Sample records for quaternary ache inhibitors

  1. New potential AChE inhibitor candidates.

    PubMed

    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

    2009-09-01

    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

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

    PubMed Central

    Zimmermann, M

    2013-01-01

    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

  3. Structure-activity relationship of quaternary acetylcholinesterase inhibitors - outlook for early myasthenia gravis treatment.

    PubMed

    Komloova, M; Musilek, K; Dolezal, M; Gunn-Moore, F; Kuca, K

    2010-01-01

    Myasthenia gravis is a rare autoimmune neuromuscular junction disorder mainly caused by antibodies being targeted against the muscle acetylcholine receptors (AChRs). The loss of AChRs leads to a defect in neuromuscular transmission resulting in muscle weakness and fatigue. Although once an often fatal illness, Myasthenia gravis can now be well managed with relatively safe and effective treatments. However, the severe myasthenic cases associated with thymus tumors remain often fatal exception in the management of the disease. The early treatment includes the use of acetylcholinesterase inhibitors (AChEI) which enhance neuromuscular transmission. To ensure a peripheral effect, charged molecules are used, particularly quaternary ammonium salts. The structure of AChEIs has been continuously modified to obtain the optimal ratio between AChE inhibition and potential side-effects. This review summarizes progress in the use of quaternary compounds as AChE inhibitors in vitro with respect to their structure and inhibitory ability. Namely, carbamic acid esters, piperidinium and pyridinium salts, bisquaternary pyridinium salts and heterogeneous quaternary inhibitors are all discussed. Among data found in the literature, many compounds have shown promising inhibition of AChE when compared to commercial standards (pyridostigmine, neostigmine). Besides a promising inhibitory ability, selectivity for AChE versus butyrylcholinesterase (BChE) for the most potent compounds (sub-nanomolar IC(50)) was also identified. PMID:20345342

  4. Quaternary and tertiary quinuclidine derivatives as inhibitors of choline uptake.

    PubMed

    Sterling, G H; Doukas, P H; Ricciardi, F J; O'Neill, J J

    1991-08-01

    The uptake of choline into cholinergic neurons for acetylcholine (ACh) synthesis is by a specific, high-affinity, sodium- and temperature-dependent transport mechanism (HAChU). Of several quaternary quinuclidinol derivatives tested, the N-allyl derivative proved to be most potent. Though the methyl, ethyl, and isopropyl derivatives were less potent at comparable concentrations, at higher concentrations they also maximally inhibited HAChU. The benzyl, hydroxyethyl, and methoxyethyl derivatives failed to inhibit HAChU by greater than 50% at concentrations up to 100 microM. N-Allyl-3-quinuclidinol (NAQ) proved to be a specific inhibitor of HAChU (IC50 = 0.9 microM) and a poor inhibitor of both sodium-independent transport (IC50 = 680 microM) and choline acetyltransferase activity (Ki = 200 microM). The NAQ exhibited noncompetitive type inhibition compared with N-methyl-3-quinuclidinol, a competitive inhibitor of HAChU. Thus, substitution at the N-functional group not only alters potency, but may change the mechanism by which inhibition is produced. The optical isomers of NAQ and several derivatives were prepared and employed to examine the stereochemical selectivity for inhibition of choline uptake. The S(+)-isomer of NAQ (IC50 = 0.1 microM) had approximately 100-fold greater inhibitory activity for HAChU than the corresponding R(-)-isomer (IC50 = 10 microM). With all other quinuclidinols tested, the S(+)-isomers were also more potent than the corresponding R(-)-isomers. In an effort to obtain a tertiary inhibitor of HAChU that would be expected to cross the blood-brain barrier following peripheral administration, 3-biphenyl-3-quinuclidinol (BHQ) and 3-naphthyl-3-quinuclidinol (NHQ) were synthesized and evaluated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1791542

  5. Lessons from functional analysis of AChE covalent and noncovalent inhibitors for design of AD therapeutic agents

    Microsoft Academic Search

    Dov Barak; Arie Ordentlich; Dana Kaplan; Chanoch Kronman; Baruch Velan; Avigdor Shafferman

    2005-01-01

    Determination of the 3D-structure of acetylcholinesterase (AChE) of Torpedo californica over a decade ago, and more recently that of human enzyme together with extensive targeted mutagenesis of the mammalian AChEs led to a fine mapping of the multiple functional domains within the active center of the enzyme. Many of the contributions of this active center architecture to accommodation of noncovalent

  6. Synthesis, Biological Evaluation, and Computational Studies of Tri- and Tetracyclic Nitrogen-Bridgehead Compounds as Potent Dual-Acting AChE Inhibitors and hH3 Receptor Antagonists

    PubMed Central

    2014-01-01

    Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimer’s disease, since both pharmacological actions are able to enhance cholinergic neurotransmission in the cortex. However, whereas AChE inhibitors prevent hydrolysis of acetylcholine also peripherally, histamine H3 antagonists will raise acetylcholine levels mostly in the brain due to predominant occurrence of the receptor in the central nervous system. In this work, we designed and synthesized two novel classes of tri- and tetracyclic nitrogen-bridgehead compounds acting as dual AChE inhibitors and histamine H3 antagonists by combining the nitrogen-bridgehead moiety of novel AChE inhibitors with a second N-basic fragment based on the piperidinylpropoxy pharmacophore with different spacer lengths. Intensive structure–activity relationships (SARs) with regard to both biological targets led to compound 41 which showed balanced affinities as hAChE inhibitor with IC50 = 33.9 nM, and hH3R antagonism with Ki = 76.2 nM with greater than 200-fold selectivity over the other histamine receptor subtypes. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds and molecular dynamics studies to explain high affinity at the hH3R. PMID:24422467

  7. From AChE to BACE1 inhibitors: The role of the amine on the indanone scaffold.

    PubMed

    Rampa, Angela; Mancini, Francesca; De Simone, Angela; Falchi, Federico; Belluti, Federica; Di Martino, Rita Maria Concetta; Gobbi, Silvia; Andrisano, Vincenza; Tarozzi, Andrea; Bartolini, Manuela; Cavalli, Andrea; Bisi, Alessandra

    2015-07-15

    In recent years, a progressive increase in age-related disorders could be observed in most western countries, among which Alzheimer's disease (AD) is one of the most challenging. BACE1 could be seen as an attractive target to develop disease-modifying compounds, and in this context, a new series of hybrid molecules was designed and synthesized, based on a previously identified multitarget lead compound. In particular, the amino side chain was appropriately modified to fit BACE1 as additional target. In vitro testing results pointed out compound 8 (IC50=2.49±0.08?M), bearing the bulky bis(4-fluorophenyl)methyl)piperazine substituent, as the most potent BACE1 inhibitor of the series. PMID:26003339

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

    Microsoft Academic Search

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

    1999-01-01

    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

  9. Facile synthesis of new carbon-11 labeled conformationally restricted rivastigmine analogues as potential PET agents for imaging AChE and BChE enzymes

    Microsoft Academic Search

    Min Wang; Ji-Quan Wang; Mingzhang Gao; Qi-Huang Zheng

    2008-01-01

    Rivastigmine is a newer-generation inhibitor with a dual inhibitory action on both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, and is used for the treatment of AChE- and BChE-related diseases such as brain Alzheimer's disease and cardiovascular disease. New carbon-11 labeled conformationally restricted rivastigmine analogues radiolabeled quaternary ammonium triflate salts, (3aR,9bS)-1-[11C]methyl-1-methyl-6-(methylcarbamoyloxy)-2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indolium triflate ([11C]8) and (3aR,9bS)-1-[11C]methyl-1-methyl-6-(heptylcarbamoyloxy)-2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indolium triflate ([11C]9), were designed and synthesized

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2011-01-01

    The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K+) channels, plays a critical role in the repolarization of the cardiac action potential. The reduction of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially lead to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity associated with the inhibition of hERG channels by environmental chemicals is also a public health concern. To assess the inhibitory effects of environmental chemicals on hERG channel function, we screened the National Toxicology Program (NTP) collection of 1408 compounds by measuring thallium influx into cells through hERG channels. Seventeen compounds with hERG channel inhibition were identified with IC50 potencies ranging from 0.26 to 22 ?M. Twelve of these compounds were confirmed as hERG channel blockers in an automated whole cell patch clamp experiment. In addition, we investigated the structure-activity relationship of seven compounds belonging to the quaternary ammonium compound (QAC) series on hERG channel inhibition. Among four active QAC compounds, tetra-n-octylammonium bromide was the most potent with an IC50 value of 260 nM in the thallium influx assay and 80 nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the number and length of their aliphatic side-chains surrounding the charged nitrogen. Profiling environmental compound libraries for hERG channel inhibition provides information useful in prioritizing these compounds for cardiotoxicity assessment in vivo. PMID:21362439

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

    PubMed Central

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

    2015-01-01

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

  13. Virtual screening of acetylcholinesterase inhibitors using the Lipinski's rule of five and ZINC databank.

    PubMed

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

    2015-01-01

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

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

    PubMed

    Schmidt, Hayden R; Radi?, Zoran; Taylor, Palmer; Fradinger, Erica A

    2015-04-15

    The zebrafish is rapidly becoming an important model system for screening of new therapeutics. Here we evaluated the zebrafish as a potential pharmacological model for screening novel oxime antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE). The ki values determined for chlorpyrifos oxon (CPO) and dichlorvos (DDVP) showed that CPO was a more potent inhibitor of both human and zebrafish AChE, but overall zebrafish AChE was less sensitive to OP inhibition. In contrast, aldoxime antidotes, the quaternary ammonium 2-PAM and tertiary amine RS-194B, showed generally similar overall reactivation kinetics, kr, in both zebrafish and human AChE. However, differences between the Kox and k2 constants suggest that zebrafish AChE associates more tightly with oximes, but has a slower maximal reactivation rate than human AChE. Homology modeling suggests that these kinetic differences result from divergences in the amino acids lining the entrance to the active site gorge. Although 2-PAM had the more favorable in vitro reactivation kinetics, RS-194B was more effective antidote in vivo. In intact zebrafish embryos, antidotal treatment with RS-194B rescued embryos from OP toxicity, whereas 2-PAM had no effect. Dechorionation of the embryos prior to antidotal treatment allowed both 2-PAM and RS-194B to rescue zebrafish embryos from OP toxicity. Interestingly, RS-194B and 2-PAM alone increased cholinergic motor activity in dechorionated embryos possibly due to the reversible inhibition kinetics, Ki and ?Ki, of the oximes. Together these results demonstrate that the zebrafish at various developmental stages provides an excellent model for investigating membrane penetrant antidotes to OP exposure. PMID:25701203

  15. Studies of the interaction between a quaternary amine inhibitor and pipeline steel using XPS and ToFSIMS surface analysis techniques

    SciTech Connect

    Palmer, J.W.; Piercy, A.R. [CAPCIS Ltd., Manchester (United Kingdom); Hibbert, S.; Mitchell, R.; Swift, A.J. [CSMA Ltd., Manchester (United Kingdom); Turgoose, S. [UMIST, Manchester (United Kingdom). Corrosion and Protection Centre

    1995-12-01

    Coupons of X60-pipeline steel have been taken directly from electrochemical testing apparatus for characterization by surface analysis using novel sample transfer methods developed for the analysis of `wet` samples. In this way the correlation between surface concentration, solution concentration and inhibitor efficiency for a quaternary amine inhibitor has been determined. The mechanisms of surface activity of the quaternary amine inhibitor has been investigated. Firstly, surface analysis data for a liquid film of neat inhibitor has been compared with that for a steel coupon rinsed after exposure to neat inhibitor in a static immersion test. Surface analysis results have then been compared to corrosion rate measurements for a range of increasing inhibitor solution concentrations from 0--100ppm for coupons removed directly from an electrochemical test cell and transferred using a novel cryogenic method for sample transfer. Coupons were exposed to solutions of pre-inhibited, deaerated 3% NaCl solution under 1 bara CO{sub 2} at 25 C. Time of flight secondary ion mass spectrometry (ToFSIMS) and X-ray photoelectron spectroscopy (XPS) were the principal surface analysis techniques used. The results show that the quaternary amine inhibitor achieved efficiencies in excess of 90% at solution concentrations of 40ppm and above. Adsorbed inhibitor was detected both by XPS and ToFSIMS at all concentrations studied. Efficiency and surface coverage of this inhibitor increase directly in proportion to solution concentration. Detailed study of surface analysis results shows that, under these cell conditions, adsorption of quaternary amine proceeds via a simple ionic interaction between the inhibitor and the coupon surface with longer chain amine components preferentially adsorbed.

  16. Presynaptic nicotinic ACh receptors

    Microsoft Academic Search

    Susan Wonnacott

    1997-01-01

    Nicotinic ACh (nACh) receptors in the CNS are composed of a diverse array of subunits and have a range of pharmacological properties. However, despite the fact that they are ligand-gated cation channels, their physiological functions have not been determined. This has led to increased interest in presynaptic nACh receptors that act to modulate the release of transmitter from presynaptic terminals.

  17. Centrally acting oximes in reactivation of tabun-phosphoramidated AChE.

    PubMed

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

    2013-03-25

    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

  18. Reaction Gorge Fluctuation in Acetylcholinesterase (AChE)

    NSDL National Science Digital Library

    McCammon, J. Andrew.

    1998-01-01

    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.

  19. Huprine X is a Novel High-Affinity Inhibitor of Acetylcholinesterase That Is of Interest for Treatment of Alzheimer's Disease

    Microsoft Academic Search

    PELAYO CAMPS; BERNADETTE CUSACK; WILLIAM D. MALLENDER; JORDI MORRAL; DIEGO MU; TERRONE L. ROSENBERRY

    Inhibitors of the enzyme acetylcholinesterase (AChE) slow and sometimes reverse the cognitive decline experienced by indi- viduals with Alzheimer's disease. Huperzine A, a natural prod- uct used in traditional Chinese herbal medicine, and tacrine (Cognex) are among the potent AChE inhibitors used in this treatment, but the search for more selective inhibitors contin- ues. We report herein the synthesis and

  20. Quaternary Studies

    NSDL National Science Digital Library

    First, 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" (1). Visitors can learn about the importance of quaternary studies as well as find out the latest news and upcoming meetings. At the second website, the University of Wisconsin-Madison describes the current and recent studies dealing with "basic and applied problems in glacial geology, surficial geology, palynology, sedimentology, geologic mapping, hydrogeology, soils, and environmental geology "(2). The website offers abstracts of publications of members of the Department of Geology and Geophysics and the Wisconsin Geological and Natural History Survey along with descriptions of the lab, a shaded relief map of the Wisconsin area, and amusing glacial songs. Next, the Godwin Institute of Quaternary Research (GIQR) presents the University of Cambridge's history in quaternary research and the seven current research groups and four recent research projects (3 ). The website furnishes news from the research groups, a gallery of historical images of the East Anglia excursion, and summaries of the Institute's reference collections. Fourth, the International Union for Quaternary Research (INQUA) discusses quaternary scientists' investigations "to interpret the changing world of the glacial ages and their impact on our planet's surface environments" (4). Researchers can find out about INQUA-funded projects, meetings, and scientific commissions. Next, the Quaternary Research Association explains that it "exists to promote understanding of the Quaternary Period by publishing field guides, technical guides, and an international journal as well as holding field meetings and speaker meetings" (5). Students and researchers can discover employment, research, grant, meetings, and educational opportunities. Sixth, the University of Wales presents its investigations in the Remote Sensing Laboratory, Palaeoecology Laboratory, and the Luminescence Laboratory (6 ). Users can find concise descriptions of individual researchers' successes, abstracts of published papers, and links to conference information. The seventh website illustrates the Alaska Quaternary Center's commitment "to the promotion of interdisciplinary research and the enhancement of interdisciplinary instruction in Quaternary sciences" (7). Users can view images of the field work and learn how to obtain quaternary data from the Geographic Information Network of Alaska (GINA). Lastly, 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 (8). Students and educators can find information on the researchers involved with the program and the necessary course work.

  1. Quaternary investigation

    SciTech Connect

    Stieve, A.

