammonium chloride and about 20% by weight of an oxidizer, dissolved in a solvent, such as...

D. T. Crounce

1997-01-01

281

Fusion Properties of Some Ionic Quaternary Ammonium Compounds.  

National Technical Information Service (NTIS)

Enthalpy, entropy and molar volume changes during the fusion process of a wide range of quaternary ammonium compounds are presented. This group of compounds has hitherto been unexplored and is of interest since, as far as melting mechanisms are concerned,...

T. G. Coker J. Ambrose G. J. Janz

1970-01-01

282

Sorption and desorption of quaternary amine cations on clays  

SciTech Connect

The authors have studied the sorption and desorption of three quaternary amines, namely, nonyltrimethylammonium, dodecyltrimethylammonium, and hexadecyltrimethylammonium, on homoionic Na- and K-montmorillonite using a titration procedure. More than 99% of all three of the quaternary amine cations studied were sorbed on the montmorillonite when the added amines were less than 70% of the cation-exchange capacity of the montmorillonite. Sorption of quaternary amine cations involves at least two types of reactions, namely, an exchange reaction and the adsorption of amines at nonexchangeable sites. The exchange reaction proceeded almost to completion when Na[sup +] was the exchangeable cation. Exchangeable K[sup +] was much more difficult to replace. The adsorbed quaternary amine cations were not easily desorbed in the presence of 0.1 M NaCl and KCl solutions. In addition, desorption of quaternary amines did not increase with prolonged equilibrium time, up to 180 days. Therefore, it appears that there is good promise in using quaternary amine-modified clays as effective sorbents for removing organic pollutants or mitigating their mobilities in the environment. 26 refs., 5 figs., 6 tabs.

Zhang, Z.Z.; Sparks, D.L. (Univ. of Delaware, Newark, DE (United States)); Scrivner, N.C. (DuPont Engineering, Newark, DE (United States))

1993-08-01

283

Quaternary cave levels in peninsular Florida  

NASA Astrophysics Data System (ADS)

The hypothesis that caves in the Florida Peninsula are tied to Quaternary sea levels was proposed by hydrogeologists, without data, some 40 years ago. The hypothesis is a version of glacial control of cave levels, which is the logical combination of the water-table theory of speleogenesis and the concept that base level positions the water table. At the USA type example of glacial control of cave levels—Mammoth Cave in the Paleozoic rocks of Kentucky—the intermediary is base level determined by rivers. By hypothesis, the intermediary for Florida is glacioeustatic sea level. This paper presents elevation data that supports this hypothesis. Recent cave surveys in the air-filled caves and spot elevations from archived maps reveal prominent levels of passages centered at 5, 12, 21, and 30 m above sea level over broad areas. They do not follow the large-scale structure of the Floridan aquifer. Instead, they align with nearby, coastal marine terraces identified as modal peaks on frequency plots from various topographic data bases. Levels matching with the three highest terraces—Wicomico, Penholoway, and Talbott—are particularly clear. Lower levels, if they accord with sea-level stands, are likely composites. Data from cavities encountered in drilled wells (e.g., bit drops) and spot elevations from archived underwater cave maps demonstrate passage levels at depths of 15, 30, 70, and 90 120 m below the modern water table. The depths below water table are similar to the depths below sea level of distant submerged terraces and paleoshoreline features identified using multibeam bathymetric data in the Gulf of Mexico. The cave, bit-drop, and terrace data are all consistent with the concept that Quaternary sea level is the fundamental control on the cave-scale porosity within the Floridan aquifer. This conclusion does not rule out the possibility that lithologically favored positions, paleokarst features and confining units, and mixing zones are also involved in the location of caves levels in this near-coastal environment.

Florea, Lee J.; Vacher, H. L.; Donahue, Brian; Naar, David

2007-05-01

284

A Case Report of Congenital Fiber Type Disproportion with an Increased Level of Anti-ACh Receptor Antibodies.  

PubMed

Congenital fiber type disproportion (CFTD) is a form of congenital myopathy, which is defined by type 1 myofibers that are 12% smaller than type 2 myofibers, as well as a general predominance of type 1 myofibers. Conversely, myasthenia gravis (MG) is an acquired immune-mediated disease, in which the acetylcholine receptor (AChR) of the neuromuscular junction is blocked by antibodies. Thus, the anti-AChR antibody is nearly specific to MG. Herein, we report on a case of CFTD with increased anti-AChR antibody levels. A 23-month-old boy exhibited muscle hypotonia and weakness. Although he could walk by himself, he easily fell down and could not control his head for a long time. His blood test was positive for the anti-AChR antibody, while a muscle biopsy revealed characteristics of CFTD. We could not explain the relationship between MG and CFTD. However, we considered different diagnoses aside from MG, even when the patient's blood is positive for the anti-AChR antibody. PMID:23762716

Kimura, Shigemi; Ozasa, Shiro; Nomura, Keiko; Kosuge, Hirofumi; Yoshioka, Kowasi

2013-05-16

285

A Case Report of Congenital Fiber Type Disproportion with an Increased Level of Anti-ACh Receptor Antibodies  

PubMed Central

Congenital fiber type disproportion (CFTD) is a form of congenital myopathy, which is defined by type 1 myofibers that are 12% smaller than type 2 myofibers, as well as a general predominance of type 1 myofibers. Conversely, myasthenia gravis (MG) is an acquired immune-mediated disease, in which the acetylcholine receptor (AChR) of the neuromuscular junction is blocked by antibodies. Thus, the anti-AChR antibody is nearly specific to MG. Herein, we report on a case of CFTD with increased anti-AChR antibody levels. A 23-month-old boy exhibited muscle hypotonia and weakness. Although he could walk by himself, he easily fell down and could not control his head for a long time. His blood test was positive for the anti-AChR antibody, while a muscle biopsy revealed characteristics of CFTD. We could not explain the relationship between MG and CFTD. However, we considered different diagnoses aside from MG, even when the patient's blood is positive for the anti-AChR antibody.

Ozasa, Shiro; Nomura, Keiko; Kosuge, Hirofumi; Yoshioka, Kowasi

2013-01-01

286

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

PubMed

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

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

2013-03-15

287

Highly fatal fast-channel syndrome caused by AChR ? subunit mutation at the agonist binding site  

PubMed Central

Objective: To characterize the molecular basis of a novel fast-channel congenital myasthenic syndrome. Methods: We used the candidate gene approach to identify the pathogenic mutation in the acetylcholine receptor (AChR) ? subunit, genetically engineered the mutant AChR into HEK cells, and evaluated the level of expression and kinetic properties of the mutant receptor. Results: An 8-year-old boy born to consanguineous parents had severe myasthenic symptoms since birth. He is wheelchair bound and pyridostigmine therapy enables him to take only a few steps. Three similarly affected siblings died in infancy. He carries a homozygous p.W55R mutation at the ?/? subunit interface of the AChR agonist binding site. The mutant protein expresses well in HEK cells. Patch-clamp analysis of the mutant receptor expressed in HEK cells reveals 30-fold reduced apparent agonist affinity, 75-fold reduced apparent gating efficiency, and strikingly attenuated channel opening probability (Popen) over a range agonist concentrations. Conclusion: Introduction of a cationic Arg into the anionic environment of ?/? AChR binding site hinders stabilization of cationic ACh by aromatic residues and accounts for the markedly perturbed kinetic properties of the receptor. The very low Popen explains the poor response to pyridostigmine and the high fatality of the disease.

Brengman, Joan M.; Edvardson, Simon; Sine, Steve M.; Engel, Andrew G.

2012-01-01

288

Quaternary ammonium analogs of ether lipids inhibit the activation of protein kinase C and the growth of human leukemia cell lines  

Microsoft Academic Search

Purpose: ET-18-OCH3 (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is a representative of the first generation of antitumor ether lipids and is a model in the development\\u000a of new compounds including a series of quaternary ammonium analogs (QAA). In the present study, we evaluated the QAA as inhibitors\\u000a of cell growth and studied their mechanism of action. Methods: We compared the effects of the QAA on

Francesca Civoli; Larry W. Daniel

1998-01-01

289

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

PubMed Central

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.

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

2010-01-01

290

BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide  

Microsoft Academic Search

BZYX was designed as a dual-binding-site acetylcholinesterase (AChE) inhibitor and selected from series of indanone derivatives. The present study was designed to examine the cognition-enhanced, anti-cholinesterase, and neuroprotective effects of BZYX. In the passive avoidance performance and radial arm maze, BZYX showed a comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO2 and

Jing Zhang; Difeng Zhu; Rong Sheng; Honghai Wu; Yongzhou Hu; Feng Wang; Tianyu Cai; Bo Yang; Qiaojun He

2009-01-01

291

Novel Dimeric Acetylcholinesterase Inhibitor Bis(7)-tacrine, but Not Donepezil, Prevents Glutamate-induced Neuronal Apoptosis by Blocking N-Methyl-D-aspartate Receptors  

Microsoft Academic Search

The neuroprotective properties of bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 M glutamate resulted in neuro- nal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-ta- crine treatment (0.01-1 M) on CGNs markedly reduced glutamate-induced apoptosis in dose- and

Wenming Li; Rongbiao Pi; Hugh H. N. Chan; Hongjun Fu; Nelson T. K. Lee; Hing Wai Tsang; Yongmei Pu; Donald C. Chang; Chaoying Li; Jialie Luo; Keming Xiong; Zhiwang Li; Hong Xue; Paul R. Carlier; Yuanping Pang; Karl W. K. Tsim; Mingtao Li; Yifan Han

2004-01-01

292

Quaternary phylogeography: the roots of hybrid zones.  

PubMed

The older history of hybrid zones is explored through consideration of recent advances in climatology, paleontology and phylogeography in the Late Cenozoic, particularly the Quaternary Period with its major climatic cycles. The fossil record shows that these ice ages and their nested millennial oscillations caused substantial changes in species distributions and with genetic evidence allows deduction of refugia and colonization routes in arctic, temperate, desert and tropical regions. The age of divergence between hybridizing lineages varies from the Late Pleistocene to the Late Miocene, implying much range change and varying selection on sister lineages. Hybridizing lineages in the Tropical and Temperate regions range in age from young to old, but those studied in the Arctic are no more than a few ice ages old and their refugial roots are not clear. Mid to low latitude regions often show parapatric patchworks of lineages and multiple refugia stable through many climatic oscillations. Particular hybrid zones may have formed more than once; while some expansions were not the same, producing reticulation and introgression in previous glacial cycles. Hybrid-zone roots are complex and deep, and considerations of their complexity can reveal evolutionary pathways of species. They are indeed windows on evolution. PMID:21234647

Hewitt, Godfrey M

2011-01-15

293

Stereocontrolled Alkylative Construction of Quaternary Carbon Centers  

PubMed Central

Protocols for the stereodefined formation of ?,?-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of ?,?-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine ?-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the ?-C-H bond with ?-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common ?-face of the E- and Z-enolates, proposed to be that opposite the pseudoephedrine alkoxide side-chain. Pseudoephedrine ?-phenylbutyramides are found to undergo highly stereoselective but not stereospecific ?-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that ?, ?-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an ?-alkyl-?,?-unsaturated pseudoephedrine amide, providing ?,?-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the ?-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes.

Kummer, David A.; Chain, William J.; Morales, Marvin R.; Quiroga, Olga; Myers, Andrew G.

2009-01-01

294

Quaternary structure of hemoglobin in solution  

NASA Astrophysics Data System (ADS)

Many important proteins perform their physiological functions under allosteric control, whereby the binding of a ligand at a specific site influences the binding affinity at a different site. Allosteric regulation usually involves a switch in protein conformation upon ligand binding. The energies of the corresponding structures are comparable, and, therefore, the possibility that a structure determined by x-ray diffraction in the crystalline state is influenced by its intermolecular contacts, and thus differs from the solution structure, cannot be excluded. Here, we demonstrate that the quaternary structure of tetrameric human normal adult carbonmonoxy-hemoglobin can readily be determined in solution at near-physiological conditions of pH, ionic strength, and temperature by NMR measurement of 15N-1H residual dipolar couplings in weakly oriented samples. The structure is found to be a dynamic intermediate between two previously solved crystal structures, known as the R and R2 states. Exchange broadening at the subunit interface points to a rapid equilibrium between different structures that presumably include the crystallographically observed states.

Lukin, Jonathan A.; Kontaxis, Georg; Simplaceanu, Virgil; Yuan, Yue; Bax, Ad; Ho, Chien

2003-01-01

295

In situ selection of lead compounds by click chemistry: target-guided optimization of acetylcholinesterase inhibitors.  

PubMed

The target-guided, in situ click chemistry approach to lead discovery has been successfully employed for discovering acetylcholinesterase (AChE) inhibitors by incubating a selected enzyme/tacrine azide combination with a variety of acetylene reagents that were not previously known to interact with the enzyme's peripheral binding site. The triazole products, formed by the enzyme, were identified by HPLC-mass spectrometry analysis of the crude reaction mixtures. The target-guided lead discovery search was also successful when performed with reagent mixtures containing up to 10 components. From 23 acetylene reagents, the enzyme selected two phenyltetrahydroisoquinoline (PIQ) building blocks that combined with the tacrine azide within the active center gorge to form multivalent inhibitors that simultaneously associate with the active and peripheral binding sites. These new inhibitors are up to 3 times as potent as our previous phenylphenanthridinium-derived compounds, and with dissociation constants as low as 33 femtomolar, they are the most potent noncovalent AChE inhibitors known. In addition, the new compounds lack a permanent positive charge and aniline groups and possess fewer fused aromatic rings. Remarkably, despite the high binding affinity, the enzyme displayed a surprisingly low preference for one PIQ enantiomer over the other. PMID:15869290

Krasi?ski, Antoni; Radi?, Zoran; Manetsch, Roman; Raushel, Jessica; Taylor, Palmer; Sharpless, K Barry; Kolb, Hartmuth C

2005-05-11

296

Effect of cryopreservation on acetylation patterns of lysine 12 of histone H4 (acH4K12) in mouse oocytes and zygotes  

PubMed Central

Purpose To determine the effect of cryopreservation on acH4K12 in oocytes and their respective zygotes. Methods AcH4K12 in fresh or vitrified-warmed oocytes and their respective zygotes at 70 min–12 h post-fertilization were assessed using fluorescent staining. Results 1. AcH4K12 levels increased significantly in vitrified oocytes compared to controls. 2. Respective zygotes derived from vitrified oocytes had abnormal chromatin distribution or acH4K12 patterns before and after pronuclear formation. Conclusion Cryopreservation alters AcH4K12 patterns in oocytes, which subsequently affect the chromatin distribution and acH4K12 in fertilized oocytes.