    1991-05-15

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

  2. Behavioral phenotyping of heterozygous acetylcholinesterase knockout (AChE +\\/?) mice showed no memory enhancement but hyposensitivity to amnesic drugs

    Microsoft Academic Search

    Julie Espallergues; Laurie Galvan; Florence Sabatier; Vanessa Rana-Poussine; Tangui Maurice; Arnaud Chatonnet

    2010-01-01

    Decrease in the expression or activity of acetylcholinesterase (AChE) enzymatic activity results in increased cholinergic tonus in the brain and periphery, with concomitant regulations of nicotinic and muscarinic receptors expression. We generated AChE knockout mice and characterized the behavioral phenotype of heterozygous animals, focusing on learning and memory functions. Male and female, AChE+\\/? and AChE+\\/+ littermate controls (129sv strain) were

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

    Microsoft Academic Search

    Ronald J. Polinsky

    1998-01-01

    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

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

    PubMed

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

    2013-11-01

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

  5. Toxic effects of HgCl2 on activities of SOD, AchE and relative expression of SOD, AChE, CYP1A1 of zebrafish.

    PubMed

    Zhen, He; Wen, Mu; Yang, Yang; Can, Zhang; Hui, Geng; Li, Xiong; Deli, Liu

    2014-12-01

    In order to explore the impact of mercury on fish, zebrafish were exposed in various levels of HgCl2 and the superoxide dismutase (SOD), acetylcholinesterase (AChE) activities were measured after 1 and 7 days exposure. Muscle RNA was also extracted for semi-quantitative RT-PCR determination of the expression of AChE, CYP1A1, Cu/Zn-SOD. It indicated that 96 h-LC50 of HgCl2 to zebrafish is 244.06 µg L(-1). The AChE activity was decreased on 1st day and 7th day. The SOD activity was almost unchanged on 1st day, it showed a dose-response effect on 7th day. The expression of AChE was down-regulated on 1st day, it is consistent with the AChE activity, but the expression was showed a significant difference between exposed group and the control group on 7th day. The expression of CYP1A1 was decreased compared with the control group on 1st day. After 7 day exposure, the expression of CYP1A1 was up-regulated in 0.1LC(50) group, and down-regulated in 0.4LC(50) group, 0.8LC(50) group, showing a stimulation effect at low concentration and inhibition at high concentration. The expression of Cu/Zn-SOD was down-regulated on 1st day, also showing an effect of stimulation at low concentration and inhibition at high concentrations. Thus HgCl2 was highly toxic to zebrafish, both the enzymatic activities and the gene transcription were changed significantly. But the change of gene transcription is earlier than enzymes activities. It indicates that gene transcript can be used as an early warning for environmental risk assessment. PMID:25240424

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

    PubMed Central

    Itoh, Takeo; Maekawa, Takashi; Shibayama, Yasushi

    2012-01-01

    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. PMID:22595036

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

    PubMed

    Lo, Rabindranath; Ganguly, Bishwajit

    2014-07-29

    Organophosphorus nerve agents are highly toxic compounds which strongly inhibit acetylcholinesterase (AChE) in the blood and in the central nervous system (CNS). Tabun is one of the highly toxic organophosphorus (OP) compounds and is resistant to many oxime drugs formulated for the reactivation of AChE. The reactivation mechanism of tabun-conjugated AChE with various drugs has been examined with density functional theory and ab initio quantum chemical calculations. The presence of a lone-pair located on the amidic group resists the nucleophilic attack at the phosphorus center of the tabun-conjugated AChE. We have shown that the newly designed drug candidate N-(pyridin-2-yl)hydroxylamine, at the MP2/6-31+G*//M05-2X/6-31G* level in the aqueous phase with the polarizable continuum solvation model (PCM), is more effective in reactivating the tabun-conjugated AChE than typical oxime drugs. The rate determining activation barrier with N-(pyridin-2-yl)hydroxylamine was found to be ?1.7 kcal mol(-1), which is 7.2 kcal mol(-1) lower than the charged oxime trimedoxime (one of the most efficient reactivators in tabun poisonings). The greater nucleophilicity index (?(-)) and higher CHelpG charge of pyridinylhydroxylamine compared to TMB4 support this observation. Furthermore, we have also examined the reactivation process of tabun-inhibited AChE with some other bis-quaternary oxime drug candidates such as methoxime (MMB4) and obidoxime. The docking analysis suggests that charged bis-quaternary pyridinium oximes have greater binding affinity inside the active-site gorge of AChE compared to the neutral pyridinylhydroxylamine. The peripheral ligand attached to the neutral pyridinylhydroxylamine enhanced the binding with the aromatic residues in the active-site gorge of AChE through effective ?-? interactions. Steered molecular dynamics (SMD) simulations have also been performed with the charged oxime (TMB4) and the neutral hydroxylamine. From protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometry and the orientation of the drug candidates, the hydroxylamine is suggested to orchestrate the reactivation process better than TMB4. Furthermore, the calculated log?P values show the effective penetration of the neutral drug candidate through the blood-brain barrier. The toxicity measurements and the IC50 values (a measure of the intrinsic affinity toward AChE) suggest that the pyridinylhydroxylamine compound could have similar toxic behavior compared to the prototype oxime antidotes used for reactivation purposes. The newly designed pyridinylhydroxylamine drug candidate can be an effective antidote both kinetically and structurally to reactivate the tabun-inhibited enzyme. PMID:24964273

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

    PubMed Central

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

    2013-01-01

    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

  9. [Therapy of myasthenia gravis with cholinesterase inhibitors--principles and pharmacologic monitoring].

    PubMed

    Henze, T

    1996-03-01

    Cholinesterase inhibitors are still important in the treatment of myasthenic patients. Therapeutic principles, indications and adverse effects are discussed in detail. Methods of pharmacological monitoring had been searched over many years. Besides determination of pyridostigmine plasma concentration, erythrocyte-bound acetylcholinesterase (AChE) activity could provide a possibility to monitor therapy with cholinesterase inhibitors. 88 patients with myasthenia gravis were investigated. The results demonstrated that after pyridostigmine erythrocyte-bound as well as synaptic AChE is inhibited. Moreover, erythrocyte-bound AChE has proven to be a parameter of cholinesterase inhibitor effect. After injection of edrophonium-chloride (Tensilon) inhibition of AChE activity can be demonstrated as well. During steady pyridostigmine doses stable plasma concentrations and AChE inhibition depend on the respective dosage. Higher daily doses result in greater stability of pharmacologic parameters, whereas low daily doses lead to great interindividual differences of AChE inhibition even after equal pyridostigmine doses. Intraindividually there is no strong correlation, too. Therefore estimation of erythrocyte-bound AChE activity is not useful for routine pharmacological monitoring of cholinesterase inhibitor therapy, but may be helpful in some clinical conditions. The method provides some advantages over pyridostigmine plasma concentration, since it is applicable for other cholinesterase inhibitors, too, and since it requires less technical equipment and time. PMID:8900891

  10. 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.

  11. The acetylcholinesterase (AChE) inhibition analysis of medaka (Oryzias latipes) in the exposure of three insecticides.

    PubMed

    Zhu, Jianping; Huan, Cheng; Si, Guiyun; Yang, Haitang; Yin, Li; Ren, Qing; Ren, Baixiang; Fu, Rongshu; Miao, Mingsheng; Ren, Zongming

    2015-03-01

    The continuous effects on Acetylcholinesterase (AChE) activity of medaka (Oryzias latipes) caused by dichlorvos, methomyl and deltamethrin in vivo were investigated, and the trends of AChE activity inhibition due to the influence of these insecticides were discussed. The LC50-24h of dichlorvos, methomyl and deltamethrin on medaka were 2.3 mg/L, 0.2 mg/L, and 2.9×10(-3) mg/L respectively. The result suggested that at the beginning of the exposure, the AChE activity might increase, and the AChE activity in dead individuals was obviously lower than the live individuals. Though the de novo synthesis of AChE in medaka might help the AChE activity recover, the trends during the exposure in different treatments were downward, and it showed both exposure time and concentration dependent. Meanwhile, higher temperature might cause the AChE inhibition earlier due to the higher metabolic rate. Therefore, as a specific biomarker for organophosphate, carbamate pesticides and pyrethroids, the degree of the AChE inhibition with in vivo conditions is a good tool in continuous monitoring of insecticides, which may induce the nerve conduction disorders. PMID:25796143

  12. Lycopodiaceae from Panama: A new source of acetylcholinesterase inhibitors

    Microsoft Academic Search

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

    2012-01-01

    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,

  13. Cholinesterase inhibitors from botanicals

    PubMed Central

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

    2013-01-01

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

  14. Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent

    Microsoft Academic Search

    Gui-Dong Zhu; Viraj B. Gandhi; Jianchun Gong; Sheela Thomas; Yan Luo; Xuesong Liu; Yan Shi; Vered Klinghofer; Eric F. Johnson; David Frost; Cherrie Donawho; Ken Jarvis; Jennifer Bouska; Kennan C. Marsh; Saul H. Rosenberg; Vincent L. Giranda; Thomas D. Penning

    2008-01-01

    Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme,

  15. Quaternary and Geomorphology.

    ERIC Educational Resources Information Center

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

    1983-01-01

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

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

    PubMed

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

    1988-02-01

    Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 micrograms/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 mumol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2-3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinuclidinol, a potent HAChU inhibitor (1 mumol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30-60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of administration, dose-response relationships, and time to effect. PMID:3337738

  17. Time Evolution of the Quaternary Structure of Escherichia coli Aspartate Transcarbamoylase upon Reaction with the Natural Substrates and a Slow Tight Binding Inhibitor

    PubMed Central

    West, Jay M.; Xia, Jiarong; Tsuruta, Hiro; Guo, Wenyue; O’Day, Elizabeth M.; Kantrowitz, Evan R.

    2008-01-01

    Here we present a study of the conformational changes of the quaternary structure of E. coli aspartate transcarbamoylase (ATCase), as monitored by time-resolved small-angle X-ray scattering (TR-SAXS), upon combining with substrates, substrate analogs, and nucleotide effectors at temperatures between 5 – 22 °C, obviating the need for ethylene glycol. TR-SAXS time courses tracking the T ? 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 ? R transition rate, with no further increase in rate beyond that point. Most strikingly after addition of PALA to the enzyme the transition rate was over one 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 ? 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 ATCase in the presence of the heterotropic effectors. PMID:18823998

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

    Microsoft Academic Search

    Renato Scacchi; Maria Ruggeri; Rosa Maria Corbo

    2011-01-01

    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

  19. Salicylanilide diethyl phosphates as cholinesterases inhibitors.

    PubMed

    Krátký, Martin; Št?pánková, Šárka; Vor?áková, Katarína; Vinšová, Jarmila

    2015-02-01

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

  20. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

    PubMed Central

    Mehta, Mona; Adem, Abdu; Sabbagh, Marwan

    2012-01-01

    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. PMID:22216416

  1. Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.

    PubMed

    Kia, Yalda; Osman, Hasnah; Suresh Kumar, Raju; Basiri, Alireza; Murugaiyah, Vikneswaran

    2014-04-01

    Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 ?M, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 ?M, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. PMID:24594354

  2. Acetylcholine and an acetylcholinesterase inhibitor neostigmine can aggravate tularemia progress in BALB/c mice

    PubMed Central

    Pohanka, Miroslav; Pavlis, Oto; Svobodova, Hana; Pikula, Jiri

    2012-01-01

    The present experiment was aimed at assessing the application of neostigmine, an acetylcholinesterase (AChE) pseudo-irreversible inhibitor with poor penetration through the hematoencephalitic barrier, and the neurotransmitter acetylcholine (ACh). The experiment was done to evaluate their ability to modulate an infectious disease: tularemia. Mice infected with Franciselle tularensis and exposed to either ACh or neostigmine had a higher mortality and spleen bacterial burden when compared to infected mice exposed to saline solution only. The activated cholinergic anti-inflammatory pathway suppressed pathways necessary for tularemia resolution. Administration of AChE inhibitors to the individuals suffering from tularemia is contra-indicatory. Drugs based on AChE inhibition should be restricted when tularemia or disease with a similar pathogenesis is suspected. PMID:22783145

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

    PubMed

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

    2013-09-01

    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

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

    Microsoft Academic Search

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

    2011-01-01

    Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer’s disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the ?-amyloid (A?) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed

  5. Neural nAChRs PET imaging probes.

    PubMed

    Mo, Ye-Xiong; Yin, Ya-Fu; Li, Ya-Ming

    2014-02-01

    There have been a number of attempts to study PET radioligands for imaging nicotinic acetylcholine receptors (nAChRs) in the human brain, and the most successful tracers found are radioligands for imaging ?4?2-nAChRs, which is the main cerebral nAChRs subtype. C-Nicotine and 2-[F]FA have been applied in many studies in humans. However, neither is entirely ideal and efforts have been made to develop radioligands with optimized imaging properties. Only a few reports have been published on radioligands for ?7-nAChRs imaging, another important cerebral nAChRs subtype. This paper will review the development of PET radioligands for imaging cerebral nAChRs. PMID:24240192

  6. Prenylated xanthones from mangosteen as promising cholinesterase inhibitors and their molecular docking studies.

    PubMed

    Khaw, K Y; Choi, S B; Tan, S C; Wahab, H A; Chan, K L; Murugaiyah, V

    2014-09-25

    Garcinia mangostana is a well-known tropical plant found mostly in South East Asia. The present study investigated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of G. mangostana extract and its chemical constituents using Ellman's colorimetric method. Cholinesterase inhibitory-guided approach led to identification of six bioactive prenylated xanthones showing moderate to potent cholinesterases inhibition with IC50 values of lower than 20.5 ?M. The most potent inhibitor of AChE was garcinone C while ?-mangostin was the most potent inhibitor of BChE with IC50 values of 1.24 and 1.78 ?M, respectively. Among the xanthones, mangostanol, 3-isomangostin, garcinone C and ?-mangostin are AChE selective inhibitors, 8-deoxygartanin is a BChE selective inhibitor while ?-mangostin is a dual inhibitor. Preliminary structure-activity relationship suggests the importance of the C-8 prenyl and C-7 hydroxy groups for good AChE and BChE inhibitory activities. The enzyme kinetic studies indicate that both ?-mangostin and garcinone C are mixed-mode inhibitors, while ?-mangostin is a non-competitive inhibitor of AChE. In contrast, both ?-mangostin and garcinone C are uncompetitive inhibitors, while ?-mangostin is a mixed-mode inhibitor of BChE. Molecular docking studies revealed that ?-mangostin, ?-mangostin and garcinone C interacts differently with the five important regions of AChE and BChE. The nature of protein-ligand interactions is mainly hydrophobic and hydrogen bonding. These bioactive prenylated xanthones are worthy for further investigations. PMID:25172794

  7. Lycopodiaceae from Panama: a new source of acetylcholinesterase inhibitors.

    PubMed

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

    2013-03-01

    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

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

    NASA Astrophysics Data System (ADS)

    Wang, Jing; Gu, Jiande; Leszczynski, Jerzy

    2006-11-01

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

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

    Microsoft Academic Search

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

    2010-01-01

    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

  10. Quaternary Research Association

    NSDL National Science Digital Library

    The Quaternary Research Association explains that it "exists to promote understanding of the Quaternary Period by publishing field guides, technical guides, and an international journal as well as holding field meetings and speaker meetings." Students and researchers can discover employment, research, grant, meetings, and educational opportunities.

  11. The neurotoxicity of subchronic acetylcholinesterase (AChE) inhibition in rat hippocampus.

    PubMed

    Veronesi, B; Jones, K; Pope, C

    1990-07-01

    The neurotoxic effects of long-term, low-level exposure to the commercially available insecticide, Fenthion, were examined in the present study. Young (2 month) adult, male Long-Evans rats were dermally exposed to Fenthion (25 mg/kg, 3X week) and sampled after 2 and 10 months exposure to assess neurotoxic damage in the hippocampus using morphological and biochemical endpoints. Histopathology, consisting of gliosis, swollen and necrotic neurons, and cell dropout, occurred in the dentate gyrus (DG), CA4 (hilus), and CA3 sectors as early as 2 months postexposure. Acetylcholinesterase (AChE) staining of brain tissues taken at this time was severely reduced in the septal nuclei, the DG molecular layer, the CA4, and the hippocampus proper. After 10 months exposure to Fenthion, cellular necrosis and gliosis intensified in the CA4 and CA3 regions and occasionally involved the CA2. Radiometric assays of AChE activity in the hippocampus indicated a 65 and 85% depression after 2 and 10 months exposure, respectively. Quinuclidinyl benzilate binding for the hippocampal muscarinic receptor was reduced by 6 and 15%, after 2 and 10 months exposure, respectively. A separate group of older (12 month) rats was exposed to the same dosing regimen of Fenthion and examined for neuropathological damage after 2 and 10 months exposure. Aged animals exposed for only 2 months expressed severe hippocampal degeneration in a pattern similar to that seen in the young adult after 10 months exposure (viz., DG, CA4, CA3). Aged animals exposed for 10 months showed more extensive histopathology of the CA4-2 and occasionally CA1. These observations indicate that in both young adult and aged animals, subchronic, low-level exposure to anticholinesterase compounds can result in serious neurotoxic consequences to the mammalian hippocampus. PMID:2385836

  12. INTRODUCTION Acetylcholine (ACh) plays a major role in insect synaptic

    E-print Network

    Nieh, James

    receptor (nAChR), belongs to the superfamily of Cys-loop ligand-gated ion channels and mediates signal neurobiology. In honey bees, the neonicotinoid imidacloprid inhibits receptors for -aminobutyric acid (GABA (Breer and Sattelle, 1987; Tomizawa and Casida, 2003). One ACh receptor, the nicotinic acetylcholine

  13. Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of ?-Amyloid Aggregation

    PubMed Central

    2014-01-01

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

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

    Microsoft Academic Search

    Carey Pope; Subramanya Karanth; Jing Liu

    2005-01-01

    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

  15. International Union for Quaternary Research

    NSDL National Science Digital Library

    The International Union for Quaternary Research (INQUA) discusses quaternary scientists' investigations "to interpret the changing world of the glacial ages and their impact on our planet's surface environments.". Researchers can find out about INQUA-funded projects, meetings, scientific commissions, and INQUA's two publicaions, Quaternary International, and Quaternary Perspectives.

  16. INCOMING WIRE/ACH University units expecting to receive funds via wire or ACH (Automated Clearing House) should inform the

    E-print Network

    Arnold, Jonathan

    INCOMING WIRE/ACH University units expecting to receive funds via wire or ACH (Automated Clearing form. The Bursar's Office cannot properly record there funds until University units provide deposit Transmittal and fax the completed form to 706-583-0832. OUTGOING WIRES University units needing to wire funds

  17. A Novel Application of Multiscale Entropy in Electroencephalography to Predict the Efficacy of Acetylcholinesterase Inhibitor in Alzheimer's Disease.

    PubMed

    Tsai, Ping-Huang; Chang, Shih-Chieh; Liu, Fang-Chun; Tsao, Jenho; Wang, Yung-Hung; Lo, Men-Tzung

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia. According to one hypothesis, AD is caused by the reduced synthesis of the neurotransmitter acetylcholine. Therefore, acetylcholinesterase (AChE) inhibitors are considered to be an effective therapy. For clinicians, however, AChE inhibitors are not a predictable treatment for individual patients. We aimed to disclose the difference by biosignal processing. In this study, we used multiscale entropy (MSE) analysis, which can disclose the embedded information in different time scales, in electroencephalography (EEG), in an attempt to predict the efficacy of AChE inhibitors. Seventeen newly diagnosed AD patients were enrolled, with an initial minimental state examination (MMSE) score of 18.8 ± 4.5. After 12 months of AChE inhibitor therapy, 7 patients were responsive and 10 patients were nonresponsive. The major difference between these two groups is Slope 2 (MSE6 to 20). The area below the receiver operating characteristic (ROC) curve of Slope 2 is 0.871 (95% CI = 0.69-1). The sensitivity is 85.7% and the specificity is 60%, whereas the cut-off value of Slope 2 is -0.024. Therefore, MSE analysis of EEG signals, especially Slope 2, provides a potential tool for predicting the efficacy of AChE inhibitors prior to therapy. PMID:26120358

  18. A Novel Application of Multiscale Entropy in Electroencephalography to Predict the Efficacy of Acetylcholinesterase Inhibitor in Alzheimer's Disease

    PubMed Central

    Tsai, Ping-Huang; Chang, Shih-Chieh; Liu, Fang-Chun; Tsao, Jenho; Wang, Yung-Hung; Lo, Men-Tzung

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia. According to one hypothesis, AD is caused by the reduced synthesis of the neurotransmitter acetylcholine. Therefore, acetylcholinesterase (AChE) inhibitors are considered to be an effective therapy. For clinicians, however, AChE inhibitors are not a predictable treatment for individual patients. We aimed to disclose the difference by biosignal processing. In this study, we used multiscale entropy (MSE) analysis, which can disclose the embedded information in different time scales, in electroencephalography (EEG), in an attempt to predict the efficacy of AChE inhibitors. Seventeen newly diagnosed AD patients were enrolled, with an initial minimental state examination (MMSE) score of 18.8 ± 4.5. After 12 months of AChE inhibitor therapy, 7 patients were responsive and 10 patients were nonresponsive. The major difference between these two groups is Slope 2 (MSE6 to 20). The area below the receiver operating characteristic (ROC) curve of Slope 2 is 0.871 (95% CI = 0.69–1). The sensitivity is 85.7% and the specificity is 60%, whereas the cut-off value of Slope 2 is ?0.024. Therefore, MSE analysis of EEG signals, especially Slope 2, provides a potential tool for predicting the efficacy of AChE inhibitors prior to therapy. PMID:26120358

  19. Gripped by Gout: Avoiding the Ache and Agony

    MedlinePLUS

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

    The toxicological and biochemical characteristics of acetylcholinesterases (AChE) in nine populations of the common pistachio psyllid, Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Psyllidae), were investigated in Kerman Province, Iran. Nine A. pistaciae populations were collected from pistachio orchards, Pistacia vera L. (Sapindales: Anacardiaceae), located in Rafsanjan, Anar, Bam, Kerman, Shahrbabak, Herat, Sirjan, Pariz, and Paghaleh regions of Kerman province. The previous bioassay results showed these populations were susceptible or resistant to phosalone, and the Rafsanjan population was most resistant, with a resistance ratio of 11.3. The specific activity of AChE in the Rafsanjan population was significantly higher than in the susceptible population (Bam). The affinity (KM) and hydrolyzing efficiency (Vmax) of AChE on acetylthiocholine iodide, butyrylthiocholine iodide, and propionylthiocholine odide as artificial substrates were clearly lower in the Bam population than that in the Rafsanjan population. These results indicated that the AChE of the Rafsanjan population had lower affinity to these substrates than that of the susceptible population. The higher Vmax value in the Rafsanjan population compared to the susceptible population suggests a possible over expression of AChE in the Rafsanjan population. The in vitro inhibitory effect of several organophosphates and carbamates on AChE of the Rafsanjan and Bam populations was determined. Based on I50, the results showed that the ratios of AChE insensitivity of the resistant to susceptible populations were 23 and 21.7-fold to monocrotophos and phosphamidon, respectively. Whereas, the insensitivity ratios for Rafsanjan population were 0.86, 0.8, 0.78, 0.46, and 0.43 for carbaryl, eserine, propoxur, m-tolyl methyl carbamate, and carbofuran, respectively, suggesting negatively correlated sensitivity to organophosphate-insensitive AChE. Therefore, AChE from the Rafsanjan population showed negatively correlated sensitivity, being insensitive to phosphamidon and monocrotophos and sensitive to N-methyl carbamates. PMID:25373165

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

    PubMed

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

    2014-10-01

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

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

    PubMed Central

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

    2015-01-01

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

  4. Quaternary Research Center

    NSDL National Science Digital Library

    "The Quaternary Research Center (QRC) fosters interdisciplinary research on the last two million years of the global environment: a time which encompasses massive, abrupt changes of climate, sea level, global biota and ice extent, as well the evolution of humans and the advent of civilization." Divided into six laboratories, the University of Washington's Center studies Cosmogenic Isotopes, Stable Isotopes, Old Quaternary Isotopes, Periglacial environments, quaternary ecology, paleoecology, and remote sensing. Researchers can find a tremendous amount of isotope, carbon dioxide, and chemistry data on the Taylor Dome, a part of the East Antarctic ice sheet. Students and educators can read papers by the center covering topics such as interactions among climate, surface, and tectonics; and glaciations and climate variations in the Pacific Northwest.

  5. Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines.

    PubMed

    Lodarski, Krzysztof; Jo?czyk, Jakub; Guzior, Natalia; Bajda, Marek; G?adysz, Joanna; Walczyk, Joanna; Jele?, Ma?gorzata; Morak-M?odawska, Beata; Pluta, Krystian; Malawska, Barbara

    2015-02-01

    The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand - AChE and ligand - BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 µM. The IC50 values for active BuChE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent. PMID:24666296

  6. Screening of ?-secretase and acetylcholinesterase inhibitors from plant resources.

    PubMed

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

    2015-01-01

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

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

    PubMed Central

    2013-01-01

    The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2–7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14–18), and quinolinodonepezils (19–21) are described. Pyridonepezils 15–18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19–21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC50 (hAChE) = 0.25 ± 0.02 ?M]. Pyridonepezils 15–18 and quinolinodonepezils 20–21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC50 (EeAChE) = 0.0167 ± 0.0002 ?M], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by A?1–42. All compounds were effective in preventing the enhancement of AChE activity induced by A?1–42. Compounds 2–7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by A?1–42. Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer’s disease. PMID:23379636

  8. Aldose reductase inhibitors zopolrestat and ferulic acid alleviate hypertension associated with diabetes: effect on vascular reactivity.

    PubMed

    Badawy, Dina; El-Bassossy, Hany M; Fahmy, Ahmed; Azhar, Ahmad

    2013-02-01

    This study investigated the effect of aldose reductase (AR) inhibitors on hypertension in diabetes. Diabetes was induced with streptozotocin, while AR inhibitors zopolrestat and ferulic acid were administered at 2 weeks after streptozotocin treatment and for 6 weeks afterwards. Then, blood pressure (BP) and serum level of glucose were determined. Concentration-response curves for phenylephrine (PE), KCl, and acetylcholine (ACh) were obtained in isolated aorta. In addition, ACh-induced NO and reactive oxygen species (ROS) generation in aorta and histopathology were examined. Compared with the control animals, diabetes increased diastolic and systolic BP. AR inhibitors reduced diastolic BP elevation without affecting the developed hyperglycaemia. Diabetes increased the contractile response of aorta to KCl, and decreased the relaxation response to Ach, while administering AR inhibitors prevented an impaired response to ACh. Incubation of aorta isolated from diabetic animals with AR inhibitors did not affect the impaired relaxation response to ACh. In addition, AR inhibitors negated the impaired Ach-stimulated NO generation seen in aorta isolated from diabetic animals. Furthermore, diabetes was accompanied with marked infiltration of leukocytes in aortic adventitia, endothelial cell pyknosis, and increased ROS formation. AR inhibitors reduced leukocyte infiltration and inhibited endothelial pyknosis and ROS formation. In conclusion, AR inhibitors negate diabetes-evoked hypertension via ameliorating impaired endothelial relaxation and NO production. PMID:23458193

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

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

    2012-01-01

    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. PMID:22148173

  11. Complete Genome Sequence of Agrobacterium tumefaciens Ach5.

    PubMed

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

    2015-01-01

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

  12. Complete Genome Sequence of Agrobacterium tumefaciens Ach5

    PubMed Central

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

    2015-01-01

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

  13. The Pediocin AcH Precursor Is Biologically Active

    PubMed Central

    Ray, Bibek; Schamber, Robin; Miller, Kurt W.

    1999-01-01

    The properties of the pediocin AcH precursor, prepediocin AcH, have been studied to gain insight into how producer cells may protect themselves from the activity of intracellular prebacteriocins. The native 62-amino-acid precursor and the 44-amino-acid mature species were expressed in Escherichia coli host strains that lack the leader peptide processing enzyme, PapD. Both forms inhibited the growth of the test bacterium Listeria innocua Lin11, indicating that the native precursor is biologically active. The two species also were synthesized in the context of maltose-binding protein chimeric proteins to facilitate the measurement of their relative specific activities. The chimeric form of the precursor was ?80% as active as the chimeric mature species. Of relevance to cell protection and pediocin AcH production, it was determined that the precursor is strongly susceptible to inactivation by reducing agents and to degradation by chymotrypsin and endogenous E. coli proteases. Taken together, the results indicate that the activity of prepediocin AcH may have to be controlled prior to secretion to prevent toxicity to the host. Perhaps producer cells avoid membrane damage by maintaining the precursor in a reduced inactive state or by degrading molecules whose secretion is delayed. PMID:10347002

  14. Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors.

    PubMed

    Baharloo, Farzaneh; Moslemin, Mohammad Hossein; Nadri, Hamid; Asadipour, Ali; Mahdavi, Mohammad; Emami, Saeed; Firoozpour, Loghman; Mohebat, Razieh; Shafiee, Abbas; Foroumadi, Alireza

    2015-03-26

    A series of benzofuran-based N-benzylpyridinium derivatives 5a-o were designed and synthesized as novel AChE inhibitors. The synthetic pathway of the compounds involved the preparation of 4-(benzofuran-2-yl)pyridine intermediates via the reaction of different salicylaldehyde derivatives and 4-(bromomethyl)pyridine, followed by intramolecular cyclization. Subsequently, the 4-(benzofuran-2-yl)pyridines were N-benzylated by using appropriate benzyl bromide to afford the final product 5a-o. The results of in vitro AChE activity evaluation of synthesized compounds revealed that all compound had potent anti-AChE activity comparable or more potent than standard drug donepezil. The N-(3,5-dimethylbenzyl) derivative 5e with IC50 value of 4.1 nM was the most active compound, being 7-fold more potent than donepezil. PMID:25681712

  15. 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

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

    2011-07-15

    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

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

    PubMed

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

    2013-01-01

    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

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

    PubMed Central

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

    2013-01-01

    Acetylcholinesterase and Butyrylcholinesterase share unravelling link with components of metabolic syndromes that’s characterised by low levels of HDL cholesterol, obesity, high fast aldohexose levels, hyper-trigliceridaemia and high blood pressure, by regulation of cholinergic transmission and therefore the enzyme activity within a living system. The phosphomotifs associated with amino acid and tyrosine binding motifs in AChE and BChE were known to be common. Phylogenetic tree was constructed to these proteins usinf UPGMA and Maximum Likelihood methods in MEGA software has shown interaction of AChE and BChE with ageing diseases like Alzheimer’s disease and Diabetes. AChE has shown closely related to BChE, retinol dehydrogenase and ?-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

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

    PubMed Central

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

    2006-01-01

    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 ?. Normal mode analysis with a C? Gaussian network of a new structural model of the neuronal ?7 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

  19. Quaternary Research Association Educational Resources

    NSDL National Science Digital Library

    The Quaternary Research Association (QRA) is an organization comprising archaeologists, botanists, civil engineers, geographers, geologists, soil scientists, zoologists and others interested in research into the problems of the Quaternary. This site describes their activities and organization. This direct link to the educational teaching resources provides access to glacier and glaciation resources.

  20. Relaxation of the ACh-induced potassium current in the rabbit sinoatrial node cell

    Microsoft Academic Search

    A. Noma; W. Trautwein

    1978-01-01

    Voltage clamp experiments were carried out in order to study the mechanism of the ACh action in the rabbit S-A node cell. The following results were obtained:1.The reversal potential of the ACh-induced current behaved like a potassium electrode, confirming that the ACh-operated channels pass potassium ions selectively.2.On depolarizing voltage jumps the ACh-induced current showed an instantaneous peak from which the

  1. Selectivity of antagonists for the Cys-loop native receptors for ACh, 5-HT and GABA in guinea-pig myenteric neurons.

    PubMed

    Juárez, E H; Ochoa-Cortés, F; Miranda-Morales, M; Espinosa-Luna, R; Montaño, L M; Barajas-López, C

    2014-01-01

    The three most common Cys-loop receptors expressed by myenteric neurons are nACh, 5-HT3 and GABAA . To investigate the function of these proteins researchers have used channel inhibitors such as hexamethonium (antagonist of nACh receptors), ondansetron (antagonist of 5-HT3 receptors), picrotoxin and bicuculline (both antagonists of GABAA receptors). The aim of this study was to investigate the specificity of these inhibitors on Cys-loop receptors of primary cultured neurons obtained from the guinea-pig small intestine. The whole-cell configuration of the patch clamp techniques was used to record membrane currents induced by ACh (IACh ), 5-HT (I5-HT ) and GABA (IGABA ) in the absence and the presence of various concentrations of hexamethonium, ondansetron, picrotoxin or bicuculline. The three Cys-loop receptors present in enteric neurons are expressed independently and they do not cross-desensitized. Hexamethonium inhibited IACh without affecting I5-HT and IGABA . Ondansetron inhibited I5-HT and also IACh but did not affect IGABA . Picrotoxin and bicuculline inhibited I5-HT , IACh and IGABA with different potency, being the lowest potency on 5-HT3 receptors. All these inhibitory effects were concentration dependent and reversible. Our observations showed that except for hexamethonium, all other inhibitors used here show different degrees of selectivity, which has to be considered when these antagonists are used in experimental studies aimed to investigate the functions of these receptors. In particular, in tissues expressing nACh receptors because these are the targets of all other inhibitors used here. The low potency of picrotoxin and bicuculline to inhibit 5-HT3 receptors suggests that these receptors are heteromeric proteins. PMID:24151989

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

    PubMed Central

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

    2014-01-01

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

  3. Low Back Ache Treatment with Botulinum Neurotoxin Type A

    Microsoft Academic Search

    Venkatesan Nagarajan; Asmahan Al-Shubaili; Yasser M. Ayad; John Alexander; Khadijah Al-Ramezi

    2007-01-01

    Objective: To investigate the efficacy, safety and tolerability of paraspinal administration of botulinum neurotoxin type A (BoNT-A) in patients with chronic low back ache (LBA). Subjects and Methods: Eight patients with chronic LBA were injected with BoNT-A at three sites on either side of lumbar paraspinal muscles. The patients rated their pain intensity using a visual analogue scale (VAS) from

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

    PubMed

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

    2014-02-12

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

  5. Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and ?-amyloid aggregation inhibitors with neuroprotective properties.