Suo, Lun; Meng, QingGang; Pei, Yan; Fu, XiangWei; Wang, YanPing; Bunch, Thomas D.

2010-01-01

297

Unresponsive Correlated Motion in ?7 nAChR to Halothane Binding Explains Its Functional Insensitivity to Volatile Anesthetics  

PubMed Central

Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as targets for general anesthetics, but the functional responses to anesthetic modulation vary considerably among different subtypes of nAChRs. Inhaled general anesthetics, such as halothane, could effectively inhibit the channel activity of the ?4?2 nAChR, but not the homologous ?7 nAChR. To understand why ?7 is insensitive to inhaled general anesthetics, we performed multiple sets of 20-ns molecular dynamics (MD) simulations on the closed- and open-channel ?7 in the absence and presence of halothane, and critically compared the results with those from our studies on the ?4?2 nAChR (Liu et al., J. Phys. Chem. B 2009, 113, 12581; J. Phys. Chem. B 2010, 114, 626) Several halothane binding sites with fairly high binding affinities were identified in both closed- and open-channel ?7, suggesting that lack of sensitive functional responses of the ?7 nAChR to halothane in the previous experiments was unlikely due to lack of halothane interaction with ?7. The binding affinities of halothane in ?7 seemed to be protein conformation dependent. Overall halothane affinity was higher in the closed-channel ?7. Halothane binding to ?7 did not induce profound changes in ?7 structure and dynamics that could be related to the channel function. In contrast, correlated motion of the open-channel ?4?2 was reduced substantially in the presence of halothane, primarily due to the more susceptible nature of ?2 to anesthetic modulation. The amphiphilic EC/TM interface of the ?2 subunit is attractive to halothane and is susceptible to halothane perturbation, which may be why ?4?2 is functionally more sensitive to halothane than ?7.

Mowrey, David; Haddadian, Esmael J.; Liu, Lu Tian; Willenbring, Dan; Xu, Yan; Tang, Pei

2010-01-01

298

Proteinase inhibitors  

Microsoft Academic Search

Enzymatic protein hydrolysis plays a major role in various physiological processes, including digestion, and is regulated by proteinase inhibitors. Inhibitors in foods and food ingredients can reduce the absorption of free amino acids, and can impair protein hydrolysis in industrial processes. However, inhibitors can be useful tools in pest control, in the prevention and treatment of diseases such as cancers

Fernando Luis García-Carreño

1996-01-01

299

Consequences of linker length alteration of the ?7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333.  

PubMed

A series of ligands based on SEN12333, containing either contracted or elongated alkyl chains, were synthesized and evaluated in molecular docking studies against a homology model of the ?7 nicotinic acetylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the exception of the analog containing a 5 methylene unit spacer. However, in vitro competition binding assays revealed that the ligands possessed dissimilar binding affinities, with a K(i) range of more than an order of magnitude (K(i)=0.50 to >10 ?M), and only SEN12333 itself exhibited functional activity at the ?7 nAChR. PMID:22410083

Beinat, Corinne; Banister, Samuel D; van Prehn, Saundra; Doddareddy, Munikumar Reddy; Hibbs, David; Sako, Michael; Chebib, Mary; Tran, Thao; Al-Muhtasib, Nour; Xiao, Yingxian; Kassiou, Michael

2012-02-24

300

The isotope hydrology of Quaternary climate change.  

PubMed

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. PMID:21051074

Darling, W G

2010-11-03

301

Intracoronary administration of a thromboxane A2 synthase inhibitor relieves acetylcholine-induced coronary spasm.  

PubMed

This study sought to clarify the effectiveness of intracoronary administration of a thromboxane (TX) A2 synthase inhibitor, Ozagrel Na, to relieve coronary spasms induced by intracoronary injection of acetylcholine (ACh). An ACh spasm provocation test was performed in 92 consecutive patients with coronary spastic angina using incremental doses of 20, 50, and 80 microg into the right coronary artery, and 20, 50, and 100 microg into the left coronary artery within 20s. A coronary spasm was defined as TIMI 0 or 1 flow and an intracoronary injection of 20 mg Ozagrel Na was administered when it was provoked. Within 2 min of the administration of the TXA2 synthase inhibitor, ACh-induced coronary spasms were relieved (TIMI 3 flow) in 88.1% of procedures without complications. In only 4 cases (4.3%), it took more than 3 min to relieve the coronary spasms. Intracoronary administration of 20mg Ozagrel Na when ACh-induced spasms occurred, shortened the spasm relief time in all 7 patients (200 +/- 59s vs 111 +/- 23s, p < 0.01), improved the maximal ST segment elevation in 5 of them (3.9 +/- 3.7 mm vs 0.7 +/- 1.5 mm, p < 0.05), and stopped chest pain in 4 patients. In 4 patients who had ACh-induced coronary spasm of the left anterior descending artery, the TXB2 concentration in the coronary sinus decreased after intracoronary administration of Ozagrel Na into the left coronary artery (463 +/- 562 vs 96 +/- 45, p < 0.01). In conclusion, intracoronary administration of a TXA2 synthase inhibitor can relieve ACh-induced coronary spasms by inhibiting TXA2 synthesis in the local coronary circulation. PMID:12224820

Sueda, Shozo; Kohno, Hiroaki; Inoue, Katsuji; Fukuda, Hiroshi; Suzuki, Jun; Watanabe, Kouki; Ochi, Naoto; Kawada, Hiroyuki; Uraoka, Tadao

2002-09-01

302

Effects of novelty and pain on behavior and hippocampal extracellular ACh levels in male and female rats  

Microsoft Academic Search

In vivo microdialysis was used to assess the effects of novelty and pain on hippocampal ACh release in male and female rats. Experiments were carried out during the dark phase and consisted of 2 days of tests: on Day 1, after Baseline 1, animals were exposed to a new cage (Novelty) to which, 30 min later, a plastic cylinder (Object)

Ilaria Ceccarelli; Fiorella Casamenti; Cosimo Massafra; Giancarlo Pepeu; Carla Scali; Anna Maria Aloisi

1999-01-01

303

New insights on the molecular recognition of imidacloprid with Aplysia californica AChBP: a computational study.  

PubMed

The binding of imidacloprid (IMI), the forerunner of neonicotinoid insecticides, with the acetylcholine binding protein (AChBP) from Aplysia californica, the established model for the extracellular domain of insects nicotinic acetylcholine receptors, has been studied with a two-layer ONIOM partition approach (M06-2X/6-311G(d):PM6). Our calculations allow delineating the contributions of the key residues of AChBP for IMI binding. In particular, the importance of Trp147 and Cys190-191, through weak CH···? interactions and both van der Waals and hydrogen-bond (H-bond) interactions, respectively, are highlighted. Furthermore, H-bonds between hydroxyl groups of both Ser189 and Tyr55 and the IMI nitro group are pointed out. The participation of Ile118, whose main chain NH and carbonyl group are hydrogen-bonded with the IMI pyridinic nitrogen through a water molecule, is characterized. Our simulations also indicate the presence of a significant contribution of this residue through van der Waals interactions. The various trends obtained by the calculations of the pairwise interaction energies are confirmed through a complementary noncovalent interaction (NCI) analysis of selected IMI-AChBP amino acid pairs. Indeed, the contribution of a halogen-bond interaction between IMI and AChBP, recently proposed in the literature, is corroborated by our NCI analysis. PMID:23521537

Cerón-Carrasco, José P; Jacquemin, Denis; Graton, Jérôme; Thany, Steeve; Le Questel, Jean-Yves

2013-04-09

304

Investigation of the structure and properties of a-C:H coatings with metal and silicon containing interlayers  

NASA Astrophysics Data System (ADS)

The structure of the interface of a-C:H coatings deposited with metal and Si-containing interlayers has been studied. Carbide forming metals (Al, Ti, Cr) can improve the chemical bonding compared with a substrate material which does not form carbides extensively by itself. In addition, a graded transition zone enlarges the interface between the carbon layer and the interlayer metal. In the present work the metal atoms were evaporated and ionized into a dense Ar plasma and deposited onto Si (100) substrates. A graded interface between the metal interlayer and the a-C:H coating was produced by introducing C 2H 2 with increasing amount into the Ar/He plasma during the PAPVD metal deposition process. The PACVD a-C:H deposition process was continued after the termination of metal evaporation to produce the pure a-C:H top layer. Further to Al-, Cr-, Ti- and Cu-interlayers, Si-containing interlayers were investigated. The Si-containing interlayers were deposited by a PACVD process using tetraethoxysilane Si(OC 2H 5) 4 (TEOS) and tetramethylsilane Si(CH 3) 4 (TMS). The characterization of the deposited layer systems was performed by SIMS, SNMS and XPS analyses as well as SEM and analytical TEM methods.

Nöthe, M.; Breuer, U.; Koch, F.; Penkalla, H. J.; Rehbach, W. P.; Bolt, H.

2001-07-01

305

'Locative media workshop' for 'pixelACHE' festival, Helsinki 2004. Roles: Concept\\/workshop design, coordinator, curator, presenter  

Microsoft Academic Search

The 'Locative Media' workshop for 'pixelACHE' festival, was from the start a 'networked' or 'connected' production, and involved negotiation of different agendas, with the different collaborative partners and organisations, venues, sites, technical operators, and of course potential and selected participants. Evolving with those negotiations, a workshop was designed. A timeline is supplied below. The first 'connected agenda', was the initiator's

Andrew Paterson

306

Physiological response of the lichen Phaeophyscia hispidula (Ach.) Essl., to the urban environment of Pauri and Srinagar (Garhwal), Himalayas, India  

Microsoft Academic Search

The present study was designed with an aim to observe the effect of increasing urbanization and traffic activity on the physiology of a foliose lichen, Phaeophyscia hispidula (Ach.) Essl., collected from 13 different localities, growing in their natural habitat, in Pauri and Srinagar, two cities in the Himalayas. Six parameters i.e., Chl. a, Chl. b, total pigment, chlorophyll degradation, carotenoid

Vertika Shukla; Dalip K. Upreti

2007-01-01

307

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...

308

Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity  

SciTech Connect

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.

Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

1984-04-01

309

Redefining the Role of the Quaternary Shift in Bacillus stearothermophilus Phosphofructokinase.  

PubMed

Bacillus stearothermophilus phosphofructokinase (BsPFK) is a homotetramer that is allosterically inhibited by phosphoenolpyruvate (PEP), which binds along one dimer-dimer interface. The substrate, fructose 6-phosphate (Fru-6-P), binds along the other dimer-dimer interface. Evans et al. observed that the structure with inhibitor (phosphoglycolate) bound, compared to the structure of wild-type BsPFK with substrate and activator bound, exhibits a 7° rotation about the substrate-binding interface, termed the quaternary shift [Schirmer, T., and Evans, P. R. (1990) Nature 343, 140-145]. We report that the variant D12A BsPFK exhibits a 100-fold increase in its binding affinity for PEP, a 50-fold decrease in its binding affinity for Fru-6-P, but an inhibitory coupling comparable to that of the wild type. Crystal structures of the apo and PEP-bound forms of D12A BsPFK have been determined (Protein Data Bank entries 4I36 and 4I7E , respectively), and both indicate a shifted structure similar to the inhibitor-bound structure of the wild type. D12 does not directly bind to either substrate or inhibitor and is located along the substrate-binding interface. A conserved hydrogen bond between D12 and T156 forms across the substrate-binding subunit-subunit interface in the substrate-bound form of BsPFK. The variant T156A BsPFK, when compared to the wild type, shows a 30-fold increase in PEP binding affinity, a 17-fold decrease in Fru-6-P binding affinity, and an estimated coupling that is also approximately equal to that of the wild type. In addition, the T156A BsPFK crystal structure bound to PEP is reported (Protein Data Bank entry 4I4I ), and it exhibits a shifted structure similar to that of D12A BsPFK and the inhibitor-bound structure of the wild type. The results suggest that the main role of the quaternary shift may be to influence ligand binding and not to cause the heterotropic allosteric inhibition per se. PMID:23859543

Mosser, Rockann; Reddy, Manchi C M; Bruning, John B; Sacchettini, James C; Reinhart, Gregory D

2013-07-31

310

Quaternary tectonics of the southeastern coastal area, Korea: subsidence of marine terrace and late Quaternary faults  

NASA Astrophysics Data System (ADS)

Strong earthquake has rarely occurred in Korean peninsula and a few events were recorded since 27 A.D. Historical and recent earthquakes are concentrated in the southeastern area of Korean peninsula, where more than 30 Quaternary fault exposures have recently been founded. The southern tip of the southeastern coastal area has been known as a stable block: quaternary fault and micro-earthquakes haven’t occurred. To clarify whether the active tectonic movement is or not, digital marine terrace mapping and fracture mapping have been done for the southeastern coastal area. The area is composed of the Late Cretaceous volcanic rocks, sedimentary rocks and the Early Tertiary granite. Wave-cut platform in the area is comparatively smaller and narrower than that of other southeastern parts. Most of platforms have no Quaternary sediments and or very thin sediments. Platforms except the Holocene are generally divided into three steps. The lowest platform has a height of 8-11m. The middle one is broad with a height of 17 to 22m. The highest is narrowly scattered with a height of 33-41m. The lowest platform is correlated to the 2nd terrace of the northern area, which has been attributed to the isotopic substage, 5a. The uplift rate based on the altimetrical and indirect chronological data ranges from 0.072-0.108 m/ky. Such a low uplift rate indicates that the area is very stable because of belonging to intra-plate or continental block. The elevation of platform is getting lower from the north to the south. Reducing altitude of platform towards the south might be interpreted to a local block tilting within Yangsan Fault Belt during the Latest Pleistocene or an active tectonic subsidence to the south throughout the whole Korean peninsula. Several Quaternary faults supporting the active tectonic movement have been found from marine terrace feature mapping. Two sites have been proved the presence of fault by geophysical survey and cut-slope. Flight of marine terrace at two fault sites inclines slowly to the inland side and shows topographically vertical offset with small amount. Local block tilting and subsiding platforms from the north to the south are both due to the active tectonic fault movement of the Latest Pleistocene. Accompanied reverse Pleistocene faults dip to the east and show the top-up-to-the-west reverse movement sense. GPS measurement revealed the west of northwestern vector. Differential tectonic stress regime to the west has occurred to Korean peninsula during the Latest Pleistocene. Stronger tectonic force from the Pacific Ocean Plate gave an effect of high platform to the northern area. Weaker dynamic force due to the Philippine Plate caused low elevation to the southern area.