    PubMed

    Guzior, Natalia; Bajda, Marek; Skrok, Miros?aw; Kurpiewska, Katarzyna; Lewi?ski, Krzysztof; Brus, Boris; Pišlar, Anja; Kos, Janko; Gobec, Stanislav; Malawska, Barbara

    2015-03-01

    The presented study describes the synthesis, pharmacological evaluation (AChE and BuChE inhibition, beta amyloid anti-aggregation effect and neuroprotective effect), molecular modeling and crystallographic studies of a novel series of isoindoline-1,3-dione derivatives. The target compounds were designed as dual binding site acetylcholinesterase inhibitors with an arylalkylamine moiety binding at the catalytic site of the enzyme and connected via an alkyl chain to a heterocyclic fragment, capable of binding at the peripheral anionic site of AChE. Among these molecules, compound 15b was found to be the most potent and selective AChE inhibitor (IC50EeAChE = 0.034 ?M). Moreover, compound 13b in addition to AChE inhibition (IC50 EeAChE = 0.219 ?M) possesses additional properties, such as the ability to inhibit A? aggregation (65.96% at 10 ?M) and a neuroprotective effect against A? toxicity at 1 and 3 ?M. Compound 13b emerges as a promising multi-target ligand for the further development of the therapy for age-related neurodegenerative disorders. PMID:25621991

  6. WblAch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpAch

    PubMed Central

    Yu, Pin; Liu, Shui-Ping; Bu, Qing-Ting; Zhou, Zhen-Xing; Zhu, Zhen-Hong; Huang, Fang-Liang

    2014-01-01

    Detailed mechanisms of WhiB-like (Wbl) proteins involved in antibiotic biosynthesis and morphological differentiation are poorly understood. Here, we characterize the role of WblAch, a Streptomyces chattanoogensis L10 protein belonging to this superfamily. Based on DNA microarray data and verified by real-time quantitative PCR (qRT-PCR), the expression of wblAch was shown to be positively regulated by AdpAch. Gel retardation assays and DNase I footprinting experiments showed that AdpAch has specific DNA-binding activity for the promoter region of wblAch. Gene disruption and genetic complementation revealed that WblAch acts in a positive manner to regulate natamycin production. When wblAch was overexpressed in the wild-type strain, the natamycin yield was increased by ?30%. This provides a strategy to generate improved strains for natamycin production. Moreover, transcriptional analysis showed that the expression levels of whi genes (including whiA, whiB, whiH, and whiI) were severely depressed in the ?wblAch mutant, suggesting that WblAch plays a part in morphological differentiation by influencing the expression of the whi genes. PMID:25172865

  7. Rapid identification of cholinesterase inhibitors from the seedcases of mangosteen using an enzyme affinity assay.

    PubMed

    Ryu, Hyung Won; Oh, Sei-Ryang; Curtis-Long, Marcus J; Lee, Ji Hye; Song, Hyuk-Hwan; Park, Ki Hun

    2014-02-12

    Enzyme binding affinity has been recently introduced as a selective screening method to identify bioactive substances within complex mixtures. We used an assay which identified small molecule binders of acetylcholinesterase (AChE) using the following series of steps: incubation of enzyme with extract; centrifugation and filtration; identification of small molecule content in the flow through. The crude extract contained 10 peaks in the UPLC chromatogram. However, after incubation the enzyme, six peaks were reduced, indicating these compounds bound AChE. All these isolated compounds (2, 3, and 5-8) significantly inhibited human AChE with IC??s = 5.4-15.0 ?M and butyrylcholinsterase (IC??s = 0.7-11.0 ?M). All compounds exhibited reversible mixed kinetics. Consistent with the binding screen and fluorescence quenching, ?-mangostin 6 had a much higher affinity for AChE than 9-hydroxycalabaxanthone 9. This validates this screening protocol as a rapid method to identify inhibitors of AChE. PMID:24446804

  8. Fluorescence Quenching Determination of Uranium (VI) Binding Properties by Two Functional Proteins: Acetylcholinesterase (AChE) and Vitellogenin (Vtg).

    PubMed

    Coppin, Frédéric; Michon, Jérôme; Garnier, Cédric; Frelon, Sandrine

    2015-05-01

    The interactions between uranium and two functional proteins (AChE and Vtg) were investigated using fluorescence quenching measurements. The combined use of a microplate spectrofluorometer and logarithmic additions of uranium into protein solutions allowed us to define the fluorescence quenching over a wide range of [U]/[Pi] ratios (from 1 to 3235) at physiologically relevant conditions of pH. Results showed that fluorescence from the two functional proteins was quenched by UO2 (2+). Stoichiometry reactions, fluorescence quenching mechanisms and complexing properties of proteins, i.e. binding constants and binding sites densities, were determined using classic fluorescence quenching methods and curve-fitting software (PROSECE). It was demonstrated that in our test conditions, the protein complexation by uranium could be simulated by two specific sites (L1 and L2). The obtained complexation constant values are log K1?=?5.7 (±1.0), log K2?=?4.9 (±1.1); L1?=?83 (±2), L2?=?2220 (±150) for U(VI) - Vtg and log K1?=?8.1 (±0.9), log K2?=?6.6 (±0.5), L1?=?115 (±16), L2?=?530 (±23) for U(VI)-AChE (Li is expressed in mol/mol of protein). PMID:25764300

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

    PubMed

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

    2014-11-01

    T-superfamily conotoxins have a typical cysteine pattern of "CC-CC", and are known to mainly target calcium or sodium ion channels. Recently, we screened the targets of a series of T-superfamily conotoxins and found that a new T-superfamily conotoxin TxVC (KPCCSIHDNSCCGL-NH2) from the venom of Conus textile. It selectively targeted the neuronal nicotinic acetylcholine receptor (nAChR) subtypes ?4?2 and ?3?2, with IC50 values of 343.4 and 1047.2nM, respectively, but did not exhibit obvious pharmacological effects on voltage-gated potassium, sodium or calcium channel in DRG cells, the BK channels expressed in HEK293 cells, or the Kv channels in L?T2 cells. The changes in the inhibitory activities of its Ala mutants, the NMR structure, and molecular simulation results based on other conotoxins targeting nAChR ?4?2, all demonstrated that the residues Ile(6) and Leu(14) were the main hydrophobic pharmacophores. To our best knowledge, this is the first T-superfamily conotoxin that inhibits neuronal nAChRs and possesses high binding affinity to ?4?2. This finding will expand the knowledge of the targets of T-superfamily conotoxins and the motif information could help the design of new nAChR inhibitors. PMID:25450372

  10. Quaternary GIS Laboratory

    NSDL National Science Digital Library

    This is the home page of the Quaternary Geographic Information System (GIS) Laboratory at the Institute of Arctic and Alpine Research (INSTAAR) at the University of Colorado. The laboratory supports quantitative spatial analysis of glacier, climate, coastal, and other environmental relationships at high latitudes. Users can access a collection of climate animations for the State of Alaska which show seasonal variation in monthly temperature and precipitation. There is also a set of high-resolution imagery and terrain models for Barrow, Alaska, an animation of the land bridge between Asia and North America, an atlas of paleoglaciation for the state, and links to a variety of other projects involving climatology, paleoclimatology, and glacial geomorphology in the Sate of Alaska.

  11. Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

    PubMed Central

    Gupta, Shikhar; Mohan, C. Gopi

    2014-01-01

    In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer's randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties. PMID:25050335

  12. The ?7 nAChR selective agonists as drug candidates for Alzheimer's disease.

    PubMed

    Fan, Huaimeng; Gu, Ruoxu; Wei, Dongqing

    2015-01-01

    The nicotinic acetylcholine receptors (nAChRs) are ion channels distribute in the central or peripheral nervous system. They are receptors of the neurotransmitter acetylcholine and activation of them by agonists mediates synaptic transmission in the neuron and muscle contraction in the neuromuscular junction. Current studies reveal relationship between the nAChRs and the learning and memory as well as cognation deficit in various neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia and drug addiction. There are various subtypes in the nAChR family and the ?7 nAChR is one of the most abundant subtypes in the brain. The ?7 nAChR is significantly reduced in the patients of Alzheimer's disease and is believed to interact with the A? amyloid. A? amyloid is co-localized with ?7 nAChR in the senile plaque and interaction between them induces neuron apoptosis and reduction of the ?7 nAChR expression. Treatment with ?7 agonist in vivo shows its neuron protective and procognation properties and significantly improves the learning and memory ability of the animal models. Therefore, the ?7 nAChR agonists are excellent drug candidates for Alzheimer's disease and we summarized here the current agonists that have selectivity of the ?7 nAChR over the other nAChR, introduced recent molecular modeling works trying to explain the molecular mechanism of their selectivity and described the design of novel allosteric modulators in our lab. PMID:25387975

  13. [Acetylcholinesterase inhibitors for treatment of Alzheimer's disease].

    PubMed

    Shinagawa, Shunichiro; Shigeta, Masahiro

    2014-05-01

    Alzheimer's disease (AD) is a neurodegenerative disorder, and is the commonest cause of dementia. Acetylcholinesterase inhibitors (AChEIs) were developed under the cholinergic hypothesis of AD. Therapeutic strategies with these drugs aimed to enhance cholinergic neurotransmission in specific parts of the brain, and to improve the clinical symptoms of AD. Donepezil, galantamine and rivastigmine are commonly used AChEIs in pharmacotherapy for AD, slowing the progression and controlling the symptoms of AD. Although these drugs have different pharmacological properties, there is no clear evidence of differences between them with respect to efficacy. It is possible to adapt AChEIs for the pharmacotherapy of other conditions, such as vascular dementia, dementia with Lewy bodies, and Down syndrome. PMID:24807367

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

    PubMed

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

    2011-02-15

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

  15. Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies.

    PubMed

    Geromichalos, George D; Lamari, Fotini N; Papandreou, Magdalini A; Trafalis, Dimitrios T; Margarity, Marigoula; Papageorgiou, Athanasios; Sinakos, Zacharias

    2012-06-20

    Inhibitors of acetylcholine breakdown by acetylcholinesterase (AChE) constitute the main therapeutic modality for Alzheimer's disease. In the search for natural products with inhibitory action on AChE, this study investigated the activity of saffron extract and its constituents by in vitro enzymatic and molecular docking studies. Saffron has been used in traditional medicine against Alzheimer's disease. Saffron extract showed moderate AChE inhibitory activity (up to 30%), but IC(50) values of crocetin, dimethylcrocetin, and safranal were 96.33, 107.1, and 21.09 ?M, respectively. Kinetic analysis showed mixed-type inhibition, which was verified by in silico docking studies. Safranal interacts only with the binding site of the AChE, but crocetin and dimethylcrocetin bind simultaneously to the catalytic and peripheral anionic sites. These results reinforce previous findings about the beneficial action of saffron against Alzheimer's disease and may be of value for the development of novel therapeutic agents based on carotenoid-based dual binding inhibitors. PMID:22655699

  16. Pharmacological Evaluation and Docking Studies of 3-Thiadiazolyl- and Thioxo-1,2,4-triazolylcoumarin Derivatives as Cholinesterase Inhibitors

    PubMed Central

    Raza, Ahsan; Saeed, Aamer; Ibrar, Aliya; Muddassar, Muhammad; Khan, Aftab Ahmed; Iqbal, Jamshed

    2012-01-01

    Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment of Alzheimer's disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin analogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives were designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from electrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellman's method using neostigmine methylsulphate and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with Ki values in the micromolar range. 4b was found to be the most active compound with Ki value 0.028 ± 0.002??M and higher selectivity for AChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, and a secondary binding was revealed at the peripheral anionic site. Structure activity relationships of prepared compounds were also discussed. PMID:22966467

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

    PubMed

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

    2015-10-15

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

  18. Ionic liquid mediated synthesis of mono- and bis-spirooxindole-hexahydropyrrolidines as cholinesterase inhibitors and their molecular docking studies.

    PubMed

    Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Basiri, Alireza; Murugaiyah, Vikneswaran

    2014-02-15

    One pot, three-component reaction of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with isatin and sarcosine in molar ratios of 1:1:1 and 1:2:2 furnished to mono- and bis-spiropyrrolidine heterocyclic hybrids comprising functionalized piperidine, pyrrolidine and oxindole structural motifs. Both mono and bis-spiropyrrolidines displayed good inhibitory activity against acetylcholinesterase (AChE) with IC?? values of 2.36-9.43 ?M. For butyrylcholinesterase (BChE), mono-cycloadducts in series 8 with IC?? values of lower than 10 ?M displayed better inhibitory activities than their bis-cycloadduct analogs in series 9 with IC?? values of 7.44-19.12 ?M. The cycloadducts 9j and 8e were found to be the most potent AChE and BChE inhibitors with IC?? values of 2.35 and 3.21 ?M, respectively. Compound 9j was found to be competitive inhibitor of AChE while compound 8e was a mixed-mode inhibitor of BChE with calculated Ki values of 2.01 and 6.76 ?M, respectively. Molecular docking on Torpedo californica AChE and human BChE showed good correlation between IC?? values and free binding energy values of the synthesized compounds docked into the active site of the enzymes. PMID:24461561

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. A physical model of nicotinic ACh receptor kinetics

    E-print Network

    Ewa Nurowska; Mykola Bratiichuk; Beata Dworakowska; Roman J. Nowak

    2008-12-31

    We present a new approach to nicotinic receptor kinetics and a new model explaining random variabilities in the duration of open events. The model gives new interpretation on brief and long receptor openings and predicts (for two identical binding sites) the presence of three components in the open time distribution: two brief and a long. We also present the physical model of the receptor block. This picture naturally and universally explains receptor desensitization, the phenomenon of central importance in cellular signaling. The model is based on single-channel experiments concerning the effects of hydrocortisone (HC) on the kinetics of control wild-type (WT) and mutated alphaD200Q mouse nicotinic acetylcholine receptors (nAChRs), expressed in HEK 293 cells. The appendix contains an original result from probability renewal theory: a derivation of the probability distribution function for the duration of a process performed by two independent servers.

  2. Enantioselective Construction of Cyclic Quaternary Centers: (-)-Mesembrine

    E-print Network

    Taber, Douglass

    Enantioselective Construction of Cyclic Quaternary Centers: (-)-Mesembrine Douglass F. Taber, (-)-mesembrine 1. Amide 2 should be a useful chiron for the enantioselective construction of cyclic quaternary of mesembrine2,3 and its analogues is the enantioselective construction of the chiral quaternary center.4 We

  3. Cellular Membrane Phospholipids Act as a Depository for Quaternary Amine containing Drugs thus competing with the Acetylcholine / Nicotinic Receptor

    PubMed Central

    Barbacci, Damon; Jackson, Shelley N.; Muller, Ludovic; Egan, Thomas; Lewis, Ernest K.; Schultz, J. Albert; Woods, Amina S.

    2014-01-01

    We previously demonstrated that ammonium- or guanidinium- phosphate interactions are key to forming non-covalent complexes (NCXs) through salt bridge formation with G-protein coupled receptors (GPCR), which are immersed in the cell membrane's lipids. The present work highlights MALDI ion mobility coupled to orthogonal time-of-flight mass spectrometry (MALDI IM oTOF MS) as a method to determine qualitative and relative quantitative affinity of drugs to form NCXs with targeted GPCRs' epitopes in a model system using, bis-quaternary amine based drugs, ?- and ?- subunit epitopes of the nicotinic acetylcholine receptor' (nAChR) and phospholipids. Bis-quaternary amines proved to have a strong affinity for all nAChR epitopes and negatively charged phospholipids, even in the presence of the physiological neurotransmitter acetylcholine. Ion mobility baseline separated isobaric phosphatidyl ethanolamine and a matrix cluster, providing an accurate estimate for phospholipid counts. Overall this technique is a powerful method for screening drugs' interactions with targeted lipids and protein respectively containing quaternary amines and guanidinium moieties. PMID:22506649

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

    PubMed

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

    2013-01-01

    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 European sea bass D. labrax (L.) reared in three different intensive farms: a land-based farm of cement tanks (T), an in-shore sea cages farm (C1) and an off-shore sea cages farm (C2). The results showed that both location and typology can discriminate AChE activity, GSH content and gonad morphology. Further investigation is needed to propose these biomarkers in the protocol of fish farm quality control. PMID:22533608

  5. Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer’s brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants

    Microsoft Academic Search

    John R Fawcett; Elizabeth Z Bordayo; Kathy Jackson; Howard Liu; Jennifer Peterson; Aleta Svitak; William H Frey II

    2002-01-01

    Oxidative stress has been implicated as a contributing factor to neurodegeneration in Alzheimer’s disease. An endogenous, low molecular weight (LMW) inhibitor from Alzheimer’s brain inactivates the human brain muscarinic acetylcholine receptor (mAChR). The inhibitor prevents agonist and antagonist binding to the mAChR as assesssed by radioligand binding studies. The LMW endogenous inhibitor, which has components with molecular weights between 100

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

    PubMed Central

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

    2012-01-01

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

  7. 3'-R/S-hydroxyvoacamine, a potent acetylcholinesterase inhibitor from Tabernaemontana divaricata.

    PubMed

    Chaiyana, Wantida; Schripsema, Jan; Ingkaninan, Kornkanok; Okonogi, Siriporn

    2013-04-15

    Guided by the acetylcholinesterase inhibiting activity, the bisindole alkaloid 3'-R/S-hydroxyvoacamine was isolated from a stem extract of Tabernaemontana divaricata, a plant used in Thailand in traditional rejuvenation remedies for improving the memory. The structure of the alkaloid was elucidated by extensive use of NMR spectroscopy and the complete assignment of the (1)H and (13)C NMR spectra is reported. The alkaloid acted as a non-competitive inhibitor against AChE with an IC50 value of 7.00±1.99 ?M. An HPLC method was developed for the quantitative analysis of the AChE inhibitor. It suggested that there was 12.4% (w/w) of 3'-R/S-hydroxyvoacamine in the alkaloid enriched fraction of T. divaricata stem. PMID:23375813

  8. Lithium Inhibits a Late Step in Agrin-Induced AChR Aggregation

    E-print Network

    Sharma, Shiv K.