Choi, S.-J.; Ota, Y.; Chwae, U.

2003-04-01

311

Characterization of Quaternary and suspected Quaternary faults, Amargosa area, Nevada and California  

SciTech Connect

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.

Anderson, R.E.; Crone, A.J.; Machette, M.N.; Bradley, L.A.; Diehl, S.F.

1995-12-31

312

A CMOS Quaternary Threshold Logic Full Adder Circuit with Transparent Latch  

Microsoft Academic Search

A circuit that realizes the quaternary threshold logic full adder function with transparent latching has been realized in a standard polysilicon-gate CMOS technology. In its FOLLOW mode, the quaternary full adder accepts two quaternary inputs and a binary CARRY input, and develops a two-quaternary-digit output word that is the base-four sum of the inputs. In the HOLD mode, these output

1990-01-01

313

Corrosion inhibitor and method of use  

SciTech Connect

This paper discusses a corrosion inhibitor formulation capable of dispersion in aqueous well treating acids. It comprises from 1 to 25 wt % of a metal salt wherein the metal thereof is selected from the group consisting of Cu{sup +}, Sn, Zn, and a Group IIA metal having an atomic number from 12 to 56, a Group IVA metal having an atomic number of 22 or 40, a Group IIIB metal having an atomic number from 13 to 49, a Group VIA metal having an atomic number from 24 to 74, and a Group VB metal having an atomic number from 33 to 83; and mixtures thereof; from 3 to 50 wt% of a quaternary ammonium compound capable of forming a complex with the metal salt; sufficient amount of a highly polar aprotic solvent to dissolve the metal salt and the quaternary ammonium compounds, the concentration of the polar aprotic solvent being between 20 to 90 wt %; and from 1 to 15% of an organic amine dispersant for dispersing the complex of the quaternary ammonium compound and the metal salt in the sell treating acid, the wt % being based on the formulation. This patent also describes a method of acidizing a subterranean formation by injecting a well treating acid solution down pipe into the well. It comprises preparing the corrosion inhibitor formulation of claim 1; dispersing the formulation in the well treating acid solution to provide the solution with at least 0.08 wt % of the metal salt based on the combined weight of the well treating acid and formulation, and injecting the well treating acid solution containing the corrosion inhibitor formulation through the pipe into the formation.

Williams, D.A.; Holifield, P.K.; Looney, J.R.; McDougall, L.A.

1991-03-26

314

Bis-quaternary oximes amplify the effectiveness of acetylcholinesterase to detoxify organophosphorus compounds  

SciTech Connect

Pretreatment of rhesus monkeys with fetal bovine serum acetylcholinesterase (FBS AChE) provides complete protection against 5 LD(50), of organophosphate (OP) without any signs of toxicity or performance decrements as measured by serial probe recognition tests or primate equilibrium platform performance (7,8). Although such use of enzyme as a single pretreatment drug for OP toxicity is sufficient to provide complete protection, a relatively large (stoichiometric) amount of enzyme was required in vivo to neutralize OP. To improve the efficacy of ChEs as pretreatment drugs, we have developed an approach in which the catalytic activity of OP-inhibited FBS AChE was rapidly and continuously restored, thus detoxifying the OP and minimizing enzyme aging by having sufficient amounts of appropriate oxime present. The efficacy of FBS AChE to detoxify several OPs was amplified by addition of bisquaternary oximes, particularly HI-6. When mice were pretreated with sufficient amounts of FBS AChE and HI-6 and challenged with repeated doses of sarin, the OP was continuously detoxified so long as the molar concentration of the sarin dose was less than the molar concentration of AChE in circulation. The in vitro experiments showed that the stoichiometry of sarin:FBS AChE was higher than 3200:1 and in vivo stoichiometry with mice was as high as 57:1. Addition of HI-6 to FBS AChE as a pretreatment drug amplified the efficacy of enzyme as a scavenger of nerve agents.

Caranto, G.R.; Waibel, K.H.; Asher, J.M.; Larrison, R.W.; Brecht, K.M.

1993-05-13

315

Acetylcholinesterase capillary enzyme reactor for screening and characterization of selective inhibitors.  

PubMed

The aim of the present work is to report on the optimized preparation of capillary enzyme reactors (ICERs) based on acetylcholinesterase (AChE, EC 3.1.1.7), for the screening of selective inhibitors. The AChE-ICERs were prepared by using the homobifunctional linker glutaraldehyde through Schiff base linkage. The enzyme was anchored onto a modified fused silica capillary and employed as an LC biochromatography column for online studies, with UV-vis detection. Not only did the tailored AChE-ICER result in maintenance of the activity of the immobilized enzyme, but it also significantly improved the stability of the enzyme in the presence of organic solvents. In addition, the kinetic studies demonstrated that the enzyme retained its activity with high stability, preserving its initial activity over 10months. The absence of non-specific matrix interactions, immediate recovery of the enzymatic activity, and short analysis time were the main advantages of this AChE-ICER. The use of AChE-ICER in the ligands recognition assay was validated by evaluation of four known reversible inhibitors (galanthamine, tacrine, propidium, and rivastigmine), and the same order of inhibitory potencies described in the literature was found. The immobilized enzyme was utilized in the screening of 21 coumarin derivatives. In this library, two new potent inhibitors were identified: coumarins 20 (IC(50) 17.14±3.50?M) and 21 (IC(50) 6.35±1.20?M), which were compared to the standard galanthamine (IC(50) 12.68±2.40?M). Considering the high inhibitory activities of these compounds, with respect to the AChE-ICER, the mechanism of action was investigated. Both coumarins 20 and 21 exhibited a competitive mechanism of action, furnishing K(i) values of 8.04±0.18 and 2.67±0.18?M, respectively. The results revealed that the AChE-ICER developed herein represents a useful tool for the biological screening of inhibitor candidates and evaluation of action mechanism. PMID:22391555

da Silva, Joyce Izidoro; de Moraes, Marcela Cristina; Vieira, Lucas Campos Curcino; Corrêa, Arlene Gonçalves; Cass, Quezia Bezerra; Cardoso, Carmen Lucia

2012-02-18

316

Tyrosine urea muscarinic acetylcholine receptor antagonists: achiral quaternary ammonium groups.  

PubMed

Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction. PMID:23099092

Jin, Qi; Davis, Roderick S; Bullion, Ann M; Jin, Jian; Wang, Yonghui; Widdowson, Katherine L; Palovich, Michael R; Foley, James J; Schmidt, Dulcie B; Buckley, Peter T; Webb, Edward F; Salmon, Michael; Belmonte, Kristen E; Sarau, Henry M; Busch-Petersen, Jakob

2012-10-02

317

A quaternary logic encoder-decoder circuit design using CMOS  

NASA Astrophysics Data System (ADS)

A binary-to-quaternary encoder and quaternary-to-binary decoder circuit pair is described as designed in a 5-volt CMOS technology. These circuits communicate with logical currents. Using model parameter values for a standard 5-micron polysilicon gate process technology and 10 microamp logical currents, we have simulated propagation delays of about 20 ns from binary encoder input to binary decoder output. with the encoder using scaled-up logical currents and driving a 100 pF load on the decoder input to simulate communication between chips, we observe simulated worst-case delays of about 35ns.

Freitas, D. A.; Current, K. W.

318

Ice Age Earth: Late Quaternary geology and climate  

SciTech Connect

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.

Dawson, A.G.

1992-01-01

319

Quaternary glaciation of the Himalayan-Tibetan orogen  

Microsoft Academic Search

ABSTRACT: Glacial geological,evidence,from,throughout,the,Himalayan–Tibetan,orogen,is examined,to determine,the timing and,extent of late Quaternary,glaciation in this region and,its relation to similar changes,on a global scale. The evidence,summarised,here supports the existence of expanded,ice caps,and,extensive,valley glacier systems,throughout,the region,during,the late Quaternary. However, it cannot yet be determined whether the timing of the extent of maximum glaciation was synchronous,throughout,the entire region or whether,the response was more,varied. The lack

Lewis A. Owen; Marc W. Caffee; Robert C. Finkel; Yeong Bae Seong

2008-01-01

320

40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).  

Code of Federal Regulations, 2013 CFR

...2013-07-01 2013-07-01 false Modified polymer of vinyl acetate and quaternary ammonium...Chemical Substances § 721.8658 Modified polymer of vinyl acetate and quaternary ammonium...substance identified generically as modified polymer of vinyl acetate and quaternary...

2013-07-01

321

Ribonuclease inhibitors  

Microsoft Academic Search

RNases are important enzymes of cell metabolism, influencing gene expression, affecting cell growth and differentiation, and\\u000a participating in cell defense against pathogens and induction of apoptosis. Since RNases mostly occur in complex with their\\u000a inhibitors in the cell, the inhibitors also play a role in the above processes. The review considers natural protein RNase\\u000a inhibitors of animals, plants, and bacteria,

G. I. Yakovlev; V. A. Mitkevich; A. A. Makarov

2006-01-01

322

Surface-Wave Plasma Deposition of a-C:H Films for Field Emission  

NASA Astrophysics Data System (ADS)

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 ?A/cm^2 was obtained to be 4 V/?m. 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.

Sano, Toru; Nagatsu, Masaaki; Takada, Noriharu; Toyoda, Hirotaka; Sugai, Hideo; Guang, W. X.; Hirao, Takashi; Toyoda, Naoki

2000-10-01

323

Biocompatible Silver-containing a-C:H and a-C coatings: AComparative Study  

SciTech Connect

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.

Endrino, Jose Luis; Allen, Matthew; Escobar Galindo, Ramon; Zhang, Hanshen; Anders, Andre; Albella, Jose Maria

2007-04-01

324

Rinodina sophodes (Ach.) Massal.: a bioaccumulator of polycyclic aromatic hydrocarbons (PAHs) in Kanpur City, India.  

PubMed

The aim of this study is to determine the possibility of using Rinodina sophodes (Ach.) Massal., a crustose lichen as polycyclic aromatic hydrocarbons (PAHs) bioaccumulator for evaluation of atmospheric pollution in tropical areas of India, where few species of lichens are able to grow. PAHs were identified, quantified and compared to evaluate the potential utility of R. sophodes. The limit of detection for different PAHs was found to be 0.008-0.050 ?g g(?-?1). The total PAHs in different sites were ranged between 0.189 ± 0.029 and 0.494 ± 0.105 ?g g(?-?1). The major sources of PAHs were combustion of organic materials, traffic and vehicular exhaust (diesel and gasoline engine). Significantly higher concentration of acenaphthylene and phenanthrene indicates road traffic as major source of PAH pollution in the city. Two-way ANOVA also confirms that all PAHs content showed significant differences between all sampling sites (P 1%). This study establishes the utility of R. sophodes in monitoring the PAHs accumulation potentiality for development of effective tool and explores the most potential traits resistant to the hazardous environmental conditions in the tropical regions of north India, where no such other effective way of biomonitoring is known so far. PMID:21465135

Satya; Upreti, Dalip K; Patel, D K

2011-04-05

325

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

|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…

Barrineau, Irene T., Ed.

2003-01-01

326

Inhibitory effects on esterase enzymes buche and ache in rainbow trout (Oncorhyncus mykiss) produced by the slow release insecticide chitosan diethyl phosphate.  

PubMed

The study on the toxicity of chitosan diethyl phosphate (ChDP), a controlled release insecticide, on the activities of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) in rainbow trout exposed to this pesticide was carried out. It was found that ChDP reduced BuChE activity in O. mykiss by a factor of eight at 6 days, with high fluctuation to the end of the exposition time at 12 days. The in vitro analysis of brain AChE treated with ChDP and Phenamiphos showed that it was competitively inhibited by both organophosphates. The values obtained for Km and Vmax for the AChE-ChDP (Km: 21.23 microM; Vmax: 43.10 micromol/min/g) and AChE-Phenamiphos (Km: 38.62 microM; Vmax: 38.91 micromol/min/g) systems were relatively low compared to values of the AChE (control) system (Km: 62.99 microM; Vmax: 63.29 micromol/min/g). Results reported in this study confirmed that chitosan diethyl phosphate performs similarly to organophosphate pesticides, producing inhibition in cholinesterases in rainbow trout. PMID:16190020

Placencia, J; Rudolph, A; Cabrera, G; Cárdenas, G; Yévenes, M

2005-01-01

327

The inhibitive effect of some quaternary ammonium salts towards corrosion of aluminium in hydrochloric acid solution  

NASA Astrophysics Data System (ADS)

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.

Mohamed, A.-M. K.; Al-Nadjm, A.; Fouda, A.-A. S.

1998-10-01

328

Benzodiazepines inhibit the acetylcholine receptor-operated potassium current (IK.ACh) by different mechanisms in guinea-pig atrial myocytes.  

PubMed

The anticholinergic effects of 7 benzodiazepines, bromazepam, camazepam, chlordiazepoxide, diazepam, lorazepam, medazepam and triazolam, were compared by examining their inhibitory effects on the acetylcholine receptor-operated potassium current (I(K).(ACh)) in guinea-pig atrial myocytes. All of these benzodiazepines (0.3-300 µM) inhibited carbachol (1 µM)-induced I(K).(ACh) in a concentration-dependent manner. The ascending order of IC(50) values for carbachol-induced I(K).(ACh) was as follows; medazepam, diazepam, camazepam, triazolam, bromazepam, lorazepam and chlordiazepoxide (>300 µM). The compounds, except for bromazepam, also inhibited I(K).(ACh) activated by an intracellular loading of 100 µM guanosine 5'-[?-thio]triphosphate (GTP?S) in a concentration-dependent manner. The ascending order of IC(50) values for GTP?S-activated I(K).(ACh) was as follows; medazepam, diazepam, camazepam, lorazepam, triazolam chlordiazepoxide (>300 µM) and bromazepam (>300 µM). To clarify the molecular mechanism of the inhibition, IC(50) ratio, the ratio of IC(50) for GTP?S-activated I(K).(ACh) to carbachol-induced I(K).(ACh), was calculated. The IC(50) ratio for camazepam, diazepam, lorazepam, medazepam and triazolam was close to unity, while it for chlordiazepoxide could not be calculated. These compounds would act on the GTP binding protein and/or potassium channel to achieve the anticholinergic effects in atrial myocytes. In contrast, since the IC(50) ratio for bromazepam is presumably much higher than unity judging from the IC(50) values (104.0 ± 30.0 µM for carbachol-induced I(K).(ACh) and >300 µM for GTP?S-activated I(K).(ACh), it would act on the muscarinic receptor. In summary, benzodiazepines had the anticholinergic effects on atrial myocytes through inhibiting I(K).(ACh) by different molecular mechanisms. PMID:22333515

Okada, Muneyoshi; Mizuno, Wataru; Nakarai, Ryu; Matada, Takashi; Yamawaki, Hideyuki; Hara, Yukio

2012-02-14

329

Hydroclimatic interpretation of Quaternary shorelines on South Australian playas  

Microsoft Academic Search

The catchment of Lake Eyre is one of the world's largest internally drained basins. The playas near its depocentre, the driest region of Australia, contain a partial record of Quaternary climatic and hydrologic events for the last full glacial cycle, and probably beyond. Ancient beach-ridges marginal to lakes Eyre, Frome, Callabonna and Blanche have been dated using thermoluminescence (TL) to

Gerald C. Nanson; Roger A. Callen; David M. Price

1998-01-01

330

Adsorption of some quaternary onium salts on silica gel  

Microsoft Academic Search

The adsorption of quaternary onium salts such as hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, benzyltrimethylammonium chloride and tetrabutylammonium bromide from aqueous solution, and of tricaprylylmethylammonium chloride (Aliquat® 336) and hexadecyltributyl phosphonium bromide from organic solution has been studied using silica as an adsorbent. The adsorption from the aqueous phase was found to be dependent on the pH of the medium, giving a

A. C. Ghosh; K. Satyanarayana; R. C. Srivastava; N. N. Dutta

1995-01-01

331

Bacterial resistance to disinfectants containing quaternary ammonium compounds  

Microsoft Academic Search

Quaternary ammonium compounds (QAC) are widely used as disinfectants in both medical and food environments. Microbial contaminants are, therefore, regularly exposed to their action and the isolation from clinical and food sources of resistant bacteria continues to be reported in many countries. Resistance to QAC in clinical strains of staphylococci is encoded by one of at least three resistance genes,

G. Sundheim; S. Langsrud; E. Heir; A. L. Holck

1998-01-01

332

Supernormal optical characteristics in doped quaternary ammonium salt KDP crystals  

Microsoft Academic Search

Potassium dihydrogen phosphate, KH2PO4 (KDP) crystals with different concentrations of quaternary ammonium salt in solution were grown. In this paper, unusual transmittance ratio properties of KDP are reported. The transmittance ratio is smaller than unity at some locations. These results indicate that the plane wave effect and optical activity are highly displaced in KDP crystals, and the effect is varies

Xin-guang Xu; Xun Sun; Zheng-ping Wang; Gui-bao Xu; Zong-shu Shao; Zhang-shou Gao

2003-01-01

333

Photoluminescence Studies of InGaAlAs Quaternary Alloys.  

National Technical Information Service (NTIS)

Photoluminescence data are used to obtain the concentration and temperature dependence of the bandgap energies of epitaxial layers of quaternary alloy In/sub 0.1/Ga/sub x/Al/sub y/As for Al concentrations less than 0.6. The samples were grown by MBE witho...

E. D. Jones L. R. Dawson

1988-01-01

334

Quaternary Bimodal Volcanism in Acigol area, Cappadocia - Turkiye  

NASA Astrophysics Data System (ADS)

Cappadocia is famous with its splendid ignimbritic landscape which occurred during Miocene. The volcanic activity continued during Pliocene and Quaternary. Quaternary volcanism in Acigöl sector is represented by bimodal basaltic and rhyolitic products with a lack of intermediate compositions. Basaltic volcanic products (~47% SiO2) are characterized by diffuse monogenetic scoria cones and associated lava flows. Moreover, fissural basaltic activity is observed along N-S trending crack network. Preliminary petrographical studies indicate that basaltic products are hypocrystalline-porphyritic olivine basalts. Quaternary rhyolitic volcanism is represented by domes, dome complexes, associated lava flows and phreatomagmatic eruption centers. Besides, occurrences of spherulite bearing vitric rhyolitic intrusions are present along the probable boundary of a Miocene caldera, which is thought to be the source region for the Cappadocian ignimbrites. Rhyolitic lavas (74 -77% SiO2) are dominantly aphyric with slight transition from meta/peraluminous towards peralkaline whole rock compositions (Agpaitic Index: 0,91 - 0,96). However, Agpaitic Indices on volcanic glass are usually greater than unity. Occurrence of Quaternary bimodal basaltic - slightly peralkaline rhyolitic volcanism as well as N-S extensional tectonic features would be the result of possible intraplate rifting processes.

Cubukcu, H. E.; Aydar, E.; Sen, E.; Bayhan, H.

2009-04-01

335

Impact of quaternary structure dynamics on allosteric drug discovery.  

PubMed

The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131-143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor ?. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics. PMID:23409765

Jaffe, Eileen K

2013-01-01

336

Late Quaternary Lake-Level Record from Northern Eurasia  

Microsoft Academic Search

Lake records from northern Eurasia show regionally coherent patterns of changes during the late Quaternary. Lakes peripheral to the Scandinavian ice sheet were lower than those today but lakes in the Mediterranean zone were high at the glacial maximum, reflecting the dominance of glacial anticyclonic conditions in northern Europe and a southward shift of the Westerlies. The influence of the

Sandy P. Harrison; Ge Yu; Pavel E. Tarasov

1996-01-01

337

Quaternary phosphorites off the southeast coast of India  

Microsoft Academic Search

Detailed petrological, mineralogical, geochemical and radiogenic (U, Sr, Nd) and stable isotope (C, O, S) studies have been carried out on the Quaternary phosphorites of the continental margin off Chennai, southeast coast of India. These phosphorites are formed as a result of trapping and binding of sediments by microbial mats and are similar to phosphate stratiform stromatolites. Detrital and biogenic

V. Purnachandra Rao; A Michard; S. W. A Naqvi; M. E Böttcher; Rama Krishnaswamy; M Thamban; R Natarajan; D. V Borole

2002-01-01

338

The sequence of Quaternary glaciation in the Bayan Har Mountains  

Microsoft Academic Search

Four periods of Quaternary glaciation in the Pleistocene have been found in the area of the Bayan Har Mountains. They represent, respectively, the two stages of the Last Glacial age; the penultimate ice age, and an earlier ice age. During the late stage of the Last Glacial age, glaciers developed only near the mountain ridges of the Bayan Har. In

Shangzhe Zhou; Jijun Li

1998-01-01

339

Late Quaternary evolution of Riverine Plain paleochannels, southeastern Australia  

Microsoft Academic Search

The Riverine Plain of southeastern Australia is the result of prolonged Cenozoic fluvial activity associated with the Murray River and its major southern tributaries, the Murrumbidgee, Goulburn and Lachlan. Single thread, distributary and anabranching channels and floodplains with associated eolian dunes and lunette-bordered lake basins characterise the uppermost sequences of the Late Quaternary. Following 30 years of detailed mapping and

K. J. Page; J. Kemp; G. C. Nanson

2009-01-01

340

Quaternary research in Poland: selected achievements and prospects  

Microsoft Academic Search

A b s t r a c t . During the last thirty years there were several turnouts in Quaternary studies that increasingly accelerated our under- standing of natural processes and opened new research fields. Among others, they included complex reconstruction of palaeoclimatic phenomena, studies of deep-sea and long-term continental record, and extensive application of reliable dating methods. In Poland

Leszek Marks

341

The Late Quaternary glaciation of Africa: A regional synthesis  

Microsoft Academic Search

There are numerous mountain ranges in Africa which carry evidence of Quaternary glaciation, though few have glaciers now and these are rapidly disappearing. The best studied sites are in East Africa and Ethiopia. In East Africa, the three highest mountains, Kilimanjaro, Kenya and the Rwenzori, each have evidence of 3–5 major glaciations dating back to an estimated 400,000 BP, one

Henry A. Osmaston; Sandy P. Harrison

2005-01-01

342

Quaternary Glacial Mapping in Western Wisconsin Using Soil Survey Information  

ERIC Educational Resources Information Center

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…

Oehlke, Betsy M.; Dolliver, Holly A. S.

2011-01-01

343

Formal Quaternary stratigraphy—What do we expect and need?  

Microsoft Academic Search

At the start of my INQUA career a reasonable target for the long-term development of Quaternary stratigraphy was the construction of a table that listed a number (perhaps fewer than a dozen, perhaps more) of “stages” for each of the chief regions of the Earth, and which reliably indicated how these stages should be correlated from region to region. A

N. J. Shackleton

2006-01-01

344

Formal Quaternary stratigraphy---What do we expect and need?  

Microsoft Academic Search

At the start of my INQUA career a reasonable target for the long-term development of Quaternary stratigraphy was the construction of a table that listed a number (perhaps fewer than a dozen, perhaps more) of ``stages'' for each of the chief regions of the Earth, and which reliably indicated how these stages should be correlated from region to region. A

N. J. Shackleton

2006-01-01

345

Quaternary paleolake development in the Fen River basin, North China  

Microsoft Academic Search

The Taiyuan Graben and the Linfen Graben are two fault-controlled grabens in the Fen River basin, north China. Broad paleolakes periodically occupied the two grabens during the Pleistocene. This paper discusses how neotectonic activities and paleoclimate changes may have influenced the development of the paleolakes in the two grabens during the middle to late Quaternary, based on the lacustrine landforms

Xiaomeng Hu; Youli Li; Jingchun Yang

2005-01-01

346

Late Quaternary paleohydrologic and paleotemperature change in southern Nevada  

Microsoft Academic Search

Paleo-spring discharge activity in the southern Great Basin responded to changes in recharge, hence climate changes, in high mountain areas during the late Quaternary. In our study, we examined four stratigraphic sections in southern Nevada in order to reconstruct paleohydrologic change spanning the last two major discharge cycles. The largest discharge event in those sections is expressed as extensive wetland

Jay Quade; Richard M. Forester; Joseph F. Whelan

347

Quaternary Naltrexone Reverses Radiogenic and Morphine-Induced Locomotor Hyperactivity.  

National Technical Information Service (NTIS)

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...

G. A. Mickley K. E. Stevens J. A. Galbraith G. A. White G. L. Gibbs

1984-01-01

348

Quaternary Glacial Mapping in Western Wisconsin Using Soil Survey Information  

ERIC Educational Resources Information Center

|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…

Oehlke, Betsy M.; Dolliver, Holly A. S.

2011-01-01

349

Effects of Quaternary Sea Level Cycles on Strontium in Seawater  

Microsoft Academic Search

The effects of Quaternary sea level changes on the Sr budget of the ocean are investigated using coupled numerical models of the seawater Sr and Ca budgets. Glacial\\/interglacial sea level cycles influence the Sr concentration of seawater directly through the periodic exposure and weathering of aragonite on continental shelves and indirectly by modulating the location and extent of carbonate deposition

Heather M Stoll; Daniel P Schrag

1998-01-01

350

Quaternary glaciation in Africa: key chronologies and climatic implications  

Microsoft Academic Search

Multiple episodes of Quaternary glaciation are evidenced on >10 distinct mountain localities throughout Africa, with the best dated sites from Kilimanjaro and Mt Kenya in equatorial East Africa. A general paucity of radiogenic dates constrains the glacial chronology, and regional sequences have largely been based on correlations by relative weathering of features. Excellent glacial moraine preservation and other features of

Bryan G. Mark; Henry A. Osmaston

2008-01-01

351

Bis(12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating ?7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade.  

PubMed

Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). However, the huge discrepancy between the EC50 value and IC50 value of B12H, to protect against neuronal toxicity (0.09 ?M) and to block the NMDA receptor (21.8 ?M) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor. Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (?7nAChR), but not muscarinic acetylcholine receptor (mAChR) or ?4?2nAChR, decreased the neuroprotection of B12H. The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors. Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3?. All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating ?7nAChR/PI3-K/Akt cascade. PMID:23085120

Cui, Wei; Hu, Shengquan; Chan, Hugh H N; Luo, Jialie; Li, Wenming; Mak, Shinghung; Choi, Tony Chunglit; Rong, Jianhui; Carlier, Paul R; Han, Yifan

2012-10-16

352

Characterization of O,O-diethylphosphoryl oximes as inhibitors of cholinesterases and substrates of phosphotriesterases.  

PubMed

Reactivators of organophosphate (OP)-inhibited cholinesterases (ChEs) are believed to give rise to phosphorylated oximes (POX) that reinhibit the enzyme. Diethylphosphoryl oximes (DEP-OX) that were generated in situ were demonstrated in the past to be unstable, yet were more potent inhibitors of acetylcholinesterase (AChE) than the parent OPs. In view of the inconsistencies among reported results, and the potential toxicity of POXs, it seemed important to characterize authentic DEP-OXs, and to evaluate their interference with reactivation of diethylphosphoryl-ChE (DEP-ChE) conjugates. To this end, the diethylphosphoric acid esters of 1-methyl-2-pyridinium carboxaldehyde oxime (DEP-2PAM) and 1-methyl-4 pyridinium carboxaldehyde oxime (DEP-4PAM) were synthesized and chemically defined. The half-lives of DEP-2PAM and DEP-4PAM in 10 mM Tris buffer, pH 7.8, at 29 degrees were found to be 10 and 980 sec, respectively. The two DEP-OXs inhibited ChEs with the following ranking order: for DEP-2PAM, human butyrylcholinesterase (HuBChE, k(i) = 2.03 x 10(9) M(-1) min(-1)) > mouse AChE (MoAChE) approximately equal to fetal bovine serum AChE (FBS-AChE) approximately equal to equine BChE (EqBChE); for DEP-4PAM, HuBChE (k(i) = 0.71 x 10(9) M(-1) min(-1)) > EqBChE > MoAChE > FBS-AChE. A dialkylarylphosphate hydrolase (phosphotriesterase; PTE) from Pseudomonas sp. catalyzed the hydrolysis of DEP-4PAM with k(cat)/Km = 3.56 x 10(7) M(-1) min(-1) and Km = 0.78 mM. Reactivation of DEP-ChEs was enhanced by PTE when 4-PAM-based oximes were used as reactivators, whereas reactivation with 2-PAM-based oximes was not affected by PTE. This observation is attributed primarily to the short half-life of DEP-OXs derived from the latter oximes. Relatively low doses of PTE can detoxify large quantities of DEP-OXs rapidly, and thereby augment the efficacy of antidotes that contain the oxime function in position 4 of the pyridine ring. PMID:10424771

Leader, H; Vincze, A; Manisterski, B; Rothschild, N; Dosoretz, C; Ashani, Y

1999-08-01

353

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors.  