    Lithium Inhibits a Late Step in Agrin-Induced AChR Aggregation S. K. Sharma,* B. G. Wallace 1. Here we report that treating chick myotubes with lithium prevented any detectable agrin-induced change phosphorylation and detergent extractabil- ity. Lithium treatment also increased the rate at which AChR aggregates

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

    Microsoft Academic Search

    Patricia Wyatt; Kim Todd; Tabatha Verbick

    2006-01-01

    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

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

    PubMed

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

    2013-01-01

    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

  11. Low-dose cholinesterase inhibitors do not induce delayed effects on cerebral blood flow and metabolism

    Microsoft Academic Search

    Oscar U. Scremin; Tsung-Ming Shih; Ly Huynh; Margareth Roch; Wei Sun; Dante R. Chialvo; Donald J. Jenden

    2005-01-01

    The acetylcholinesterase (AChE) inhibitors sarin and pyridostigmine bromide (PB) have been proposed as causes of neurobehavioral dysfunction in Persian Gulf War veterans. To test possible delayed effects of these agents, we exposed rats to low (subsymptomatic) levels of sarin (0.5 LD50 s.c. 3 times weekly) and\\/or PB (80 mg\\/L in drinking water) for 3 weeks. Controls received saline s.c. and

  12. Robustness of Quaternary glacial cycles

    NASA Astrophysics Data System (ADS)

    Ganopolski, Andrei; Brovkin, Victor; Calov, Reinhard

    2015-04-01

    In spite of significant progress in paleoclimate reconstructions and modeling some aspects of Quaternary climate cycles are still poorly understood. Among them is the question of whether glacial cycles are deterministic and solely externally forced or, at least partially, they are stochastic. The answer to this question can only be obtained using a comprehensive Earth system models which incorporates all major components of the Earth system - atmosphere, ocean, land surface, northern hemisphere ice sheets, terrestrial biota and soil carbon, aeolian dust and marine biogeochemistry. Here, we used the Earth system model of intermediate complexity CLIMBER-2. The model was optimally tuned to reproduce climate, ice volume and CO2 variability for the last 0.8 million years. Using the same model version, we performed a large set of simulations covering the entire Quaternary (3 million years). By starting the model at different times (with the time step of 100,000 years) and using identical initial conditions we run the model for 500,000 years using the Earth's orbital variations as the only prescribed radiative forcing. We show that within less than 100,000 years after the beginning of each experiment the modeling results converge to the same solution which depends only on the orbital forcing and boundary conditions, such as topography and terrestrial sediment thickness for the ice sheets or volcanic CO2 outgassing for the carbon cycle. By using only several sets of the Northern Hemisphere orography and sediment thickness which represent different stages of landscape evolution during Quaternary, we are able to reproduce all major regimes of Quaternary long-term climate variability. Our results thus strongly support the notion that Quaternary glacial cycles are deterministic and externally forced.

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

    PubMed

    Ak?nc?o?lu, Ak?n; Ak?nc?o?lu, Hülya; Gülçin, ?lhami; Durdagi, Serdar; Supuran, Claudiu T; Göksu, Süleyman

    2015-07-01

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

  14. Selection of corrosion inhibitors to control microbiologically influenced corrosion

    SciTech Connect

    Prasad, R. [Champion Technologies, Inc., Fresno, TX (United States)

    1998-12-31

    Microbiologically Influenced Corrosion (MIC) is a serious problem. The establishment of a biofilm on a metal surface plays a critical role in MIC. Quaternary amines have been reported to inhibit the bacterial adhesion to the metal surface. However, most of the quaternary amines are quite toxic. In light of growing concerns of environmental impact and safety, a series of experiments was conducted to evaluate various corrosion inhibitors for their inhibition capability of bacterial adhesion as well as bacterial kill. The results indicate that some inhibitors are capable of inhibiting biofilm formation on mild steel coupons. In addition, these inhibitors have biocidal properties. Initial toxicity studies suggest that some of these inhibitors are less toxic than most industrial biocides. This paper discusses the cost-effectiveness of use of these inhibitors in some systems.

  15. Anti-amnesic effect of neurosteroid PREGS in A?25-35-injected mice through ?1 receptor- and ?7nAChR-mediated neuroprotection.

    PubMed

    Yang, Rong; Chen, Lei; Wang, Haofei; Xu, Bingzhong; Tomimoto, Hidekazu; Chen, Ling

    2012-11-01

    A single intracerebroventricular injection of ?-amyloid 25-35 peptide (A?(25-35)) (9 nmol/mouse) induces the spatial cognitive deterioration and approximately 50% loss of pyramidal cells in hippocampal CA1 region within 1 week. The present study focused on exploring the effects of neurosteroid pregnenolone sulfate (PREGS), in comparison with the selective agonists of sigma-1 receptor (?(1)R) and ?7 nicotinic acetylcholine receptor (?7nAChR), on the cognitive deficits and the death of pyramidal cells in A?(25-35)-mice. Herein, we reported that the administration of PREGS (1-100 mg/kg) for 7 days after A?(25-35)-injection could dose-dependently ameliorate the cognitive deficits and attenuate the apoptosis of pyramidal cells. Either the ?(1)R antagonist NE100 or the ?7nAChR antagonist MLA could block the neuroprotection of PREGS in A?(25-35)-mice. Both the ?(1)R agonist PRE084 and the ?7nAChR agonist DMXB could mimic the PREGS-neuroprotection against the A?(25-35)-neurotoxicity. The neuroprotection of PRE084 was attenuated by MLA, but the DMXB-action was insensitive to NE100. The neuroprotection of PREGS, PRE084 or DMXB was blocked by the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, whereas only the effect of PREGS or PRE084 was sensitive to the MAPK/ERK kinase (MEK) inhibitor U0126. PREGS prevented A?(25-35)-inhibited Akt (Serine/threonine kinase) phosphorylation leading to increase in caspase-3 activity, which was ?(1)R- and ?7nAChR-dependent. By contrast, PREGS-rescued reduction of extracellular signal-related kinase-2 (ERK2) phosphorylation in A?(25-35)-mice only required the activation of ?(1)R. Blockage of PREGS-neuroprotection by LY294002 significantly attenuated its anti-amnesic effect in A?(25-35)-mice. The findings indicate that the anti-amnesic effects of PREGS in A?(25-35)-mice depend on the ?(1)R- and ?7nAChR-mediated neuroprotection. PMID:22884465

  16. Identification of potential herbal inhibitor of acetylcholinesterase associated Alzheimer's disorders using molecular docking and molecular dynamics simulation.

    PubMed

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

    2014-01-01

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

  17. Investigating the interaction of McN-A-343 with the M1 muscarinic receptor using its nitrogen mustard derivative and ACh mustard

    PubMed Central

    Figueroa, KW; Suga, H; Ehlert, FJ

    2010-01-01

    Background and purpose: We investigated how McN-A-343 inhibited the alkylation of the M1 muscarinic receptor by its nitrogen mustard derivative and that of ACh to identify whether it interacts allosterically or orthosterically. Experimental approach: We incubated the M1 muscarinic receptor expressed in Chinese hamster ovary cells with ACh mustard for various periods of time in the presence of McN-A-343 or known allosteric and orthosteric ligands. After stopping the reaction and removing unreacted ligands, unalkylated receptors were measured using [3H]N-methylscopolamine. Analogous experiments were done using a nitrogen mustard analog of McN-A-343. Affinity constants, cooperativity values for allosteric interactions and rate constants for receptor alkylation were estimated using a mathematical model. Key results: The kinetics of receptor alkylation by the nitrogen mustard derivatives of ACh and McN-A-343 were consistent with a two-step model in which the aziridinium ion rapidly forms a reversible receptor complex, which converts to a covalent complex at a slower rate. The inhibition of receptor alkylation by acetycholine, N-methylscopolamine and McN-A-343 was consistent with competitive inhibition, whereas that caused by gallamine was consistent with allosterism. Affinity constants estimated from alkylation kinetics agreed with those measured by displacement of [3H]N-methylscopolamine binding. Conclusions and implications: Our results suggest that McN-A-343 and its nitrogen mustard derivative interact competitively with ACh and N-methylscopolamine at the orthosteric site on the M1 muscarinic receptor. Measuring how drugs modulate the kinetics of receptor alkylation by an irreversible ligand is a powerful approach for distinguishing between negative allosteric modulators and competitive inhibitors. PMID:20590642

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

    PubMed Central

    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

    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. PMID:23482465

  19. Introduction Preliminaries Construction of Quaternary Sequences Construction of Familes References New Construction of Quaternary Sequences

    E-print Network

    No, Jong-Seon

    Introduction Preliminaries Construction of Quaternary Sequences Construction of Familes References New Construction of Quaternary Sequences with Good Correlation Using Binary Sequences with Good University May 28, 2010 May 28, 2010 2010 CITS 2nd 1/ 34 #12;Introduction Preliminaries Construction

  20. Hydrogenated amorphous carbon (a:C-H) in the planetary nebula NGC 7027

    NASA Technical Reports Server (NTRS)

    Goebel, John H.

    1987-01-01

    A spectroscopic identification of the infrared continuum radiation is proposed for the planetary nebula NGC 7027. Hydrogenated amorphous carbon (a:C-H) is shown to account for the undulating spectrum between 5 and 15 microns. The unidentified infrared emission bands lie at the peaks in the a:C-H spectrum, pointing to their association with a carbon polymorph, possibly a:C-H or polycyclic aromatic hydrocarbon molecules. Except for atomic emission lines, all the infrared emission from NGC 7027 comes from one or another polymorph of carbon.

  1. Residues of dimethoate in the liver and AchE activity in blood of rats after exposure to dimethoate, and dimethoate and pyrantel embonate.

    PubMed

    Barski, D; Zasadowski, A

    2006-01-01

    The study was aimed at determining the dimethoate residues in the liver and acetylcholinesterase (AChE) activity in blood of rats exposed to dimethoate (individual intoxication), and dimethoate and pyrantel embonate (simultaneous intoxication). The experiment was carried out in two stages where various doses of preparations and exposure manners were used. In the first stage of the experiment, dimethoate (1/25 LD50) was administered to animals per os for 28 days, and pyrantel embonate (1/2 LD550) twice, i.e. on the day 14th and 28th. In the second stage, dimethoate was administered for 5 days (1/10 LD50), and pyrantel embonate (1/5 LD50) on day 3, 4 and 5 from the beginning of dimethoate intoxication. The short presence of the dimethoate residues in the liver of the animals examined was found until the 2nd day after 28-day intoxication (1/25 LD50) and until 14th day after 5-day intoxication (1/10 LD50), however, a distinct decrease in this insecticide residues in the liver of (analysed groups of) rats occurred between the 3rd hour and the 2nd day after exposure. Dimethoate in both applied doses significantly reduced AChE activity in blood. After application of the higher dose, the inhibition of AChE was more pronounced, and the return of its activity to physiological values lasted considerably longer. Co-administration of pyrantel embonate and dimethoate, slightly influenced changes of the parameters analysed, which have been dependent not only on a dose and manner of pyrantel application but also on time which lapsed from exposure. PMID:16573274

  2. Quaternary glaciation of Mount Everest

    Microsoft Academic Search

    Lewis A. Owen; Ruth Robinson; Douglas I. Benn; Robert C. Finkel; Nicole K. Davis; Chaolu Yi; Jaakko Putkonen; Dewen Li; Andrew S. Murray

    2009-01-01

    The Quaternary glacial history of the Rongbuk valley on the northern slopes of Mount Everest is examined using field mapping, geomorphic and sedimentological methods, and optically stimulated luminescence (OSL) and 10Be terrestrial cosmogenic nuclide (TCN) dating. Six major sets of moraines are present representing significant glacier advances or still-stands. These date to >330ka (Tingri moraine), >41ka (Dzakar moraine), 24–27ka (Jilong

  3. Quaternary ecology: A paleoecological perspective

    SciTech Connect

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

    1991-01-01

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

  4. 40 CFR 721.10511 - Quaternary ammonium salts (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...2014-07-01 false Quaternary ammonium salts (generic). 721.10511 Section 721...Substances § 721.10511 Quaternary ammonium salts (generic). (a) Chemical substance...identified generically as quaternary ammonium salts (PMNs P-07-320,...

  5. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...2013-04-01 false Quaternary ammonium chloride combination...Preservatives § 172.165 Quaternary ammonium chloride combination... The food additive, quaternary ammonium chloride combination...7.0-8.0; total amines, maximum 1 percent...

  6. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...2014-04-01 false Quaternary ammonium chloride combination...Preservatives § 172.165 Quaternary ammonium chloride combination... The food additive, quaternary ammonium chloride combination...7.0-8.0; total amines, maximum 1 percent...

  7. 40 CFR 721.10569 - Tricyclic quaternary amine salt (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...2013-07-01 false Tricyclic quaternary amine salt (generic). 721.10569... § 721.10569 Tricyclic quaternary amine salt (generic). (a...identified generically as tricyclic quaternary amine salt (PMN...

  8. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...2012-04-01 false Quaternary ammonium chloride combination...Preservatives § 172.165 Quaternary ammonium chloride combination... The food additive, quaternary ammonium chloride combination...7.0-8.0; total amines, maximum 1 percent...

  9. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...2009-04-01 true Quaternary ammonium chloride combination...Preservatives § 172.165 Quaternary ammonium chloride combination... The food additive, quaternary ammonium chloride combination...7.0-8.0; total amines, maximum 1 percent...

  10. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...2011-04-01 false Quaternary ammonium chloride combination...Preservatives § 172.165 Quaternary ammonium chloride combination... The food additive, quaternary ammonium chloride combination...7.0-8.0; total amines, maximum 1 percent...

  11. 40 CFR 721.10569 - Tricyclic quaternary amine salt (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...2014-07-01 false Tricyclic quaternary amine salt (generic). 721.10569... § 721.10569 Tricyclic quaternary amine salt (generic). (a...identified generically as tricyclic quaternary amine salt (PMN...

  12. Surface interaction of quaternary amines with hair

    Microsoft Academic Search

    B. C. Beard; J. Hare

    2002-01-01

    Surface analysis by X-ray photoelectron spectroscopy (XPS) has shown specific 1?1 (ionic) interaction between cationic alkyl\\u000a quaternary surfactant molecules and the anionic sulfonate groups present on the hair surface. The primary driving force for\\u000a the adsorption of alkyl quaternary amine molecules to the surface of the hair from aqueous solution is the ionic interaction\\u000a between quaternary groups and the surface

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

    PubMed

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

    2015-06-15

    Resistin is a pro-inflammatory cytokine involved in the pathogenesis of autoimmune diseases. To investigate serum resistin levels in patients with myasthenia gravis (MG) and determine if there are associations between resistin levels and disease severity, we measured serum resistin levels in 102 patients with anti-acetylcholine receptor antibody-positive MG (AChR-MG). We further analyzed associations between serum resistin levels and clinical variables in patients with MG. Our findings demonstrate that serum resistin levels are elevated in patients with AChR-generalized MG and AChR-MG with thymoma and are correlated with disease severity. Resistin has potential as a useful serum biomarker for inflammation in AChR-MG. PMID:26004149

  14. Pro-apoptotic protein-protein interactions of the extended N-AChE terminus.

    PubMed

    Toiber, Debra; Greenberg, David S; Soreq, Hermona

    2009-11-01

    The N-terminally extended "synaptic" acetylcholinesterase variant N-AChE-S operates to promote apoptosis; however, the protein partners involved in this function remain unknown. Here, we report that when microinjected to fertilized mouse oocytes, N-AChE-S caused embryonic death as early as the zygotic stage. To identify the putative protein partners involved, we first tried yeast two hybrid screening, but this approach failed, probably because of the N-AChE-S-induced lethality. In contrast, sequence analysis and a corresponding peptide array revealed possible partners, which were validated by co-immunoprecipitation. These include the kinases GSK3, Aurora and GAK, the membrane integrin receptors, and the death receptor FAS. Each of these could potentially modulate N-AChE-S-induced apoptosis with possible therapeutic value for the treatment of Alzheimer's disease. PMID:19533292

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

    E-print Network

    Review nAChR agonist-induced cognition enhancement: Integration of cognitive and neuronal for cognition enhancers . . . . . . . . . . . . . . . . . . . . . 661 5. Circuitry model for signal detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664 1. Introduction Drug-induced improvement of the cognitive capacities of patients suffering from

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

    Microsoft Academic Search

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

    2004-01-01

    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

  17. Lack of Ach1 CoA-Transferase Triggers Apoptosis and Decreases Chronological Lifespan in Yeast.

    PubMed

    Orlandi, Ivan; Casatta, Nadia; Vai, Marina

    2012-01-01

    ACH1 encodes a mitochondrial enzyme of Saccharomyces cerevisiae endowed with CoA-transferase activity. It catalyzes the CoASH transfer from succinyl-CoA to acetate generating acetyl-CoA. It is known that ACH1 inactivation results in growth defects on media containing acetate as a sole carbon and energy source which are particularly severe at low pH. Here, we show that chronological aging ach1? cells which accumulate a high amount of extracellular acetic acid display a reduced chronological lifespan. The faster drop of cell survival is completely abrogated by alleviating the acid stress either by a calorie restricted regimen that prevents acetic acid production or by transferring chronologically aging mutant cells to water. Moreover, the short-lived phenotype of ach1? cells is accompanied by reactive oxygen species accumulation, severe mitochondrial damage, and an early insurgence of apoptosis. A similar pattern of endogenous severe oxidative stress is observed when ach1? cells are cultured using acetic acid as a carbon source under acidic conditions. On the whole, our data provide further evidence of the role of acetic acid as cell-extrinsic mediator of cell death during chronological aging and highlight a primary role of Ach1 enzymatic activity in acetic acid detoxification which is important for mitochondrial functionality. PMID:22754872

  18. Opening of Aryl-Substituted Epoxides to form Quaternary Stereogenic Centers: Synthesis of (?)-Mesembrine

    PubMed Central

    Taber, Douglass F.; He, Yigang

    2011-01-01

    Cycloalkanones are easily converted into aryl-substituted cyclic alkenes by the addition of an aryl Grignard reagent followed by dehydration. These alkenes are good substrates for asymmetric epoxidation. We have found that the addition of allylic and benzylic Grignard reagents can occur preferentially at the benzylic position of the derived epoxides, to give the quaternary stereogenic center. This approach led to a short synthesis of the nanomolar serotonin re-uptake inhibitor (?)-mesembrine. PMID:16149803

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

    PubMed

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

    2014-01-01

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

  20. Natural indole butyrylcholinesterase inhibitors from Nauclea officinalis.

    PubMed

    Liew, Sook Yee; Khaw, Kooi Yeong; Murugaiyah, Vikneswaran; Looi, Chung Yeng; Wong, Yi Li; Mustafa, Mohd Rais; Litaudon, Marc; Awang, Khalijah