PubMed

A novel series of tacrine-lophine hybrids was synthesized and tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 in the nanomolar concentration scale. The key step is the one-pot four component condensation reaction of 9-aminoalkylamino-1,2,3,4-tetrahydroacridines, benzil, different substituted aromatic aldehydes and NH4OAc, using InCl3 as the best catalyst. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. As an extension of the four component approach to tetrasubstituted imidazoles, a new series of bis-(2,4,5-triphenyl-1H-imidazoles) or bis(n)-lophines was tested against AChE and BuChE. PMID:23422935

da Costa, Jessé Sobieski; Lopes, João Paulo Bizarro; Russowsky, Dennis; Petzhold, Cesar Liberato; Borges, Antonio César de Amorim; Ceschi, Marco Antonio; Konrath, Eduardo; Batassini, Cristiane; Lunardi, Paula Santana; Gonçalves, Carlos Alberto Saraiva

2013-02-04

354

Heritability and Fitness Correlates of Personality in the Ache, a Natural-Fertility Population in Paraguay  

PubMed Central

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.

Bailey, Drew H.; Walker, Robert S.; Blomquist, Gregory E.; Hill, Kim R.; Hurtado, A. Magdalena; Geary, David C.

2013-01-01

355

Seismic tomographic mapping of the Earth's interior — Back to basics revisiting the ACH inversion  

NASA Astrophysics Data System (ADS)

It is now more than 35 years since our original work on seismic tomography commenced in June 1974 upon Keiiti Aki's arrival at Kjeller near Oslo. It was published by Aki et al. (1977) and has found wide-spread applications in numerous studies of the Earth's interior from crust to core and in addition triggered many theoretical ones as well. In those times, computer technologies were rather crude and this hampered our tomographic research. In particular, we were somewhat unhappy about both our Generalized Inverse (GI) and the Stochastic Inverse (SI) solutions because of the former being too bumpy and the latter involving vertical smoothing. These problems remain in evidence also in recent studies as will be demonstrated in this review work. We start with re-examining the ACH-original work and then introduce Gauss-Markov (GM) filtering offsetting the defects of both the generalized and stochastic inverses. We highlight the relative merits of our novel inversion method by real tests on the original Norsar P-residuals and the corresponding 5 layered lithosphere model using synthetic velocity anomalies. Then we repeated the original inversion experiment adding the GM solution. The outcome was that the original SI solution was useless; GI too bumpy while the GM solution was appealing both computationally and in the context of geotectonic interpretation. We found that alternative inversion procedures like those forwarded by Backus and Gilbert (1968) and by Pijpers and Thompson (1992), the latter for helioseismology, were not applicable. The reason is that our unknowns are relative velocity anomalies within separate model layers and thus violate basic assumptions in the mentioned procedures. We also discuss source and structure parameter separation and the recent 'double difference' approach in tomography based on local earthquake data.

Christoffersson, Anders; Husebye, Eystein S.

2011-06-01

356

Dual inhibitors of ?-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates.  

PubMed

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer's disease (AD), where the overproduction and aggregation of the ?-amyloid peptide (A?) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (A? aggregation) phases of the disease. Dual inhibitors of A? aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of A? aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic A? peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multitarget anti-Alzheimer compounds that exhibit both A? aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of A? aggregation inhibitors that rely on the overexpression of A?42 alone or fused with reporter proteins in Escherichia coli. PMID:23931440

Viayna, Elisabet; Sabate, Raimon; Muñoz-Torrero, Diego

2013-01-01

357

Plasma coatings CrAlN and aC:H for high efficient power train in automobile  

Microsoft Academic Search

The aim of this study is to find out a correlation between the physical interactions, such as adhesion energy and interfacial tension, and the friction behavior of hydrogenated DLC (diamond-like Carbon) (a-C:H) and CrAlN with lubricants for increasing the efficiency of power train. The lubricants investigated are mineral oil, polyalphaolefin, synthetic ester, polyether and polyglycol. The tribological tests for determination

K. Bobzin; N. Bagcivan; S. Theiss; K. Yilmaz

2010-01-01

358

The effects of climatic pattern on lichen productivity: Cetraria cucullata (Bell.) Ach. in the arctic tundra of northern Alaska  

Microsoft Academic Search

The climatic control of productivity for two populations of the lichen Cetraria cucullata (Bell.) Ach. growing in the arctic tundra of northern Alaska (70°28'N, 157°23'W) was examined. Respiratory losses of carbon vary with tissue temperature, tissue water content, and time since wetting. Potential net photosynthetic gains of carbon are affected by photon flux density, tissue temperature, and water content. The

Martin J. Lechowicz

1981-01-01

359

Enhancement of Attentional Performance by Selective Stimulation of ?4?2* nAChRs: Underlying Cholinergic Mechanisms  

Microsoft Academic Search

Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective ?4?2* nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction

William M Howe; Jinzhao Ji; Vinay Parikh; Sarah Williams; Elisabeth Mocaër; Caryn Trocmé-Thibierge; Martin Sarter

2010-01-01

360

Chemical sputtering of aC:H films by simultaneous exposure to energetic Ar+ ions and water vapor  

Microsoft Academic Search

Amorphous hydrocarbon films (a-C:H) were exposed to a beam of 800eV Ar+ ions. The temperature of the films was varied between 110 an 800K. When backfilling the chamber with water vapor during ion bombardment there is a marked increase of the erosion rate at and below 200 K, while there is no influence on the erosion rate at room temperature

C. Hopf; M. Schlüter; W. Jacob

2008-01-01

361

Characterization of Quaternary and suspected Quaternary faults, regional studies, Nevada and California  

SciTech Connect

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.

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

362

Inactivity-induced increase in nAChRs upregulates Shal K(+) channels to stabilize synaptic potentials.  

PubMed

Long-term synaptic changes, which are essential for learning and memory, are dependent on homeostatic mechanisms that stabilize neural activity. Homeostatic responses have also been implicated in pathological conditions, including nicotine addiction. Although multiple homeostatic pathways have been described, little is known about how compensatory responses are tuned to prevent them from overshooting their optimal range of activity. We found that prolonged inhibition of nicotinic acetylcholine receptors (nAChRs), the major excitatory receptors in the Drosophila CNS, resulted in a homeostatic increase in the Drosophila ?7 (D?7)-nAChR. This response then induced an increase in the transient A-type K(+) current carried by Shaker cognate L (Shal; also known as voltage-gated K(+) channel 4, Kv4) channels. Although increasing D?7-nAChRs boosted miniature excitatory postsynaptic currents, the ensuing increase in Shal channels served to stabilize postsynaptic potentials. These data identify a previously unknown mechanism for fine tuning the homeostatic response. PMID:22081160

Ping, Yong; Tsunoda, Susan

2011-11-13

363

Is ?7-nAChR a possible target for lung cancer and malignant pleural mesothelioma treatment?  

PubMed

This paper discusses the potential therapeutic effect of ?7-nAChR antagonists for NSCLC (non small cell lung cancer) and MPM (malignant pleural mesothelioma). This therapeutic approach is based on the experimental observations that: (a) functional ?7-nAChR are expressed in NSCLC and MPM cells, (b) the activation of these receptors by agonists, namely nicotine, induces cell proliferation and inhibits apoptosis, whereas antagonists have a pro-apoptotic effect. Among competitive ?7-nAChR antagonists, d-tubocurarine and -cobratoxin (?-CbT), from the snake venom of Naja, emerged as possible drug candidates. However, some aspects of the samples must be particularly taken into account, such as the particular nature of the sample. Thus, when using natural compounds purified from snake venom, it is important to take into account the factors such as whether the venom sample was derived from different animals, purified by different methods, or contained contaminants of the same molecular weight. Finally, biological activity may be different for different batches, which could also have been stored under different conditions (e.g. temperature, dilution, suspension medium etc.). These factors, affecting the experimental results, are also discussed. PMID:22300036

Cesario, Alfredo; Russo, Patrizia; Nastrucci, Candida; Granone, Pierluigi

2012-05-01

364

Recombinant expression of the AChR-alpha1 subunit for the detection of conformation-dependent epitopes in Myasthenia Gravis  

PubMed Central

Detection of autoantibodies associated with neurological disease typically involves immunoprecipitation of radioactively labeled native proteins. We explored whether single receptor subunits, fused to Renilla luciferase (Ruc), could detect patient autoantibodies in Luciferase Immunoprecipitation Systems. Myasthenia Gravis patient sera were tested for conformational autoantibodies to only the ?1-subunit of the nicotinic acetylcholine receptor (AChR). Using a panel of 10 AChR-?1 fragments, AChR-?1-?5-Ruc demonstrated the highest immunoreactivity with a conformational-specific antibody and the highest sensitivity in a pilot cohort. Testing a larger cohort with AChR-?1-?5-Ruc demonstrated 21% sensitivity and 97% specificity. A point mutation within Ruc increased the diagnostic performance of AChR-?1-?5 (32% sensitivity, 97% specificity). The 125I-?-bungarotoxin multi-subunit AChR assay demonstrated 63% sensitivity and 97% specificity. These findings highlight the difficulty in detecting Myasthenia Gravis conformational epitopes across assay formats and lay the foundation for detecting autoantibodies to defined recombinant chains of the AChR and potentially other neurotransmitter receptors.

Ching, Kathryn H.; Burbelo, Peter D.; Kimball, Richard M.; Clawson, Lora L.; Corse, Andrea M.; Iadarola, Michael J.

2011-01-01

365

Structural basis of agonist selectivity for different nAChR subtypes: insights from crystal structures, mutation experiments and molecular simulations.  

PubMed

Nicotinic acetylcholine receptors (nAChRs) are members of ligand gated ion channels (LGICs) which transduce chemical signal into electrical signal in neuron and neuromuscular junction. They are pentamerics which contain an extra-cellular domain (also known as ligand binding domain or LBD), a trans-membrane domain and a cytoplasmic domain (intra-cellular domain). Agonist binding to the extra-cellular domain invokes positive ion flux as well as action potential in neurons, muscle cells and endocrine cells whereas antagonist binding inhibits ion flux. There are various endogenous or exogenous compounds which behave as agonists or antagonists targeting nAChRs. During the last decades, the whole structure of muscle type nAChR as well as the crystal structures of acetylcholine-binding proteins (AChBPs) which are homologues of the nAChRs extra-cellular domain has been obtained. These structures, together with other studies including mutation experiments and molecular simulations, provide insights into both of the nAChR architecture and its agonist binding cavity. Our review gives detailed accounts of the recent progresses in order to gain insights into agonist selectivity for different nAChR subtypes. PMID:21619531

Gu, Ruo-Xu; Zhong, Yu-Qing; Wei, Dong-Qing

2011-01-01

366

Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators.  

PubMed

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. PMID:12826262

Ashani, Yacov; Bhattacharjee, Apurba K; Leader, Haim; Saxena, Ashima; Doctor, Bhupendra P

2003-07-15

367

Angiogenesis Inhibitors  

MedlinePLUS

... activate the VEGF receptor. Other angiogenesis inhibitors, including sorafenib and sunitinib, bind to receptors on the surface ... approved other drugs that have antiangiogenic activity, including sorafenib ( Nexavar ®), sunitinib ( Sutent ®), pazopanib ( Votrient ®), and everolimus ( Afinitor ®). ...

368

Bilge Inhibitors.  

National Technical Information Service (NTIS)

A multifunctional borax-nitrite-base inhibitor has been developed for preventing corrosion damage in urinal, galley, and bilge areas of aircraft. Most of the corrosion tests were conducted in a synthetic urine consisting of more than twenty aggressive ing...

M. Khobaib

1982-01-01

369

Peptide Inhibitors  

PubMed Central

The proapoptotic cysteine protease caspase-6 participates in the neuropathology of several diseases. Unlike the active dimeric form, the caspase-6 zymogen forms a unique tetramer that can be stabilized by allosteric inhibitors, which prevents caspase-6 activation.

Bratton, Shawn B

2013-01-01

370

Angiogenesis inhibitors  

Microsoft Academic Search

Angiogenesis inhibitors target the neovascular development that is hypothesized to underlie tumor growth. The inhibitors that\\u000a are undergoing the clinical testing phase can be divided into five categories based on their target activity: 1) drugs that\\u000a block matrix breakdown; 2) drugs that inhibit endothelial cells directly; 3) drugs that block angiogenesis activators; 4)\\u000a drugs that inhibit endothelial cell integrins or

Thelma R. Tennant; Carrie W. Rinker-Schaeffer; Walter M. Stadler

2000-01-01

371

Heterocyclic derivatives of 3-substituted-1,1,1-trifluoro-2-propanones as inhibitors of esterolytic enzymes.  

PubMed

A series of (alkylthio)trifluoropropanones containing a heterocyclic moiety was synthesized. The compounds were tested for in vitro inhibition of four hydrolytic enzymes including insect juvenile hormone esterase (JHE), eel acetylcholinesterase (AChE), yeast lipase (LP), and bovine alpha-chymotrypsin. The I50 values ranged from 10(-3) to 10(-7) M. 3-(2-Pyridylthio)-1,1,1-trifluoro-2-propanone was found to be the most potent inhibitor as compared to the other tested heterocyclic analogues with an I50 value of 98 nM against JHE from the fifth-instar larvae of Trichoplusia ni. Results from X-ray crystallography showed that the compound exists in a tetrahedral gem-diol form stabilized by an intramolecular hydrogen bond in the solid state. X-ray crystallography of a less potent inhibitor, 3-(4-pyridylthio)-1,1,1-trifluoro-2- propanone, showed that it also exists in the hydrated form, but it lacks an intramolecular hydrogen bond. These results provide indirect support that trifluoromethyl ketones are transition-state mimic inhibitors of esterases, and the bearing of the results on the transition-state mimic theory is discussed. The I50 values against AChE were in the micromolar range. Compounds containing a imidazolyl, triazolyl, and pyrimidyl moiety showed the highest inhibition of this enzyme. Differential selectivity of inhibition was associated with the bond distances between the nitrogen and the carbonyl group as in the natural substrate, when measured in the molecules in their minimal energy conformations. Inhibition of LP was moderate to weak, when compared to JHE and AChE. None of the tested compounds showed significant inhibition of alpha-chymotrypsin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2133080

Székács, A; Halarnkar, P P; Olmstead, M M; Prag, K A; Hammock, B D

372

When the Earth has a Belly-Ache: Young Seismologists at School  

NASA Astrophysics Data System (ADS)

The INGV cohoperates with schools of different grades to promote Earth science programs and geophysical knowledge. This is particularly important in areas prone to seismic and volcanic hazards, like Italy. The E&O Group organizes every year school visits to the scientific laboratories of the INGV center of Rome, during which more than 4,000 students interact with scientists and learn about the dynamic Earth. Besides that the E&O Group brings on the road educational activities, carring out projects with schools and partecipating to science festivals. In March 2000 a small size earthquake hit the towns of Subiaco and Agosta, near Rome. This event was strongly felt by teachers and students of the local primary schools, and sprang the idea of a project focused on earthquakes. The aim of the project was to gain knowledge of what causes earthquakes and to familiarize with a phenomenon considered random and unforeseeable. Another goal was to train students and teachers to behave properly during the occurrence of an earthquake. The project was developed starting from the personal experience of the students, with theoretical lessons and practical experiments. The INGV researchers partecipated giving talks and producing educational materials. During the talks they showed that earthquakes are not phenomena so rare and random as thought by most people. They also showed the instruments used to register seismicity, and encouraged kids to produce their own earthquakes jumping close to a portable seismometer. In a second phase the students were divided in groups that investigated different topics of the seismic event, giving a talk to their school mates at the end of the research. The teachers used a cooperative learning approach to stimulate the ability of the kids to team up and work in cooperation. At the end of the project the kids published a book (When the Earth has a belly-ache) and a calendar, that tell about earthquakes using the kid's original drawings. The book illustrates using a kids language, though scientifically correct, what is an earthquake, what can be its effects, and what should be do if an earthquake occurs. The project was presented in a public conference to the local authorities and to the community, extending the issues regarding the natural hazards.

Burrato, P.; Nostro, C.; Tertulliani, A.; Winkler, A.; Casale, P.; Marsili, A.; Castellano, C.; Cultrera, G.; Scarlato, P.; Alfonsi, L.; Ciaccio, M.; Frepoli, A.

2004-12-01

373

Degradation Pathway of Bisphenol A: Does ipso Substitution Apply to Phenols Containing a Quaternary ?-Carbon Structure in the para Position?? †  

PubMed Central

The degradation of bisphenol A and nonylphenol involves the unusual rearrangement of stable carbon-carbon bonds. Some nonylphenol isomers and bisphenol A possess a quaternary ?-carbon atom as a common structural feature. The degradation of nonylphenol in Sphingomonas sp. strain TTNP3 occurs via a type II ipso substitution with the presence of a quaternary ?-carbon as a prerequisite. We report here a new degradation pathway of bisphenol A. Consequent to the hydroxylation at position C-4, according to a type II ipso substitution mechanism, the C-C bond between the phenolic moiety and the isopropyl group of bisphenol A is broken. Besides the formation of hydroquinone and 4-(2-hydroxypropan-2-yl)phenol as the main metabolites, further compounds resulting from molecular rearrangements consistent with a carbocationic intermediate were identified. Assays with resting cells or cell extracts of Sphingomonas sp. strain TTNP3 under an 18O2 atmosphere were performed. One atom of 18O2 was present in hydroquinone, resulting from the monooxygenation of bisphenol A and nonylphenol. The monooxygenase activity was dependent on both NADPH and flavin adenine dinucleotide. Various cytochrome P450 inhibitors had identical inhibition effects on the conversion of both xenobiotics. Using a mutant of Sphingomonas sp. strain TTNP3, which is defective for growth on nonylphenol, we demonstrated that the reaction is catalyzed by the same enzymatic system. In conclusion, the degradation of bisphenol A and nonylphenol is initiated by the same monooxygenase, which may also lead to ipso substitution in other xenobiotics containing phenol with a quaternary ?-carbon.

Kolvenbach, B.; Schlaich, N.; Raoui, Z.; Prell, J.; Zuhlke, S.; Schaffer, A.; Guengerich, F. P.; Corvini, P. F. X.

2007-01-01

374

CoMFA, CoMSIA and HQSAR Studies of Acetylcholinesterase Inhibitors.  

PubMed

A quantitative structure-activity relationship (QSAR) study has been carried out on acetylcholinesterase (AChE) inhibitors with comparative field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and hologram quantitative structure-activity relationship (HQSAR). In order to investigate the effect of alignment on modeling and find out the best alignment strategy, three different alignment rules were applied to generate CoMFA and CoMSIA models. Statistical results of the highly significant models (CoMFA q(2) = 0.748, r(2) =0.996, predicted r(2) =0.789; CoMSIA q(2) =0.755, r(2) =0.973, predicted r(2) = 0.706; HQSAR q(2) = 0.884, r(2) = 0.973, predicted r(2) = 0.734) reveal considerable predictive ability. Analysis of the contour maps of CoMFA and CoMSIA models and the atomic contribution maps of HQSAR model may contribute to develop novel and potential AChE inhibitors. PMID:24010934

Jiang, Yu-Ren; Yang, Yan-Yan; Chen, Yu-Ling; Liang, Zhong-Jie

2013-09-01

375

Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor.  

PubMed

The nicotinic acetylcholine receptor (AChR) is the paradigm of the neurotransmitter-gated ion channel superfamily. The pharmacological behavior of the AChR can be described as three basic processes that progress sequentially. First, the neurotransmitter acetylcholine (ACh) binds the receptor. Next, the intrinsically coupled ion channel opens upon ACh binding with subsequent ion flux activity. Finally, the AChR becomes desensitized, a process where the ion channel becomes closed in the prolonged presence of ACh. The existing equilibrium among these physiologically relevant processes can be perturbed by the pharmacological action of different drugs. In particular, non-competitive inhibitors (NCIs) inhibit the ion flux and enhance the desensitization rate of the AChR. The action of NCIs was studied using several drugs of exogenous origin. These include compounds such as chlorpromazine (CPZ), triphenylmethylphosphonium (TPMP+), the local anesthetics QX-222 and meproadifen, trifluoromethyl-iodophenyldiazirine (TID), phencyclidine (PCP), histrionicotoxin (HTX), quinacrine, and ethidium. In order to understand the mechanism by which NCIs exert their pharmacological properties several laboratories have studied the structural characteristics of their binding sites, including their respective locations on the receptor. One of the main objectives of this review is to discuss all available experimental evidence regarding the specific localization of the binding sites for exogenous NCIs. For example, it is known that the so-called luminal NCIs bind to a series of ring-forming amino acids in the ion channel. Particularly CPZ, TPMP+, QX-222, cembranoids, and PCP bind to the serine, the threonine, and the leucine ring, whereas TID and meproadifen bind to the valine and extracellular rings, respectively. On the other hand, quinacrine and ethidium, termed non-luminal NCIs, bind to sites outside the channel lumen. Specifically, quinacrine binds to a non-annular lipid domain located approximately 7 A from the lipid-water interface and ethidium binds to the vestibule of the AChR in a site located approximately 46 A away from the membrane surface and equidistant from both ACh binding sites. The non-annular lipid domain has been suggested to be located at the intermolecular interfaces of the five AChR subunits and/or at the interstices of the four (M1-M4) transmembrane domains. One of the most important concepts in neurochemistry is that receptor proteins can be modulated by endogenous substances other than their specific agonists. Among membrane-embedded receptors, the AChR is one of the best examples of this behavior. In this regard, the AChR is non-competitively modulated by diverse molecules such as lipids (fatty acids and steroids), the neuropeptide substance P, and the neurotransmitter 5-hydroxytryptamine (5-HT). It is important to take into account that the above mentioned modulation is produced through a direct binding of these endogenous molecules to the AChR. Since this is a physiologically relevant issue, it is useful to elucidate the structural components of the binding site for each endogenous NCI. In this regard, another important aim of this work is to review all available information related to the specific localization of the binding sites for endogenous NCIs. For example, it is known that both neurotransmitters substance P and 5-HT bind to the lumen of the ion channel. Particularly, the locus for substance P is found in the deltaM2 domain, whereas the binding site for 5-HT and related compounds is putatively located on both the serine and the threonine ring. Instead, fatty acid and steroid molecules bind to non-luminal sites. More specifically, fatty acids may bind to the belt surrounding the intramembranous perimeter of the AChR, namely the annular lipid domain, and/or to the high-affinity quinacrine site which is located at a non-annular lipid domain. Additionally, steroids may bind to a site located on the extracellular hydrophi PMID:9748559

Arias, H R

1998-08-21

376

Quaternary Fault and Fold Database of the United States  

NSDL National Science Digital Library

This database summarizes geologic, geomorphic, and geographic information for about 2,000 Quaternary faults and folds in the United States. These structures are believed to be sources of magnitude 6 or greater earthquakes during the Quaternary Period (the past 1,600,000 years). Maps of these geologic structures are linked to detailed descriptions, including geologic setting, fault orientation, fault type, sense of movement, slip rate, recurrence (repeat) interval, and the time of the most recent surface-faulting event. The database is searchable by using an interactive map viewer, a state/regional interactive map, or a text-based search. There is also a link to a fact sheet that provides information about the database.

377

Quaternary Fault and Fold Database of the United States  

NSDL National Science Digital Library

This database summarizes geologic, geomorphic, and geographic information for about 2,000 Quaternary faults and folds in the United States. These structures are believed to be sources of magnitude 6 or greater earthquakes during the Quaternary Period (the past 1,600,000 years). Maps of these geologic structures are linked to detailed descriptions, including geologic setting, fault orientation, fault type, sense of movement, slip rate, recurrence (repeat) interval, and the time of the most recent surface-faulting event. The database is searchable by using an interactive map viewer, a state/regional interactive map, or a text-based search. There is also a link to a fact sheet that provides information about the database.

2011-06-16

378

Unexpected primitive rodents in the Quaternary of Argentina  

NASA Astrophysics Data System (ADS)

This article describes the first fossils recorded in the Hernandarias Formation (Pleistocene) in Entre Ríos province (eastern Argentina). They are represented by three teeth assigned to the caviomorph rodents (Rodentia, Mammalia) Aenigmys diamantensis gen. et sp. nov. and Eumysops. To establish the phylogenetic affinities of the two most enigmatic teeth, their enamel microstructure was studied. Aenigmys diamantensis is considered the most primitive taxon of a clade formed by Dinomyidae Neoepiblemidae Heptaxodontidae. Evidence of the close relationships among these families also is presented herein. The new fossils reinforce previous hypotheses about the survival of primitive Brazilian taxa after their extinction in the Pampas and Patagonia of southern South America. They also show that the diversity of caviomorph rodents during the Quaternary was greater than supposed and that an important Quaternary extinction, not previously detected, affected several lineages. With the available evidence, it is not possible to determine if these rodents indicate a warm pulse or a particular biogeographic situation in Entre Ríos.

Vucetich, María G.; Vieytes, Emma C.; Verzi, Diego H.; Noriega, Jorge I.; Tonni, Eduardo P.

2005-10-01

379

Probing enzyme quaternary structure by combinatorial mutagenesis and selection.  

PubMed Central

Genetic selection provides an effective way to obtain active catalysts from a diverse population of protein variants. We have used this tool to investigate the role of loop sequences in determining the quaternary structure of a domain-swapped enzyme. By inserting random loops of four to seven residues into a dimeric chorismate mutase and selecting for functional variants by genetic complementation, we have obtained and characterized both monomeric and hexameric enzymes that retain considerable catalytic activity. The low percentage of active proteins recovered from these selection experiments indicates that relatively few loop sequences permit a change in quaternary structure without affecting active site structure. The results of our experiments suggest further that protein stability can be an important driving force in the evolution of oligomeric proteins.

MacBeath, G.; Kast, P.; Hilvert, D.

1998-01-01

380

Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of human acetylcholinesterase and butyrylcholinesterase  

PubMed Central

Background Alzheimer’s disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD. Findings A series of lycorine derivatives (1–10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 ± 0.66 ?M and 4.17 ± 0.29 ?M, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity. Conclusion Acylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary.

2012-01-01

381

Map and Data for Quaternary Faults and Folds in Wyoming  

NSDL National Science Digital Library

The primary objective of this U.S. Geological Survey Open-file Report is to improve seismic-hazard assessments in regions of Wyoming with low to moderate levels of historic seismicity. A map and pamphlet are available for download in PDF format. The map shows faults and folds with evidence of Quaternary movement including data on timing of the most recent movement, sense of movement, slip rate, and continuity of surface expression.

Michael, Machette; Survey, U. S.

382

The new basic theory on Quaternary environmental research  

Microsoft Academic Search

On the basis of extensive survey to the Quaternary paleosols, soils and weathering layers in the vast northern China and the\\u000a Loess Plateau, we found some unusually special phenomena of chemical components such as unsuccessive illuvium, twin illuviums,\\u000a unusually thick illuvium and multi-illuviums etc. According to the analysis on the content of CaCO3 and the data of penetrating experiment, a

Zhao Jingbo

2004-01-01

383

Experiments for correlating quaternary carbons in RNA bases  

Microsoft Academic Search

The paper presents a set of triple-resonance two-dimensional experiments for correlating all quaternary carbons in RNA bases\\u000a to one or more of the base protons. The experiments make use of either three-bond proton-carbon couplings and one selective\\u000a INEPT step (the long-range selective HSQC experiment) to transfer the magnetization between a proton and the carbon of interest\\u000a and back, or they

Radovan Fiala; Markéta L. Munzarová; Vladimír Sklená?