    2015-01-15

    Nine monoterpenoid indole alkaloids; naucletine (1), angustidine (2), nauclefine (3), angustine (4), naucline (5), angustoline (6), harmane (7), 3,14-dihydroangustoline (8), strictosamide (9) and one quinoline alkaloid glycoside; pumiloside (10) from Nauclea officinalis were tested for cholinesterase inhibitory activity. All the alkaloids except for pumiloside (10) showed strong to weak BChE inhibitory effect with IC50 values ranging between 1.02-168.55 ?M. Angustidine (2), nauclefine (3), angustine (4), angustoline (6) and harmane (7) showed higher BChE inhibiting potency compared to galanthamine. Angustidine (2) was the most potent inhibitor towards both AChE and BChE. Molecular docking (MD) studies showed that angustidine (2) docked deep into the bottom gorge of hBChE and formed hydrogen bonding with Ser 198 and His 438. Kinetic study of angustidine (2) on BChE suggested a mixed inhibition mode with an inhibition constant (Ki) of 6.12 ?M. PMID:25636869

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

    NASA Astrophysics Data System (ADS)

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

    2000-05-01

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

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

    PubMed

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

    2015-01-01

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

  3. Congo red modulates ACh-induced Ca2+ oscillations in single pancreatic acinar cells of mice

    PubMed Central

    Huang, Ze-bing; Wang, Hai-yan; Sun, Na-na; Wang, Jing-ke; Zhao, Meng-qin; Shen, Jian-xin; Gao, Ming; Hammer, Ronald P; Fan, Xue-gong; Wu, Jie

    2014-01-01

    Aim: Congo red, a secondary diazo dye, is usually used as an indicator for the presence of amyloid fibrils. Recent studies show that congo red exerts neuroprotective effects in a variety of models of neurodegenerative diseases. However, its pharmacological profile remains unknown. In this study, we investigated the effects of congo red on ACh-induced Ca2+ oscillations in mouse pancreatic acinar cells in vitro. Methods: Acutely dissociated pancreatic acinar cells of mice were prepared. A U-tube drug application system was used to deliver drugs into the bath. Intracellular Ca2+ oscillations were monitored by whole-cell recording of Ca2+-activated Cl? currents and by using confocal Ca2+ imaging. For intracellular drug application, the drug was added in pipette solution and diffused into cell after the whole-cell configuration was established. Results: Bath application of ACh (10 nmol/L) induced typical Ca2+ oscillations in dissociated pancreatic acinar cells. Addition of congo red (1, 10, 100 ?mol/L) dose-dependently enhanced Ach-induced Ca2+ oscillations, but congo red alone did not induce any detectable response. Furthermore, this enhancement depended on the concentrations of ACh: congo red markedly enhanced the Ca2+ oscillations induced by ACh (10–30 nmol/L), but did not alter the Ca2+ oscillations induced by ACh (100–10000 nmol/L). Congo red also enhanced the Ca2+ oscillations induced by bath application of IP3 (30 ?mol/L). Intracellular application of congo red failed to alter ACh-induced Ca2+ oscillations. Conclusion: Congo red significantly modulates intracellular Ca2+ signaling in pancreatic acinar cells, and this pharmacological effect should be fully considered when developing congo red as a novel therapeutic drug. PMID:25345744

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

    PubMed

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

    2014-08-12

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

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

    PubMed Central

    Kuryatov, Alexander; Mukherjee, Jayanta; Lindstrom, Jon

    2013-01-01

    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. PMID:23638015

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

    PubMed Central

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

    2011-01-01

    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. PMID:22114680

  7. Modulation of ACh release from airway cholinergic nerves in horses with recurrent airway obstruction.

    PubMed

    Zhang, X Y; Robinson, N E; Zhu, F X

    1999-05-01

    To evaluate the functional status of neuronal alpha2-adrenoceptors (ARs) and beta2-ARs on ACh release in horses with recurrent airway obstruction (RAO), we examined the effects of the physiological agonists epinephrine (Epi) and norepinephrine (NE) and the beta2-agonists RR- and RR/SS-formoterol on ACh release from airway cholinergic nerves of horses with RAO. Because SS-formoterol, a distomer of the beta2-agonist, increases ACh release from airways of control horses only after the autoinhibitory muscarinic receptors are blocked by atropine, we also tested the hypothesis that if there is an M2-receptor dysfunction in equine RAO, SS-formoterol should increase ACh release even in the absence of atropine. ACh release was evoked by electrical field stimulation and measured by HPLC. Epi and NE caused less inhibition of ACh release in horses with RAO than in control horses. At the catecholamine concentration achieved during exercise (10(-7) M), the inhibition induced by Epi and NE was 10.8 +/- 13.2 and 3.4 +/- 6.8%, respectively, in equine RAO versus 41.0 +/- 6.4 and 27.1 +/- 5.6%, respectively, in control horses. RR- and RR/SS-formoterol (10(-8) to 10(-5) M) increased ACh release to a similar magnitude as that in control horses. These results indicate that neuronal beta2-ARs are functioning; however, the alpha2-ARs are dysfunctional in the airways of horses with RAO in response to circulating catecholamines. SS-formoterol (10(-8) to 10(-5) M) facilitated ACh release in horses with RAO even in the absence of atropine. Addition of atropine did not cause significantly more augmentation of ACh release over the effect of SS-formoterol alone. The magnitude of augmentation in horses with RAO in the absence of atropine was similar to that in control horses in the presence of atropine. The latter observations could be explained by neuronal muscarinic-autoreceptor dysfunction in equine RAO. PMID:10330033

  8. Novel approaches to study the involvement of ?7-nAChR in human diseases.

    PubMed

    Palma, Eleonora; Conti, Luca; Roseti, Cristina; Limatola, Cristina

    2012-05-01

    The alpha7 nicotinic acetylcholine receptor (?7 nAChR) is widely distributed in the human brain and has been implicated in a number of human central nervous system (CNS) diseases, including Alzheimer's and Parkinson's disease, schizophrenia and autism. Recently, new roles for ?7 nAChRs in lung cancer and heart disease have been elucidated. Despite the importance of this receptor in human pathology, many technical difficulties are still encountered when investigating the role of ?7 nAChRs. Electrophysiological analysis of the receptor upon heterologous expression or in human tissues was limited by the fast desensitization of ?7-mediated nicotinic currents and by tissue availability. In addition, animal models for the human diseases related to ?7 nAChRs have long been unavailable. The recent development of new imaging and analysis approaches such as PET and receptor microtransplantation have rendered the study of ?7 nAChRs increasingly feasible, paving new roads to the design of therapeutic drugs. This review summarizes the current knowledge and recent findings obtained by these novel approaches. PMID:22300023

  9. Structural and Functional Characterization of a Novel ?-Conotoxin Mr1.7 from Conus marmoreus Targeting Neuronal nAChR ?3?2, ?9?10 and ?6/?3?2?3 Subtypes

    PubMed Central

    Wang, Shuo; Zhao, Cong; Liu, Zhuguo; Wang, Xuesong; Liu, Na; Du, Weihong; Dai, Qiuyun

    2015-01-01

    In the present study, we synthesized and, structurally and functionally characterized a novel ?4/7-conotoxin Mr1.7 (PECCTHPACHVSHPELC-NH2), which was previously identified by cDNA libraries from Conus marmoreus in our lab. The NMR solution structure showed that Mr1.7 contained a 310-helix from residues Pro7 to His10 and a type I ?-turn from residues Pro14 to Cys17. Electrophysiological results showed that Mr1.7 selectively inhibited the ?3?2, ?9?10 and ?6/?3?2?3 neuronal nicotinic acetylcholine receptors (nAChRs) with an IC50 of 53.1 nM, 185.7 nM and 284.2 nM, respectively, but showed no inhibitory activity on other nAChR subtypes. Further structure-activity studies of Mr1.7 demonstrated that the PE residues at the N-terminal sequence of Mr1.7 were important for modulating its selectivity, and the replacement of Glu2 by Ala resulted in a significant increase in potency and selectivity to the ?3?2 nAChR. Furthermore, the substitution of Ser12 with Asn in the loop2 significantly increased the binding of Mr1.7 to ?3?2, ?3?4, ?2?4 and ?7 nAChR subtypes. Taken together, this work expanded our knowledge of selectivity and provided a new way to improve the potency and selectivity of inhibitors for nAChR subtypes. PMID:26023835

  10. A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia.

    PubMed

    Agrawal, Rahul; Tyagi, Ethika; Shukla, Rakesh; Nath, Chandishwar

    2009-03-01

    In the present study, role of brain insulin receptors (IRs) in memory functions and its correlation with acetylcholinesterase (AChE) activity and oxidative stress in different brain regions were investigated in intracerebroventricular (ICV) streptozotocin (STZ) induced dementia model. Rats were treated with STZ (3 mg/kg, ICV) on day 1 and 3. Donepezil (5 mg/kg po) and melatonin (20 mg/kg ip) were administered in pre- and post-treatment schedules. Morris water maze test was done on day 14 and animals were sacrificed on day 21 from 1st STZ injection. Memory deficit was found in STZ group as indicated by no significant decrease in latency time antagonized by donepezil and melatonin. IR protein level was found significantly increased in trained group as compared to control, whereas STZ decreased IR level significantly as compared to trained rats in hippocampus which indicates that IR is associated with memory functions. STZ induced decrease in IR was reversed by melatonin but not by donepezil. Melatonin per se did not show any significant change in IR level as compared to control. AChE activity (DS and SS fraction) was found to be increased in hippocampus in STZ group as compared to trained which was inhibited by donepezil and melatonin. Increase in MDA level and decrease in GSH level were obtained in STZ group indicating oxidative stress, which was attenuated by donepezil and melatonin. Effectiveness of antioxidant, melatonin but not of anti-cholinesterase, donepezil against STZ induced changes in IR indicates that IR is more affected with oxidative stress than cholinergic changes. PMID:19705549

  11. Fiber-optic biosensor for the detection of organophosphorus compounds using AChE-immobilized viologen LB films

    Microsoft Academic Search

    Jeong-Woo Choi; Junhong Min; Jung-Won Jung; Hee-Woo Rhee; Won Hong Lee

    1998-01-01

    Acetylcholinesterase (AChE)-immobilized viologen Langmuir–Blodgett (LB) film was fabricated for the development of a fiber-optic biosensor to detect organophosphorus compounds in contaminated water. AChE was adsorbed onto viologen monolayer by electrostatic force. The optimal amount of the dissolved enzyme for the LB film formation was determined based on the enzyme adsorption isotherm and relative enzyme amount adsorbed. The surface characteristics of

  12. Insect nicotinic acetylcholine receptors (nAChRs): Important amino acid residues contributing to neonicotinoid insecticides selectivity and resistance

    Microsoft Academic Search

    Zewen Liu; Xiangmei Yao; Yixi Zhang

    2008-01-01

    Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels which mediate fast cholinergic synaptic transmission in insect and vertebrate nervous systems. The great abundance of nAChRs within the insect central nervous system has led to the development of insecticides targeting these receptors, such as neonicotinoid insecticides. Neonicotinoid insecticides act selectively on insect nAChRs, accounting at least in part for the selective

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

    PubMed

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

    2013-09-01

    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

  14. Proteasome inhibitors.

    PubMed

    Teicher, Beverly A; Tomaszewski, Joseph E

    2015-07-01

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

  15. Calcium/Calmodulin Kinase II-dependent AChR Cycling at the Mammalian Neuromuscular Junction in Vivo

    PubMed Central

    Martinez-Pena y Valenzuela, Isabel; Mouslim, Chakib; Akaaboune, Mohammed

    2010-01-01

    At the mammalian skeletal neuromuscular junction, cycling of nicotinic acetylcholine receptors (nAChRs) is critical for the maintenance of a high postsynaptic receptor density. However, the mechanisms that regulate nAChRs recycling in living animals remain unknown. Using in vivo time-lapse imaging, fluorescence recovery after photobleaching, and biochemical pull down assays, we demonstrated that recycling of internalized nAChRs into fully functional and denervated synapses was promoted by both direct muscle stimulation and pharmacologically induced intracellular calcium elevations. Most of internalized nAChRs are recycled directly into synaptic sites. Chelating of intracellular calcium below resting level drastically decreased cycling of nAChRs. Furthermore we found that calcium-dependent AChR recycling is mediated by Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of CaMKII selectively blocked recycling and caused intracellular accumulation of internalized nAChRs, whereas internalization of surface receptors remained unaffected. Electroporation of CaMKII-GFP isoforms into the sternomastoid muscle showed that muscle-specific CaMKII?m isoform is highly expressed at NMJ and precisely co-localized with nAChRs at crests of synaptic folds while the CaMKII? and ? isoforms are poorly expressed in synaptic sites. These results indicate that Ca2+ along with CaMKII activity are critical for receptor recycling and may provide a mechanism by which the postsynaptic AChR density is maintained at the NMJ in vivo. PMID:20844140

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

    PubMed Central

    2014-01-01

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

  17. The 'aromatic patch' of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors.

    PubMed Central

    Ariel, N; Ordentlich, A; Barak, D; Bino, T; Velan, B; Shafferman, A

    1998-01-01

    The role of the functional architecture of the human acetylcholinesterase (HuAChE) active centre in accommodating the non-covalent inhibitors tacrine and huperzine A, or the carbamates pyridostigmine and physostigmine, was analysed using 16 mutants of residues lining the active-centre gorge. Despite the structural diversity of the ligands, certain common properties of the complexes could be observed: (a) replacement of aromatic residues Tyr133, Tyr337 and especially Trp86, resulted in pronounced changes in stability of all the complexes examined; (b) effects due to replacements of the five other aromatic residues along the active-centre gorge, such as the acyl pocket (Phe295, Phe297) or at the peripheral anionic site (Tyr124, Trp286, Tyr341) were relatively small; (c) effects due to substitution of the carboxylic residues in the gorge (Glu202, Glu450) were moderate. These results and molecular modelling indicate that the aromatic side chains of residues Trp86, Tyr133 and Tyr337 form together a continuous 'aromatic patch' lining the wall of the active-centre gorge, allowing for the accommodation of the different ligands via multiple modes of interaction. Studies with HuAChE mutants carrying replacements at positions 86, 133 and 337 indicate that the orientations of huperzine A and tacrine in the HuAChE complexes in solution are significantly different from those observed in X-ray structures of the corresponding complexes with Torpedo californica AChE (TcAChE). These discrepancies may be explained in terms of structural differences between the complexes of HuAChE and TcAChE or, more likely, by the enhanced flexibility of the AChE active-centre gorge in solution as compared with the crystalline state. PMID:9742217

  18. Antibacterial and Hemolytic Activities of Quaternary Pyridinium

    E-print Network

    Antibacterial and Hemolytic Activities of Quaternary Pyridinium Functionalized Polynorbornenesa] They found that polymers with higher cationic functionality had stronger antibacterial activity. Sepa- rately, it was shown that methacrylate based polymers with pendant pyridinium moieties exhibited antibacterial activity

  19. Analysis of residual corrosion inhibitors by fluorescence and ultraviolet spectrophotometry

    SciTech Connect

    Son, A.J. [Champion Technologies, Inc., Fresno, TX (United States); Chakravarty, J. [Champion Technologies, Ltd., Calgary, Alberta (Canada)

    1996-11-01

    The paper describes the development of a fully automated instrumental procedure for testing residual corrosion inhibitors in production waters in the field. Initial investigations were conducted in the laboratory to evaluate the suitability of ultraviolet and fluorescence spectrophotometric techniques to different types of corrosion inhibitors. Parameters for comparison included selectivity, sensitivity, speed, accuracy and precision of the methods under flowing conditions as in high performance liquid chromatography and static conditions as encountered in stand alone instruments. The laboratory evaluations showed that fluorescence is more suitable for the field application because errors from high salinity, contamination and matrix effect are minimized in fluorescence analysis. Although the development work included most of the nitrogen-containing corrosion inhibitors (quaternary amines, imidazolines, amides, etc.), the procedure for quaternary amines is used as the example and presented in detail.