2004-01-01

384

Vegetation ecotone dynamics in Southwest Alaska during the Late Quaternary  

Microsoft Academic Search

To examine Late Quaternary vegetation change across the modern vegetation gradient from continuous boreal forest (central Alaska) to Betula shrub tundra (Bristol Bay region), pollen records from Idavain and Snipe Lakes are described and compared to those of four other sites in southwest Alaska. Major features of the vegetation history at Idavain Lake include herb-dominated tundra (ca 14–12kaBP), mixed herb\\/Betula

Linda B. Brubaker; Patricia M. Anderson; Feng Sheng Hu

2001-01-01

385

Integrating Quaternary Science Research in Land Management, Restoration, and Conservation  

Microsoft Academic Search

Most of us have come to expect that the general public will ignore the primary message of Quaternary science that change happens. A flurry, however, of recent media attention to 20th-century global warming and its anomalies from climates of the last millennium has brought climate science at least momentarily into popular focus. Similarly, public land-managing agencies and conservation groups have

Constance I. Millar; Wallace B. Woolfenden

386

Quaternary faulting history along the Deep Springs fault, California  

Microsoft Academic Search

New geologic mapping, structural stud- ies, geochronology, and diffusion erosion modeling along the Deep Springs fault, Cal- ifornia, shed light on its Quaternary fault- ing history. The Deep Springs fault, a 26- km-long, predominantly north-northeast- striking, west-northwestdipping normal fault bounding the eastern side of Deep Springs Valley, cuts Jurassic batholithic rocks nonconformably overlain by middle Miocene to Pleistocene stream gravels,

Jeffrey Lee; Charles M. Rubin; Andrew Calvert

2001-01-01

387

Petrogenesis of Plio-Quaternary basalts in Mahabad, NW Iran  

NASA Astrophysics Data System (ADS)

The Mahabad1:100000 sheet is located mostly in the Kurdestan district on southern part of west Azerbijan province between east Longitude 45? 30'- 46 ?, and northern Latitude 36? 30'- 37?. Geographic position, geological and structural setting as well as general geological characters of this zone is very similar to Sanandaj-Sirjan zone. Topography is dominated by mountainous terrain with an average elevation around 1800 meters. The oldest rocks belong to intrusive rocks, Mahabad Rhyolite. The younger ones include Plio-Quaternary basalt to alkali basalt, andesite, trachyte and alluvium terraces and salt marsh. The young quaternary volcanoes occur in the southern range east and east of mahabad map sheet. The Plio-Quaternary volcanic lava are seen in the Borhan village? It is built almost entirely of fluid lava flows?. The volcanic rocks are basic in composition (basalt, tephrit basanite). The petrographic and geochemical evidences, related diagrams show fractionation. By studying the major and trace elements variation diagrams, a trend of normal crystallization can be seen crustal contamination in extensional environments. It seems that the original magma has an ultrabasic composition. Some of the phenocrysts of olivine, pyroxene & plagioclase are seen in thin sections. These rocks have microlitic porphyritic? hyallo microlithic porphyritic textures in thin sections. On the basis of chemical analysis? magma that has formed the rocks had alkaline nature. The ratio of nephelin norm is around 5.3 in this rocks. A primitive mantle- normalized incompatible trace element diagram shows close similarity to typical OIB pattern. All of documents denote that magma originated from an enriched asthenospheric mantle and low degree of partial melting in source. Key words: alkali basalt, Quaternary, Volcanic, Compression. asthenospher

Shojaei, Masoomeh; Kheirkhah, Monireh; Hashem Emami, Mohamad; Maleki, Glavig

2010-05-01

388

Titration of long-chain quaternary ammonium compounds using tetraphenylboron  

Microsoft Academic Search

A rapid macro procedure for the determination of long-chain quaternary ammonium compounds (QAC) has been developed using sodium\\u000a tetraphenylboron as a titrant. About 1–1.5 meq of QAC is dissolved or dispersed in 50 ml of water. Dichlorofluorescein is\\u000a added as an indicator. The sample is then titrated with 0.06 N aqueous sodium tetraphenylboron. As long as free QAC is present

L. D. Metcalfe; R. J. Martin; A. A. Schmitz

1966-01-01

389

Assay of quaternary ammonium antimicrobial compounds by aqueous potentiometric titration  

Microsoft Academic Search

An automatic potentiometric titration method for the determination of quaternary ammonium antimicrobial compounds at the macro\\u000a level is described. The procedure involves the use of standard sodium lauryl sulfate as the titrant and a nitrate ion-selective\\u000a or surfactant electrode to detect the end point. The method, which includes a new, simpler means of titrant standardization,\\u000a avoids the use of hazardous

George T. Battaglini

2002-01-01

390

Low Sensitivity of Listeria monocytogenes to Quaternary Ammonium Compounds  

Microsoft Academic Search

Ninety-seven epidemiologically unrelated strains of Listeria monocytogenes were investigated for their sen- sitivities to quaternary ammonium compounds (benzalkonium chloride and cetrimide). The MICs for seven serogroup 1\\/2 strains were high. Three came from the environment and four came from food; none were isolated from human or animal samples. All 97 strains carried the mdrL gene, which encodes a multidrug efflux

L. Mereghetti; R. Quentin; N. Marquet-Van Der Mee; A. Audurier

2000-01-01

391

The impact of Quaternary Ice Ages on mammalian evolution.  

PubMed Central

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 generalist species.

Lister, Adrian M

2004-01-01

392

Late quaternary turnover of mammals in Borneo: the zooarchaeological record  

Microsoft Academic Search

The Quaternary has been a period of repeated, oscillating patterns of climate change. Global fluctuations in sea level affected\\u000a the island status of Borneo, which was probably joined to continental Asia for more than half of the last 250,000 years. Alternating\\u000a connection and isolation, coupled with the ecological barrier of a savanna corridor running from the Malay Peninsula to Java\\u000a during

2010-01-01

393

Geological provenance of Quaternary deposits from the southeastern Brazilian coast  

NASA Astrophysics Data System (ADS)

Natural gamma radiation measurements of beach sand deposits were performed with the aim of understanding the provenance and transport processes of sediments along the coastal zone of three Brazilian States. The method employs thorium, uranium and potassium as tracers of the mineralogical properties of beach sand minerals, which reflect the geological history of transport and sorting processes. A considerable positive correlation with the geological evolution of these Quaternary coastal deposits was observed.

Anjos, R. M.; Veiga, R.; Carvalho, C.; Macario, K. D.; Gomes, P. R. S.

2007-05-01

394

Ternary and quaternary selenide crystals for nonlinear optical applications  

NASA Astrophysics Data System (ADS)

We have developed several binary, ternary and quaternary sulfide and selenide crystals for nonlinear optical applications and present an overview on the crystal growth and characterization of crystals for nonlinear optical (NLO) conversion efficiency. We have summarized the performance of silver gallium selenide (AgGaSe2), thallium arsenic selenide (Tl3AsSe3), and silver gallium germanium selenide (AgGaGe3Se8 and AgGaGe5Se12) crystals and have compared with gallium selenide (GaSe). All these crystals were grown by vertical Bridgman method in quartz ampoules by using stoichiometric compounds synthesized from constituent elements. The significant problem of cleaving of GaSe was reduced in ternary and quaternary compounds. Experimental results showed that binary, ternary and quaternary selenide compounds transmit at wavelengths up to 16 ?m, have reasonably high value of nonlinear conversion merit (d2/n3, where d is the NLO coefficient and n is the refractive index) and have the lowest absorption coefficient compared to arsenides, phosphides and other nonlinear optical (NLO) materials.

Singh, N. B.; Knuteson, D. J.; Kanner, G.; Berghmans, A.; Green, K.; Wagner, B.; Kahler, D.; King, M.; McLaughlin, S.

2011-09-01

395

Polycationic antimicrobial dendrimers: a comparison of alkyl pyridinium,quaternary ammonium, quaternary phosphonium and tertiary sulfonium salts  

NASA Astrophysics Data System (ADS)

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.

Chen, Chris; Cooper, Stuart

2000-03-01

396

RNA editing and alternative splicing of the insect nAChR subunit alpha6 transcript: evolutionary conservation, divergence and regulation  

Microsoft Academic Search

BACKGROUND: RNA editing and alternative splicing play an important role in expanding protein diversity and this is well illustrated in studies of nicotinic acetylcholine receptors (nAChRs). RESULTS: Here, we compare the RNA editing and alternative splicing of the nAChR alpha6 subunit genes from different insects spanning ~300 million years of evolution– Drosophila melanogaster, Anopheles gambiae, Bombyx mori, Tribolium castaneum and

Yongfeng Jin; Nan Tian; Jun Cao; Jing Liang; Zhaolin Yang; Jianning Lv

2007-01-01

397

Structure and mechanical properties of low temperature magnetron sputtered nanocrystalline (nc-)Ti(N,C)\\/amorphous diamond like carbon (aC:H) coatings  

Microsoft Academic Search

This paper reports on the structure and mechanical properties of ~2?m thick nanocomposite (nc-) Ti(N,C)\\/amorphous diamond like carbon (a-C:H) coatings deposited on 100Cr6 steel substrates, using low temperature (~200°C) DC reactive magnetron sputtering. The carbon content was varied with acetylene partial pressure in order to obtain single layer coatings with different a-C:H carbon phase fractions. The nanocrystalline Ti(N,C) phase is

C. Tsotsos; M. A. Baker; K. Polychronopoulou; P. N. Gibson; K. Giannakopoulos; A. A. Polycarpou; K. Böbel; C. Rebholz

2010-01-01

398

Crystal structure of the extracellular domain of nAChR ?1 bound to ?-bungarotoxin at 1.94 Å resolution  

Microsoft Academic Search

We determined the crystal structure of the extracellular domain of the mouse nicotinic acetylcholine receptor (nAChR) ?1 subunit bound to ?-bungarotoxin at 1.94 Å resolution. This structure is the first atomic-resolution view of a nAChR subunit extracellular domain, revealing receptor-specific features such as the main immunogenic region (MIR), the signature Cys-loop and the N-linked carbohydrate chain. The toxin binds to

Cosma D Dellisanti; Yun Yao; James C Stroud; Zuo-Zhong Wang; Lin Chen

2007-01-01

399

Lack of nAChR Activity Depresses Cochlear Maturation and Up-Regulates GABA System Components: Temporal Profiling of Gene Expression in alpha9 Null Mice  

Microsoft Academic Search

BackgroundIt has previously been shown that deletion of chrna9, the gene encoding the ?9 nicotinic acetylcholine receptor (nAChR) subunit, results in abnormal synaptic terminal structure. Additionally, all nAChR-mediated cochlear activity is lost, as characterized by a failure of the descending efferent system to suppress cochlear responses to sound. In an effort to characterize the molecular mechanisms underlying the structural and

Sevin Turcan; Donna K. Slonim; Douglas E. Vetter; Huibert D. Mansvelder

2010-01-01

400

PARP Inhibitors  

Microsoft Academic Search

Poly (ADP-ribose) polymerase (PARP) is a novel therapeutic target in cancer. Preclinical studies demonstrate that PARP inhibitors\\u000a selectively kill BRCA-deficient cells and potentiate the effects of DNA-damaging agents. There are several PARP inhibitors in clinical development,\\u000a including olaparib, iniparib, veliparib, PF-01367338, and MK-4827. Phase II studies of single-agent olaparib demonstrate activity\\u000a in BRCA-associated cancers. A randomized phase II trial showed

Hongyan Liang; Antoinette R. Tan

2011-01-01

401

Chronic ethanol (EtOH) feeding increases muscarinic receptor (mAChR) density in esophagus without parallel change in dose response (D-R) to cholinergic agonists  

SciTech Connect

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.

Keshavarzian, A.; Gordon, J.H.; Urban, G.; Fields, J.Z. (Loyola Univ., Maywood (United States) VA Hospital, Hines, IL (United States))

1991-03-11

402

The Role of Structured Water in Mediating General Anesthetic Action on ?4?2 nAChR  

PubMed Central

Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming water clathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within ?4?2 nAChR, a putative protein target hypersensitive to volatile anesthetics. Experimental structure-derived closed- and open-channel nAChR systems in a fully hydrated lipid bilayer were examined using all-atom molecular dynamics simulations. At the majority of binding sites in ?4?2 nAChR, halothane replaced the slow-exchanging water molecules and caused a regional water population decrease. Only two binding sites had an increased quantity of water in the presence of halothane, where water arrangements resemble clathrate-like structures. The small number of such clathrate-like water clusters suggests that the formation of water clathrates is unlikely to be a primary cause for anesthesia. Despite the decrease in water population at most of the halothane binding sites, the number of sites that can be occupied transiently by water is actually increased in the presence of halothane. Many of these water sites were located between two subunits or in regions containing agonist binding sites or critical structural elements for transducing agonist binding to channel gating. Changes in water sites in the presence of halothane affected water-mediated protein-protein interactions and the protein dynamics, which can have direct impact on protein function. Collectively, water contributes to the action of anesthetics in proteins by mediating interactions between protein subunits and altering protein dynamics, instead of forming water clathrates around anesthetics.

Willenbring, Dan; Xu, Yan; Tang, Pei

2010-01-01

403

Polarization-encoded all-optical quaternary universal inverter and design of multivalued flip-flop  

NASA Astrophysics Data System (ADS)

Quaternary inverters are the fundamental building blocks of multivalued flip-flops (MVFFs). A novel all-optical quaternary universal inverter circuit with the help of a semiconductor optical amplifier-assisted Sagnac switch is proposed and described. This circuit exploits the polarization properties of light. Different logical states are represented by different polarization states of light. A terahertz optical asymmetric multiplexer-based gate plays an important role here. Numerical simulation results confirming the described method are given. An all-optical circuit for a MVFF (quaternary) with the help of our proposed quaternary universal inverter is also designed, and simulation results are presented.

Chattopadhyay, Tanay; Roy, Jitendra Nath

2010-03-01

404

Formal synthesis of (+)-madindoline A, a potent IL-6 inhibitor, utilizing enzymatic discrimination of quaternary carbon.  

PubMed

A formal synthesis of (+)-madindoline A was achieved. The Sunazuka's key intermediate, (4R,5S)-(-)-3-butyl-4-(tert-butyldimethylsiloxy)-5-methoxycarbonyl-2,5-dimethyl-2-cyclopentenone, was synthesized from easily available (2S,3S)-3-acetoxy-2-ethenyl-2-methylcyclopentanone. The starting material was reliably supplied by a chemo-enzymatic procedure in enantiomerically pure form. The synthesis was performed by straightforward transformations involving enone formation and regioselective introduction of the two alkyl side chains. PMID:23980418

Shimizu, Ken-ichi; Tomita, Mina; Fuhshuku, Ken-ichi; Sugai, Takeshi; Shoji, Mitsuru

2013-07-01

405

Chemical sputtering of a-C:H films by simultaneous exposure to energetic Ar+ ions and water vapor  

NASA Astrophysics Data System (ADS)

Amorphous hydrocarbon films (a-C:H) were exposed to a beam of 800eV Ar+ ions. The temperature of the films was varied between 110 an 800K. When backfilling the chamber with water vapor during ion bombardment there is a marked increase of the erosion rate at and below 200 K, while there is no influence on the erosion rate at room temperature and above. We explain the observed synergism by an ion-induced reaction between adsorbed water molecules and the film surface in which volatile erosion products are formed.

Hopf, C.; Schlüter, M.; Jacob, W.

2008-03-01

406

Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]thiazoles as cholinesterase inhibitors.  