  20. Functional expression and axonal transport of ?7 nAChRs by peptidergic nociceptors of rat dorsal root ganglion.

    PubMed

    Shelukhina, Irina; Paddenberg, Renate; Kummer, Wolfgang; Tsetlin, Victor

    2015-07-01

    In recent pain studies on animal models, ?7 nicotinic acetylcholine receptor (nAChR) agonists demonstrated analgesic, anti-hyperalgesic and anti-inflammatory effects, apparently acting through some peripheral receptors. Assuming possible involvement of ?7 nAChRs on nociceptive sensory neurons, we investigated the morphological and neurochemical features of the ?7 nAChR-expressing subpopulation of dorsal root ganglion (DRG) neurons and their ability to transport ?7 nAChR axonally. In addition, ?7 receptor activity and its putative role in pain signal neurotransmitter release were studied. Medium-sized ?7 nAChR-expressing neurons prevailed, although the range covered all cell sizes. These cells accounted for one-fifth of total medium and large DRG neurons and <5 % of small ones. 83.2 % of ?7 nAChR-expressing DRG neurons were peptidergic nociceptors (CGRP-immunopositive), one half of which had non-myelinated C-fibers and the other half had myelinated A?- and likely A?/?-fibers, whereas 15.2 % were non-peptidergic C-fiber nociceptors binding isolectin B4. All non-peptidergic and a third of peptidergic ?7 nAChR-bearing nociceptors expressed TRPV1, a capsaicin-sensitive noxious stimulus transducer. Nerve crush experiments demonstrated that CGRPergic DRG nociceptors axonally transported ?7 nAChRs both to the spinal cord and periphery. ?7 nAChRs in DRG neurons were functional as their specific agonist PNU282987 evoked calcium rise enhanced by ?7-selective positive allosteric modulator PNU120596. However, ?7 nAChRs do not modulate neurotransmitter CGRP and glutamate release from DRG neurons since nicotinic ligands affected neither their basal nor provoked levels, showing the necessity of further studies to elucidate the true role of ?7 nAChRs in those neurons. PMID:24706047

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

    PubMed Central

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

    2011-01-01

    Colonic chloride secretion is induced by chemical stimuli via the enteric nervous reflex. We have previously demonstrated that propionate stimulates chloride secretion via sensory and cholinergic systems of the mucosa in rat distal colon. In this study, we demonstrate non-neuronal release of ACh in the secretory response to propionate using an Ussing chamber. Mucosa preparations from the colon, not including the myenteric and submucosal plexuses, were used. Luminal addition of propionate and serosal addition of ACh caused biphasic changes in short-circuit current (Isc). TTX (1 ?m) had no effects, while atropine (10 ?m) significantly inhibited the Isc response to propionate and abolished that to ACh. In response to luminal propionate stimulation, ACh was released into the serosal fluid. A linear relationship was observed between the maximal increase in Isc and the amounts of ACh released 5 min after propionate stimulation. This ACh release induced by propionate was not affected by atropine and bumetanide, although both drugs significantly reduced the Isc responses to propionate. Luminal addition of 3-chloropropionate, an inactive analogue of propionate, abolished both ACh release and Isc response produced by propionate. RT-PCR analysis indicated that isolated crypt cells from the distal colon expressed an enzyme of ACh synthesis (ChAT) and transporters of organic cation (OCTs), but not neuronal CHT1 and VAChT. The isolated crypt cells contained comparable amounts of ACh to the residual muscle tissues including nerve plexuses. In conclusion, the non-neuronal release of ACh from colonocytes coupled with propionate stimulation plays a key role in chloride secretion, via the paracrine action of ACh on muscarinic receptors of colonocytes. PMID:21135046

  2. Effects of irreversible and reversible cholinesterase inhibitors on single acetylcholine-activated channels

    Microsoft Academic Search

    Robert Zorec; Maria Scuka; Marjan Kordaš

    1992-01-01

    The use of cholinesterase (CHE) inhibitors provided valuable information about the mechanism(s) of neuromuscular transmission, but questions on side effects at the level of AChactivated channels were raised. Patch-clamp recording was used to study the effects of prostigmine (PST) and methanesulfonyl fluoride (MSF), a reversible and an irreversible cholinesterase inhibitor, respectively, on ACh-activated channels. We found that these drugs diminish

  3. Investigation into the efficacy of the acetylcholinesterase inhibitor, donepezil, and novel procognitive agents to induce gamma oscillations in rat hippocampal slices

    Microsoft Academic Search

    J. P. Spencer; L. J. Middleton; C. H. Davies

    2010-01-01

    One of the major neuropathological hallmarks in Alzheimer’s disease (AD) is the loss of cholinergic neurones of the nucleus basalis of Meynert (NbM). This consistent finding gave rise to the ‘cholinergic’ hypothesis of AD and lead to the subsequent development of acetylcholinesterase (AChE) inhibitors; the first class of drug to be approved for the treatment of AD. However, several studies

  4. Maturation of the Acetylcholine Receptor in Skeletal Muscle: Regulation of the AChR ?-to-? Switch

    Microsoft Academic Search

    Andrea C. Missias; Gerald C. Chu; Barbara J. Klocke; Joshua R. Sanes; John P. Merlie

    1996-01-01

    During the development of the mammalian neuromuscular junction, acetylcholine receptors (AChRs) become localized to the postsynaptic muscle membrane. As this process nears completion, the fetal form of the receptor, containing a ? subunit (composition ?2???) is gradually replaced by an ? subunit-containing adult form (?2???). To understand how this transition is controlled, we compared the expression and regulation of the

  5. ach year across the US, mesoscale weather events--flash floods, tornadoes, hail,

    E-print Network

    Plale, Beth

    E ach year across the US, mesoscale weather events--flash floods, tornadoes, hail, strong winds of mesoscale weather research; its disparate, high-volume data sets and streams; or the tremendous urgent need for a comprehensive national cyberinfrastructure in mesoscale meteorology--particularly one

  6. Amplification and deletion of the ACHE and BCHE cholinesterase genes in sporadic breast cancer

    Microsoft Academic Search

    Caroline C. Bernardi; Enilze de S. F. Ribeiro; Iglenir J. Cavalli; Eleidi A. Chautard-Freire-Maia; Ricardo L. R. Souza

    2010-01-01

    Increasing evidence supports the involvement of acetylcholinesterase and butyrylcholinesterase in cell proliferation control and differentiation, reinforcing the hypothesis that these enzymes might have an influence in tumorigenesis. It has already been shown that the cholinesterase genes are structurally altered or aberrantly expressed in a variety of tumor types. In this study, amplifications and deletions in the ACHE and BCHE genes

  7. Breakdown of the Coulomb friction law in TiC /a-C:H nanocomposite coatings

    NASA Astrophysics Data System (ADS)

    Pei, Y. T.; Huizenga, P.; Galvan, D.; De Hosson, J. Th. M.

    2006-12-01

    Advanced TiC /a-C:H nanocomposite coatings have been produced via reactive deposition in a closed-field unbalanced magnetron sputtering system (Hauzer HTC-1000 or HTC 1200). In this paper, we report on the tribological behavior of TiC /a-C:H nanocomposite coatings in which ultralow friction is tailored with superior wear resistance, two properties often difficult to achieve simultaneously. Tribotests have been performed at room temperature with a ball-on-disk configuration. In situ monitoring of the wear depth of the coated disk together with the wear height of the ball counterpart at nanometer scale reveals that the self-lubricating effects are induced by the formation of transfer films on the surface of the ball counterpart. A remarkable finding is a breakdown of the Coulomb friction law in the TiC /a-C:H nanocomposite coatings. In addition, the coefficient of friction of TiC /a-C:H nanocomposite coatings decreases with decreasing relative humidity. A superior wear resistance of the coated disk at a level of 10-17m3/Nm (per lap) has been achieved under the condition of superlow friction and high toughness, both of which require fine TiC nanoparticles (e.g., 2nm) and a wide matrix separation that must be comparable to the dimensions of the nanoparticles.

  8. Application of Temperature Fuzzy Control System in RF Treatment for Nerve Ache

    Microsoft Academic Search

    Chao Meng; WanRong Sun; Yao Chen; Yang Li; LiPing Liu

    2009-01-01

    As a new pain treatment method, radio frequency (RF) ablation received rapid application and development in the treatment of pain disease in the medicine field. In this paper, we introduce the structure of hardware components and major program modules of the RF treatment system for nerve ache. In the treatment, since the RF trocar is in the body and the

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

    PubMed Central

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

    2014-01-01

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

  10. Analysis of rare variations reveals roles of amino acid residues in the N-terminal extracellular domain of nicotinic acetylcholine receptor (nAChR) alpha6 subunit in the functional expression of human alpha6*-nAChRs

    PubMed Central

    2014-01-01

    Background Functional heterologous expression of naturally-expressed and apparently functional mammalian ?6*-nicotinic acetylcholine receptors (nAChRs; where ‘*’ indicates presence of additional subunits) has been difficult. Here we wanted to investigate the role of N-terminal domain (NTD) residues of human (h) nAChR ?6 subunit in the functional expression of h?6*-nAChRs. To this end, instead of adopting random mutagenesis as a tool, we used 15 NTD rare variations (i.e., Ser43Pro, Asn46Lys, Asp57Asn, Arg87Cys, Asp92Glu, Arg96His, Glu101Lys, Ala112Val, Ser156Arg, Asn171Lys, Ala184Asp, Asp199Tyr, Asn203Thr, Ile226Thr and Ser233Cys) in nAChR h?6 subunit to probe for their effect on the functional expression of h?6*-nAChRs. Results N-terminal ?-helix (Asp57); complementary face/inner ?-fold (Arg87 or Asp92) and principal face/outer ?-fold (Ser156 or Asn171) residues in the h?6 subunit are crucial for functional expression of the h?6*-nAChRs as variations in these residues reduce or abrogate the function of h?6h?2*-, h?6h?4- and h?6h?4h?3-nAChRs. While variations at residues Ser43 or Asn46 (both in N-terminal ?-helix) in h?6 subunit reduce h?6h?2*-nAChRs function those at residues Arg96 (?2-?3 loop), Asp199 (loop F) or Ser233 (?10-strand) increase h?6h?2*-nAChR function. Similarly substitution of NTD ?-helix (Asn46), loop F (Asp199), loop A (Ala112), loop B (Ala184), or loop C (Ile226) residues in h?6 subunit increase the function of h?6h?4-nAChRs. All other variations in h?6 subunit do not affect the function of h?6h?2*- and h?6h?4*-nAChRs. Incorporation of nAChR h?3 subunits always increase the function of wild-type or variant h?6h?4-nAChRs except for those of h?6(D57N, S156R, R87C or N171K)h?4-nAChRs. It appears Asp57Lys, Ser156Arg or Asn171Lys variations in h?6 subunit drive the h?6h?4h?3-nAChRs into a nonfunctional state as at spontaneously open h?6(D57N, S156R or N171K)h?4h?3V9’S-nAChRs (V9’S; transmembrane II 9’ valine-to-serine mutation) agonists act as antagonists. Agonist sensitivity of h?6h?4- and/or h?6h?4h?3-nAChRs is nominally increased due to Arg96His, Ala184Asp, Asp199Tyr or Ser233Cys variation in h?6 subunit. Conclusions Hence investigating functional consequences of natural variations in nAChR h?6 subunit we have discovered additional bases for cell surface functional expression of various subtypes of h?6*-nAChRs. Variations (Asp57Asn, Arg87Cys, Asp92Glu, Ser156Arg or Asn171Lys) in h?6 subunit that compromise h?6*-nAChR function are expected to contribute to individual differences in responses to smoked nicotine. PMID:24886653

  11. Corrosion inhibitor

    SciTech Connect

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

    1989-10-31

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

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

    NASA Astrophysics Data System (ADS)

    Stewart, John R.; Cooper, Alan

    2008-12-01

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

  13. Quaternary geologic map of Minnesota

    NASA Technical Reports Server (NTRS)

    Goebel, J. E.

    1977-01-01

    The Quaternary Geologic Map of Minnesota is a compilation based both on the unique characteristics of satellite imagery and on the results of previous field investigations, both published and unpublished. The use of satellite imagery has made possible the timely and economical construction of this map. LANDSAT imagery interpretation proved more useful than expected. Most of the geologic units could be identified by extrapolating from specific sites where the geology had been investigated into areas where little was known. The excellent geographic registry coupled with the multi-spectral record of these images served to identify places where the geologic materials responded to their ecological environment and where the ecology responded to the geologic materials. Units were well located on the map at the scale selected for the study. Contacts between till units could be placed with reasonable accuracy. The reference points that were used to project delineations between units (rivers, lakes, hills, roads and other features), which had not been accurately located on early maps, could be accurately located with the help of the imagery. The tonal and color contrasts, the patterns reflecting geologic change and the resolution of the images permitted focusing attention on features which could be represented at the final scale of the map without distraction by other interesting but site-specific details.

  14. Quaternary glaciation of Mount Everest

    NASA Astrophysics Data System (ADS)

    Owen, Lewis A.; Robinson, Ruth; Benn, Douglas I.; Finkel, Robert C.; Davis, Nicole K.; Yi, Chaolu; Putkonen, Jaakko; Li, Dewen; Murray, Andrew S.

    2009-07-01

    The Quaternary glacial history of the Rongbuk valley on the northern slopes of Mount Everest is examined using field mapping, geomorphic and sedimentological methods, and optically stimulated luminescence (OSL) and 10Be terrestrial cosmogenic nuclide (TCN) dating. Six major sets of moraines are present representing significant glacier advances or still-stands. These date to >330 ka (Tingri moraine), >41 ka (Dzakar moraine), 24-27 ka (Jilong moraine), 14-17 ka (Rongbuk moraine), 8-2 ka (Samdupo moraines) and ˜1.6 ka (Xarlungnama moraine), and each is assigned to a distinct glacial stage named after the moraine. The Samdupo glacial stage is subdivided into Samdupo I (6.8-7.7 ka) and Samdupo II (˜2.4 ka). Comparison with OSL and TCN defined ages on moraines on the southern slopes of Mount Everest in the Khumbu Himal show that glaciations across the Everest massif were broadly synchronous. However, unlike the Khumbu Himal, no early Holocene glacier advance is recognized in the Rongbuk valley. This suggests that the Khumbu Himal may have received increased monsoon precipitation in the early Holocene to help increase positive glacier mass balances, while the Rongbuk valley was too sheltered to receive monsoon moisture during this time and glaciers could not advance. Comparison of equilibrium-line altitude depressions for glacial stages across Mount Everest reveals asymmetric patterns of glacier retreat that likely reflects greater glacier sensitivity to climate change on the northern slopes, possibly due to precipitation starvation.

  15. Bacterial adhesion inhibition of the quaternary ammonium functionalized silica nanoparticles

    Microsoft Academic Search

    Jooyoung Song; Hyeyoung Kong; Jyongsik Jang

    2011-01-01

    Quaternary ammonium compounds have been considered as excellent antibacterial agents due to their effective biocidal activity, long term durability and environmentally friendly performance. In this work, 3-(trimethoxysilyl)-propyldimethyloctadecylammonium chloride as a quaternary ammonium silane was applied for the surface modification of silica nanoparticles. The quaternary ammonium silane provided silica surface with hydrophobicity and antibacterial properties. In addition, the glass surface which

  16. Synthesis of Surface-Active Quaternary Amino Polyfluorosiloxanes

    E-print Network

    Chaudhury, Manoj K.

    , on further reaction with various amines followed by quaternization, gave quaternary amino polyfluorosiloxanes prepared by quaternization of fluorocarbon amines using alkyl halide. Quaternary fluorocarbon7 (CF3)2CF(CF2Synthesis of Surface-Active Quaternary Amino Polyfluorosiloxanes ASHISH VAIDYA, MANOJ CHAUDHURY

  17. Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) ?2 subunit influence nAChR function.

    PubMed

    Dash, Bhagirathi; Li, Ming D

    2014-10-01

    There occur two rare variations, Asp(D)478Asn(N) and Asp(D)478Glu(E), in the putative cytoplasmic amphipathic ?-helices of human nicotinic acetylcholine receptor (nAChR) ?2 subunit as a result of mutation in the 1st (G ? A: rs141072985) and 3rd (C ? A: rs56344740) nucleotide of its 478th triplet codon (GAC). We assessed the effects of these two variations on the function of ?2?2- and ?2?4-nAChRs as they could alter the electronegativity and/or the structure of the cytoplasmic 'portals' (framed by subunit amphipathic ?-helices) necessary for obligate ion permeation from extracellular space to cytoplasm. We injected decreasing ratio of subunit cRNAs (?:?; 10:1, 1:1 and 1:10) into Xenopus oocytes to express putative low-sensitivity (LS; 10:1), intermediate-sensitivity (IS; 1:1) and high sensitivity (HS; 1:10) isoforms of wild type and variant ?2?2- and ?2?4-nAChRs. Two-electrode voltage clamp analyses indicate that the agonist (ACh or nicotine) induced peak current responses (Imax) of ?2?2-nAChR isoforms and those of ?2?4-nAChR isoforms are increased (1.3-4.7-fold) as a result of D478E variation. The ?2 subunit D478N variation only increases the Imax of IS (?2-fold) or HS (1.4-2.1-fold) ?2?2-nAChRs. Concentration-response curves constructed indicate no effect on agonist sensitivities of LS and HS isoforms of ?2?2- or ?2?4-nAChRs as a result of either variation in ?2 subunit. Between the two variant nAChRs, ?2(D478E)*-nAChR isoforms generally yield higher Imax than those of respective ?2(D478N)*-nAChR isoforms. These effects could be attributed to alteration in cytoplasmic 'portals' and/or ion permeation through it owing to change in amino acid electronegativity (D ? N) and side chain length (D ? E) in nAChR ?2 subunit. PMID:24950454

  18. Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective ?4?2-nAChR Ligands.

    PubMed

    Onajole, Oluseye K; Eaton, J Brek; Lukas, Ronald J; Brunner, Dani; Thiede, Lucinda; Caldarone, Barbara J; Kozikowski, Alan P

    2014-11-13

    We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at ?4?2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR ?2 subunit-containing nAChR subtypes (?2*-nAChRs) over ?4*-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for ?4?2- and ?4?2*-nAChRs with negligible interaction. Functional assays confirm selectivity for ?4?2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15. PMID:25408831

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

    PubMed

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

    2014-08-01

    Helmets provide soldiers with ballistic and fragmentation protection but impair auditory spatial processing. Missed auditory information can be fatal for a soldier; therefore, helmet design requires compromise between protection and optimal acoustics. Twelve soldiers localised two sound signals presented from six azimuth angles and three levels of elevation presented at two intensity levels and with three background noises. Each participant completed the task while wearing no helmet and with two U.S. Army infantry helmets - the Personnel Armor System for Ground Troops (PASGT) helmet and the Advanced Combat Helmet (ACH). Results showed a significant effect of helmet type on the size of both azimuth and elevation error. The effects of level, background noise, azimuth and elevation were found to be significant. There was no effect of sound signal type. As hypothesised, localisation accuracy was greatest when soldiers did not wear helmet, followed by the ACH. Performance was worst with the PASGT helmet. PMID:24840132

  20. Selective activation of ?7 nicotinic acetylcholine receptor (nAChR?7) inhibits muscular degeneration in mdx dystrophic mice.