PubMed

A series of novel cholinesterase inhibitors based on 2-substituted 6-fluorobenzo[d]thiazole were synthesised and characterised by IR, (1)H, (13)C and (19)F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound. PMID:23462716

Imramovský, Aleš; Pejchal, Vladimír; Št?pánková, Šárka; Vor?áková, Katarína; Jampílek, Josef; Van?o, Ján; Šim?nek, Petr; Královec, Karel; Br??ková, Lenka; Mandíková, Jana; Trejtnar, František

2013-02-01

407

Angiotensin-Converting Enzyme Inhibitor Prevents Age-Related Endothelial Dysfunction  

Microsoft Academic Search

Abstract—Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme,inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg z kg,5 mol\\/L ACh in the

Kenichi Goto; Koji Fujii; Uran Onaka; Isao Abe; Masatoshi Fujishima

408

Comparing effectiveness of rhamnolipid biosurfactant with a quaternary ammonium salt surfactant for hydrate anti-agglomeration.  

PubMed

Natural gas is projected to be the premium fuel of the 21st century because of availability, as well as economical and environmental considerations. Natural gas is coproduced with water from the subsurface forming gas hydrates. Hydrate formation may result in shutdown of onshore and offshore operations. Industry practice has been usage of alcohols--which have undesirable environmental impacts--to affect bulk-phase properties and inhibit hydrate formation. An alternative to alcohols is changing the surface properties through usage of polymers and surfactants, effective at 0.5-3 wt % of coproduced water. One group of low-dosage hydrate inhibitors (LDHI) are kinetic inhibitors, which affect nucleation rate and growth. A second group of LDHI are anti-agglomerants, which prevent agglomeration of small hydrate crystallites. Despite great potential, reported work on hydrate anti-agglomeration is very limited. In this paper, our focus is on the use of two vastly different surfactants as anti-agglomerants. We use a model oil, water, and tetrahydrofuran as a hydrate-forming species. We examine the effectiveness of a quaternary ammonium salt (i.e., quat). Visual observation measurements show that a small concentration of the quat (0.01%) can prevent agglomeration. However, a quat is not a green chemical and therefore may be undesirable. We show that a rhamnolipid biosurfactant can be effective to a concentration of 0.05 wt %. One difference between the two surfactants is the stability of the water-in-oil emulsions created. The biosurfactant forms a less stable emulsion, which makes it very desirable for hydrate application. PMID:18171051

York, J Dalton; Firoozabadi, Abbas

2008-01-03

409

Displacement and nonlinear chromatographic techniques in the investigation of interaction of noncompetitive inhibitors with an immobilized alpha3beta4 nicotinic acetylcholine receptor liquid chromatographic stationary phase.  

PubMed

A liquid chromatographic column containing immobilized alpha3beta4 nicotinic acetylcholine receptors (alpha3beta4-nAChRs) has been used to determine the equilibrium association constants (Ka), desorption rate constants (kd), and adsorption rate constants (ka) for the noncompetitive inhibitors: mecamylamine, ketamine, bupropion, and dextromethorphan. Displacement chromatography, with mecamylamine as the displacer, was used to verify that the four compounds bound to the same site on the immobilized alpha3beta4-nAChRs. Nonlinear chromatographic techniques were then utilized to calculate the Ka, ka, and kd values associated with the formation of the noncompetitive inhibitor-alpha3beta4-nAChR complexes. The ka values determined in this study ranged from 19.7 to 10.5 microM(-1) sec(-1), with a relative order of mecamylamine > dextromethorphan > or = ketamine > bupropion. The kd values determined in this study indicated that dextromethorphan-induced inhibition should produce a longer recovery time than the other three NCIs. This was consistent with results from a previous in vitro study. The data from this study indicate that the immobilized alpha3beta4-nAChR column and nonlinear chromatography can be used in the study of NCIs at the alpha3beta4-nAChR. PMID:12349962

Jozwiak, Krzysztof; Haginaka, Jun; Moaddel, Ruin; Wainer, Irving W

2002-09-15

410

Population variation and differences in serum leptin independent of adiposity: a comparison of Ache Amerindian men of Paraguay and lean American male distance runners  

PubMed Central

Background Serum leptin variation is commonly associated with fat percentage (%), body mass index (BMI), and activity. In this investigation, we report population differences in mean leptin levels in healthy men as well as associations with fat % and BMI that are independent of these factors and reflect likely variation resulting from chronic environmental conditions. Methods Serum leptin levels, fat %, and BMI were compared between lean American distance runners and healthy Ache Native Americans of Paraguay. Mean levels were compared as were the regressions between fat %, BMI, and leptin. Comparisons were performed between male American distance runners (n = 13, mean age 32.2 ± 9.2 SD) and highly active male New World indigenous population (Ache of Paraguay, n = 20, mean age 32.8 ± 9.2) in order to determine whether significant population variation in leptin is evident in physically active populations living under different ecological circumstances independent of adiposity and BMI. Results While the Ache were hypothesized to exhibit higher leptin due to significantly greater adiposity (fat %, Ache 17.9 ± 1.8 SD; runners 9.7 ± 3.2, p < 0.0001), leptin levels were nonetheless significantly higher in American runners (Ache 1.13 ng/ml ± 0.38 SD; runners 2.19 ± 1.15; p < 0.007). Significant differences in the association between leptin and fat % was also evident between Ache and runner men. Although fat % was significantly related with leptin in runners (r = 0.90, p < 0.0001) fat % was negatively related in Ache men (r = -0.50, p < 0.03). Conclusion These results illustrate that chronic ecological conditions in addition to activity are likely factors that contribute to population variation in leptin levels and physiology. Population variation independent of adiposity should be considered to be an important source of variation, especially in light of ethnic and population differences in the incidence and etiology of obesity, diabetes, and other metabolic conditions.

Bribiescas, Richard G; Hickey, Matthew S

2006-01-01

411

Inhibitory effects of psychotropic drugs on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes.  

PubMed

Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTP?S). To elucidate mechanism for anticholinergic action, IC50 ratio, the ratio of IC50 for GTP?S-activated IK.ACh to CCh-induced IK.ACh, was calculated. Antipsychotics and antidepressants inhibited CCh-induced IK.ACh in a concentration-dependent manner. The IC50 values were as follows; chlorpromazine 0.53 ?M, clozapine 0.06 ?M, fluphenazine 2.69 ?M, haloperidol 2.66 ?M, sulpiride 42.3 ?M, thioridazine 0.07 ?M, amitriptyline 0.03 ?M, imipramine 0.22 ?M and maprotiline 1.81 ?M. The drugs, except for sulpiride, inhibited GTP?S-activated IK.ACh with following IC50 values; chlorpromazine 1.71 ?M, clozapine 14.9 ?M, fluphenazine 3.55 ?M, haloperidol 2.73 ?M, thioridazine 1.90 ?M, amitriptyline 7.55 ?M, imipramine 7.09 ?M and maprotiline 5.93 ?M. The IC50 ratio for fluphenazine and haloperidol was close to unity. The IC50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress IK.ACh. Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel. PMID:23343658

Okada, Muneyoshi; Watanabe, Shinya; Matada, Takashi; Asao, Yoko; Hamatani, Ramu; Yamawaki, Hideyuki; Hara, Yukio

2013-01-24

412

Mutagenesis of the 43-kD postsynaptic protein defines domains involved in plasma membrane targeting and AChR clustering  

PubMed Central

The postsynaptic membrane of the neuromuscular junction contains a myristoylated 43-kD protein (43k) that is closely associated with the cytoplasmic face of the nicotinic acetylcholine receptor (AChR)-rich plasma membrane. Previously, we described fibroblast cell lines expressing recombinant AChRs. Transfection of these cell lines with 43k was necessary and sufficient for reorganization of AChR into discrete 43k-rich plasma membrane domains (Phillips, W. D., C. Kopta, P. Blount, P. D. Gardner, J. H. Steinbach, and J. P. Merlie. 1991. Science (Wash. DC). 251:568-570). Here we demonstrate the utility of this expression system for the study of 43k function by site-directed mutagenesis. Substitution of a termination codon for Asp254 produced a truncated (28- kD) protein that associated poorly with the cell membrane. The conversion of Gly2 to Ala2, to preclude NH2-terminal myristoylation, reduced the frequency with which 43k formed plasma membrane domains by threefold, but did not eliminate the aggregation of AChRs at these domains. Since both NH2 and COOH-termini seemed important for association of 43k with the plasma membrane, a deletion mutant was constructed in which the codon Gln15 was fused in-frame to Ile255 to create a 19-kD protein. This mutated protein formed 43k-rich plasma membrane domains at wild-type frequency, but the domains failed to aggregate AChRs, suggesting that the central part of the 43k polypeptide may be involved in AChR aggregation. Our results suggest that membrane association and AChR interactions are separable functions of the 43k molecule.

1991-01-01

413

An aminostratigraphy for the British Quaternary based on Bithynia opercula.  

PubMed

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 combination with other lines of evidence, allows tentative correlation with the marine oxygen isotope record. PMID:23396683

Penkman, Kirsty E H; Preece, Richard C; Bridgland, David R; Keen, David H; Meijer, Tom; Parfitt, Simon A; White, Tom S; Collins, Matthew J

2013-02-01

414

Electrochemically stable fluorohydrogenate ionic liquids based on quaternary phosphonium cations  

Microsoft Academic Search

Fluorohydrogenate ionic liquids of quaternary phosphonium cations, tri-n-butylmethylphosphonium (P4441) fluorohydrogenate, tetra-n-butylphosphonium (P4444) fluorohydrogenate, and tri-n-butyl-n-octylphosphonium (P4448) fluorohydrogenate, have been synthesized by the metatheses of anhydrous hydrogen fluoride and the corresponding phosphonium chloride precursors. All the obtained salts have melting points below room-temperature with a vacuum-stable composition of P444m(FH)2.3F (m=1, 4, and 8) and were characterized by density, conductivity, and viscosity

Shunsuke Kanematsu; Kazuhiko Matsumoto; Rika Hagiwara

2009-01-01

415

Quaternary Faults and Folds by State and Region  

NSDL National Science Digital Library

This interactive map of the United states provides access to maps of Quaternary faults and folds by state or region (for example, the Gulf Coast). Clicking on the colored areas of the map links the user to state/regional maps and further, to 1x2 degree sheets for each area. On the sheets, users can find faults numbered and indexed to a legend. Links from the legend provide access to written information, where available, for each fault. There are three levels of written reports, ranging from a brief synopsis to a "complete" report that includes references.

416

Quaternary Fault and Fold Database for the United States: California  

NSDL National Science Digital Library

This interactive map shows the major fault systems of the Quaternary for the State of California. It is subdivided into 1x2 degree sheets, each of which is linked to a more detailed map. Users can select a sheet and see an enlargement of the area. Individual fault systems are numbered and keyed to a legend which provides a link to a written synopsis of information for the fault, including fault type and geologic history. Links are also provided to more extensive reports for the faults, including a "complete" report with references.

417

Thermal properties of quaternary ammonium and pyridinium compounds  

SciTech Connect

In the present work an attempt was made at a comprehensive investigation of the influence of the chemical structure of a whole series of cation-active surfactants on the stability to temperature influences, and the general directions of the irreversible transformations at high temperature were established. As a result of a study of processes of thermal decomposition of quaternary ammonium and syridinium salts, quantitative correlations were established according to the influence of the chemical structure of the salts on the limits of thermal stability. On the basis of a detailed analysis of volatile pyrolysis products, concrete schemes of the conversions in the objects studied were proposed.

Aksenova, V.P.; Khar'kov, S.N.; Logovotovskaya, V.D.; Belotserkovets, N.I.; Chegolya, A.S.

1982-12-10

418

Cytotoxic quaternary alkaloids from the flowers of Narcissus tazetta.  

PubMed

Intensive chromatographic separation of the polar fraction of an ethanolic extract of the fresh flowers of Narcissus tazetta L. (Amaryllidaceae) yielded two new quaternary alkaloids with a phenanthrene skeleton, N-methyl-8,9-methylenedioxy-phenantridinium methylsulfate (1) and N-methyl-8,9-methylenedioxy-phenantridinium malate (2). The structure determination of the alkaloids was based on one- and two-dimensional NMR studies including HMQC, and HMBC studies, and mass spectroscopic analysis. The existence, in 1, of the methylsulfate group was confirmed by X-ray diffraction analysis. Cytotoxic activities for 1 and 2 against a panel of cancer cell lines are also reported. PMID:11683132

Youssef, D T; Khalifa, A A

2001-10-01

419

Two new quaternary protoberberine alkaloids from Corydalis yanhusuo.  

PubMed

Two new quaternary protoberberine alkaloids, namely corydayanine (1) and yanhusuine (2), were isolated from the tubers of Corydalis yanhusuo. On the basis of extensive chemical and spectroscopic evidences, especially 1D and 2D NMR and HRMS experiments, their structures were elucidated as 5,6-dihydro-3,9-dihydroxy-2,10-dimethoxy-13-methyl-dibenzo[a,g] quinolizinium alkaloid and 5,6-dihydro-12-hydroxy-2,3,9-trimethoxy-13-methyl-dibenzo[a,g] quinolizinium alkaloid, respectively. PMID:22530675

Zhou, Qiong; Deng, An-Jun; Qin, Hai-Lin

2012-01-01

420

Spatial Response of Mammals to Late Quaternary Environmental Fluctuations  

PubMed

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. PMID:8662471

Graham; Lundelius; Graham; Schroeder; Toomey; Anderson; Barnosky; Burns; Churcher; Grayson; Guthrie; Harington; Jefferson; Martin; McDonald; Morlan; Semken; Webb; Werdelin; Wilson

1996-06-14

421

Identification of N-terminal Extracellular Domain Determinants in Nicotinic Acetylcholine Receptor (nAChR) ?6 Subunits That Influence Effects of Wild-type or Mutant ?3 Subunits on Function of ?6?2*- or ?6?4*-nAChR*  

PubMed Central

Despite the apparent function of naturally expressed mammalian ?6*-nicotinic acetylcholine receptors (?6*-nAChR; where * indicates the known or possible presence of additional subunits), their functional and heterologous expression has been difficult. Here, we report that coexpression with wild-type ?3 subunits abolishes the small amount of function typically seen for all-human or all-mouse ?6?4*-nAChR expressed in Xenopus oocytes. However, levels of function and agonist potencies are markedly increased, and there is atropine-sensitive blockade of spontaneous channel opening upon coexpression of ?6 and ?4 subunits with mutant ?3 subunits harboring valine-to-serine mutations at 9?- or 13?-positions. There is no function when ?6 and ?2 subunits are expressed alone or in the presence of wild-type or mutant ?3 subunits. Interestingly, hybrid nAChR containing mouse ?6 and human (h) ?4 subunits have function potentiated rather than suppressed by coexpression with wil