    PubMed

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

    2014-07-21

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

  1. Catalytic enantioselective synthesis of quaternary carbon stereocentres

    NASA Astrophysics Data System (ADS)

    Quasdorf, Kyle W.; Overman, Larry E.

    2014-12-01

    Quaternary carbon stereocentres--carbon atoms to which four distinct carbon substituents are attached--are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials.

  2. Mechanism of Interaction of Novel Uncharged, Centrally Active Reactivators with OP-hAChE Conjugates

    PubMed Central

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

    2012-01-01

    A library of more than 200 novel uncharged oxime reactivators was used to select and refine lead reactivators of human acetylcholinesterase (hAChE) covalently conjugated with sarin, cyclosarin, VX, paraoxon and tabun. N-substituted 2-hydroxyiminoacetamido alkylamines were identified as best reactivators and reactivation kinetics of the lead oximes, RS41A and RS194B, were analyzed in detail. Compared to reference pyridinium reactivators, 2PAM and MMB4, molecular recognition of RS41A reflected in its Kox constant was compromised by an order of magnitude on average for different OP-hAChE conjugates, without significant differences in the first order maximal phosphorylation rate constant k2. Systematic structural modifications of the RS41A lead resulted in several-fold improvement with reactivator, RS194B. Kinetic analysis indicated Kox reduction for RS194B as the main kinetic constant leading to efficient reactivation. Subtle structural modifications of RS194B were used to identify essential determinants for efficient reactivation. Computational molecular modeling of RS41A and RS194B interactions with VX inhibited hAChE, bound reversibly in Michaelis type complex and covalently in the pentacoordinate reaction intermediate suggests that the faster reactivation reaction is a consequence of a tighter RS194B interactions with hAChE peripheral site (PAS) residues, in particular with D74, resulting in lower interaction energies for formation of both the binding and reactivation states. Desirable in vitro reactivation properties of RS194B, when coupled with its in vivo pharmacokinetics and disposition in the body, reveal the potential of this oxime design as promising centrally and peripherally active antidotes for OP toxicity. PMID:22975155

  3. AChR deficiency due to ?-subunit mutations: two common mutations in the Netherlands

    Microsoft Academic Search

    Catharina G. Faber; Peter C. Molenaar; Johannes S. H. Vles; Domenic M. Bonifati; Jan J. G. M. Verschuuren; Pieter A. van Doorn; Jan B. M. Kuks; John H. J. Wokke; David Beeson; Marc De Baets

    2009-01-01

    Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular\\u000a transmission. We have identified mutations within the acetylcholine receptor (AChR) ?-subunit gene underlying congenital myasthenic\\u000a syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations ?1369delG and ?R311Q were found\\u000a to be common; ?1369delG was present on at least one allele in seven

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

    PubMed

    Graupner, Michael; Gutkin, Boris

    2009-06-01

    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

  5. Hydrogen contents and related properties of aC:H formed with unbalanced magnetron sputtering

    Microsoft Academic Search

    G. C. Xu; Y. Hibino; K. Kurotobi; Y. Suzuki; M. Iwaki

    2003-01-01

    Hydrogenated amorphous carbon (a-C:H) coatings have been deposited on titanium substrate with an unbalanced magnetron sputtering apparatus. The hydrogen contents of the coatings were adjusted by introducing hydrogen-containing gases such as hydrogen, methane, and acetylene. The hydrogen contents of the coatings are determined using elastic recoil detection. The effects of the hydrogen contents on the related properties such as hardness,

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

    PubMed Central

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

    2013-01-01

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

  7. Different approaches to study acetylcholine release: endogenous ACh versus tritium efflux

    Microsoft Academic Search

    L. Beani; C. Bianchi; A. Siniscalchi; L. Sivilotti; S. Tanganelli; E. Veratti

    1984-01-01

    Superfused slices of guinea-pig cerebral cortex (CC), caudate nucleus (CN) and thalamus (Th) were used to compare i) the resting and electrically-evoked release of endogenous acetylcholine (ACh) in the presence of physostigmine (Phys) and ii) the resting and electrically-evoked tritium efflux (after preloading with 3H choline) in the absence or in the presence of Phys and hemicholinium (HC-3).

  8. Corrosion inhibitor and method of use

    SciTech Connect

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

    1991-03-26

    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.

  9. Rapid and sensitive detection of the inhibitive activities of acetyl- and butyryl-cholinesterases inhibitors by UPLC-ESI-MS/MS.

    PubMed

    Liu, Wei; Yang, Yadi; Cheng, Xuemei; Gong, Can; Li, Shuping; He, Dandan; Yang, Li; Wang, Zhengtao; Wang, Changhong

    2014-06-01

    Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are legitimate therapeutic targets for Alzheimer's disease. The classical approach for screening potential AChE/BChE inhibitors was developed by Ellman. However, the background color of compounds or plant extracts remained uncertain and frequently interfered with the detection of the secondary reaction, thereby easily yielding false positive or false negative results. Rapid, selective, and sensitive ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry method was developed and used for the detection of AChE and BChE inhibition by directly determining the common product, choline (Ch). Proper separation was achieved for choline and chlormequat (internal standard) within 1.2min via isocratic elution (0.1% fromic acid:methanol=98:2) on an HSS T3 column following a simple precipitation of proteins for sample treatment. The relative standard deviations of the intra- and inter-day precisions were below 7.34 and 9.09%, respectively, whereas the mean accuracy for the quality control samples was 100.31±10.93%. The method exhibited the advantages of small total reaction volume (100?L), short analysis time (1.2min), high sensitivity (LOQ of 0.036?M for Ch), and low cost (little consumption enzymes of 0.0035 and 0.008unitmL(-1) for AChE and BChE, and substrates of 5.505 and 7.152?M for ACh and BCh in individual inhibition, respectively), and without matrix effect (90.00-105.03%). The developed method was successfully applied for detecting the AChE and BChE inhibitive activities for model drugs, including galanthamine, tacrine, neostigmine methylsulfate, eserine, as well as ?-carboline and quinazoline alkaloids from Peganum harmala. PMID:24631841

  10. Higher Susceptibility to Halothane Modulation in Open-Than in Closed-Channel r4 2 nAChR Revealed by Molecular Dynamics Simulations

    E-print Network

    Xu, Yan

    AChR to investigate the conformation-dependent anesthetic effects on channel structures and dynamics. Flexible ligand anesthetics and alcohols were also observed on nAChRs.4­7 Moreover, dual action of alcohols on neuronal n. A mechanistic understanding of how anesthetics altered the function of the R4 2 nAChR is still lacking

  11. Selective Acetylcholinesterase Inhibitor Activated by Acetylcholinesterase Releases an Active Chelator with Neurorescuing and Anti-Amyloid Activities

    PubMed Central

    2010-01-01

    The finding that acetylcholinesterase (AChE) colocalizes with ?-amyloid (A?) and promotes and accelerates A? aggregation has renewed an intense interest in developing new multifunctional AChE inhibitors as potential disease-modifying drugs for Alzheimer’s therapy. To this end, we have developed a new class of selective AChE inhibitors with site-activated chelating activity. The identified lead, HLA20A, exhibits little affinity for metal (Fe, Cu, and Zn) ions but can be activated following inhibition of AChE to liberate an active chelator, HLA20. HLA20 has been shown to possess neuroprotective and neurorescuing activities in vitro and in vivo with the ability to lower amyloid precursor holoprotein (APP) expression and A? generation and inhibit A? aggregation induced by metal (Fe, Cu, and Zn) ion. HLA20A inhibited AChE in a time and concentration dependent manner with an HLA20A?AChE complex constant (Ki) of 9.66 × 10?6 M, a carbamylation rate (k+2) of 0.14 min?1, and a second-order rate (ki) of 1.45 × 10 4 M?1 min?1, comparable to those of rivastigmine. HLA20A showed little iron-binding capacity and activity against iron-induced lipid peroxidation (LPO) at concentrations of 1?50 ?M, while HLA20 exhibited high potency in iron-binding and in inhibiting iron-induced LPO. At a concentration of 10 ?M, HLA20A showed some activity against monoamine oxidase (MAO)-A and -B when tested in rat brain homogenates. Defined restrictively by Lipinski’s rules, both HLA20A and HLA20 satisfied drug-like criteria and possible oral and brain permeability, but HLA20A was more lipophilic and considerably less toxic in human SHSY5Y neuroblastoma cells at high concentrations (25 or 50 ?M). Together our data suggest that HLA20A may represent a promising lead for further development for Alzheimer's disease therapy. PMID:22778810

  12. Pharmacological chaperoning of nAChRs: a therapeutic target for Parkinson's disease.

    PubMed

    Srinivasan, Rahul; Henderson, Brandon J; Lester, Henry A; Richards, Christopher I

    2014-05-01

    Chronic exposure to nicotine results in an upregulation of neuronal nicotinic acetylcholine receptors (nAChRs) at the cellular plasma membrane. nAChR upregulation occurs via nicotine-mediated pharmacological receptor chaperoning and is thought to contribute to the addictive properties of tobacco as well as relapse following smoking cessation. At the subcellular level, pharmacological chaperoning by nicotine and nicotinic ligands causes profound changes in the structure and function of the endoplasmic reticulum (ER), ER exit sites, the Golgi apparatus and secretory vesicles of cells. Chaperoning-induced changes in cell physiology exert an overall inhibitory effect on the ER stress/unfolded protein response. Cell autonomous factors such as the repertoire of nAChR subtypes expressed by neurons and the pharmacological properties of nicotinic ligands (full or partial agonist versus competitive antagonist) govern the efficiency of receptor chaperoning and upregulation. Together, these findings are beginning to pave the way for developing pharmacological chaperones to treat Parkinson's disease and nicotine addiction. PMID:24593907

  13. Production of pediocin AcH by Lactobacillus plantarum WHE 92 isolated from cheese.

    PubMed Central

    Ennahar, S; Aoude-Werner, D; Sorokine, O; Van Dorsselaer, A; Bringel, F; Hubert, J C; Hasselmann, C

    1996-01-01

    Among 1,962 bacterial isolates from a smear-surface soft cheese (Munster cheese) screened for activity against Listeria monocytogenes, six produced antilisterial compounds other than organic acids. The bacterial strain WHE 92, which displayed the strongest antilisterial effect, was identified at the DNA level as Lactobacillus plantarum. The proteinaceous nature, narrow inhibitory spectrum, and bactericidal mode of action of the antilisterial compound produced by this bacterium suggested that it was a bacteriocin. Purification to homogeneity and sequencing of this bacteriocin showed that it was a 4.6-kDa, 44-amino-acid peptide, the primary structure of which was identical to that of pediocin AcH produced by different Pediococcus acidilactici strains. We report the first case of the same bacteriocin appearing naturally with bacteria of different genera. Whereas the production of pediocin AcH from P. acidilactici H was considerably reduced when the final pH of the medium exceeded 5.0, no reduction in the production of pediocin AcH from L. plantarum WHE 92 was observed when the pH of the medium was up to 6.0. This fact is important from an industrial angle. As the pH of dairy products is often higher than 5.0, L. plantarum WHE 92, which develops particularly well in cheeses, could constitute an effective means of biological combat against L. monocytogenes in this type of foodstuff. PMID:8953710

  14. Muscle aches

    MedlinePLUS

    Muscle pain is most frequently related to tension, overuse, or muscle injury from exercise or physically-demanding ... are: Injury or trauma including sprains and strains Overuse: using a muscle too much, too soon, too ...

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

    PubMed Central

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

    1996-01-01

    1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by otilonium. This extraordinary potency of otilonium in blocking nicotinic AChR, unrecognised until now, might account in part for its well known spasmolytic effects. Images Figure 8 PMID:8821535

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

    PubMed

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

    1996-02-01

    1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by otilonium. This extraordinary potency of otilonium in blocking nicotinic AChR, unrecognised until now, might account in part for its well known spasmolytic effects. PMID:8821535

  17. The 3D structure of the anticancer prodrug CPT11 with Torpedo californica acetylcholinesterase rationalizes its inhibitory action on AChE and its hydrolysis by butyrylcholinesterase and carboxylesterase

    Microsoft Academic Search

    Michal Harel; Janice L. Hyatt; Boris Brumshtein; Christopher L. Morton; Randy M. Wadkinsc; Israel Silman; Joel L. Sussman; Philip M. Potter

    2005-01-01

    The anticancer prodrug CPT-11 is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. The 2.6Å resolution crystal structure of its complex with Torpedo californica acetylcholinesterase (TcAChE) demonstrates that CPT-11 binds to TcAChE and spans its gorge similarly to the Alzheimer drug, Aricept. The crystal structure clearly reveals the interactions, which contribute to the

  18. Enantioselective construction of remote quaternary stereocentres

    NASA Astrophysics Data System (ADS)

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

    2014-04-01

    Small molecules that contain all-carbon quaternary stereocentres--carbon atoms bonded to four distinct carbon substituents--are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted ?-, ?-, ?-, ?- or ?-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

  19. Action of Quaternary Ammonium Salts on Nerve

    Microsoft Academic Search

    S. L. Cowan

    1933-01-01

    EXPERIMENTS similar to those of Fromherz with curare on medullated nerve, referred to by Prof. A. V. Hill in his article on ``The Physical Nature of the Nerve Impulse'',1 in NATURE of April 8, have been made with pure quaternary ammonium salts prepared by Dr. H. R. Ing. These have a curare-like action, preventing transmission of excitation from nerve to

  20. Method for clay stabilization with quaternary amines

    SciTech Connect

    Himes, R.E.

    1992-03-24

    This patent describes a method of treating a subterranean formation. It comprises: contacting the formation with an aqueous treatment fluid containing a formation control additive in an amount effective to stabilize the formation; the additive comprising a quaternary ammonium compound selected from compounds.

  1. Surface modification of sepiolite with quaternary amines

    Microsoft Academic Search

    Jovan Lemi?; Magdalena Tomaševi?-?anovi?; Mirjana Djuri?i?; Tanja Stani?

    2005-01-01

    This study was aimed at elucidating the mechanism of adsorption of quaternary amines, stearyldimethylbenzylammoniumchloride (SDBAC), as monomers and as micelles, distearyldimethylammoniumchloride (DDAC) and hexadecyltrimethylammoniumchloride (HTAC), on the surface of sepiolite. The adsorption capacity for these surfactants onto sepiolite, calculated by fitting the experimental data to the Langmuir–Freundlich equation, were 324% (SDBAC), 278% (DDAC), and 258% (HTAC) of the cation exchange

  2. ADSORPTION MECHANISM OF QUATERNARY AMINES BY SEPIOLITE

    Microsoft Academic Search

    E. Sabah; M. S. Çelik

    2002-01-01

    A series of adsorption tests examined the uptake of typical quaternary cationic surfactants, dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide from water by a clay mineral, sepiolite. Adsorption tests conducted under different conditions revealed that sepiolite is highly receptive to adsorption of cationic surfactants. Adsorption of cationic surfactants on sepiolite exhibits two distinct regions. The first stage is characterized by low rate

  3. Connections between Quaternary and Binary Bent Functions

    E-print Network

    Connections between Quaternary and Binary Bent Functions Patrick Solâ??e 1 and Natalia Tokareva 2 1@math.nsc.ru Abstract. Boolean bent functions were introduced by Rothaus (1976) as combinatorial objects related to di functions (Schmidt, 2006) and quater­ nary bent functions (Kumar, Scholtz, Welch, 1985) are explored. We

  4. Connections between Quaternary and Binary Bent Functions

    E-print Network

    Tokareva, Natalia

    Connections between Quaternary and Binary Bent Functions Patrick Sol´e1 and Natalia Tokareva2 1@math.nsc.ru Abstract. Boolean bent functions were introduced by Rothaus (1976) as combinatorial objects related functions (Schmidt, 2006) and quater- nary bent functions (Kumar, Scholtz, Welch, 1985) are explored. We

  5. CM ofe ach pe riod, th e se m ak e up th e CA CM ofth e nanotube

    E-print Network

    Adler, Joan

    alize ultra-se nsitive m ass re sonators, and to ach ie ve th e ultim ate single m ole cule de te ction lim it. Th e de te ction sch e m e for m ass se nsing w ith a m e ch anicalre sonator is ach ie ve d ode fre q ue ncy on th e e ffe ctive m ass M allow s for se nsitive de te ction ofadditionalm ass

  6. UltraHigh Tribological Performance of Magnetron Sputtered aC:H Films in Sand-Dust Environment

    Microsoft Academic Search

    Jianwei Qi; Liping Wang; Fengyuan Yan; Qunji Xue

    2010-01-01

    The hydrogenated amorphous carbon (a-C:H) films were prepared on AISI 440C steel substrates using a RF magnetron sputtering\\u000a graphite target in the CH4 and Ar mixture atmosphere. The friction and wear behavior of a-C:H films were comparatively investigated by pin-on-disc tester\\u000a under dry sliding and simulated sand-dust wear conditions. In addition, the effects of applied load, amount of sand and

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

    Microsoft Academic Search

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

    2001-01-01

    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, gamma-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

  8. [Cl-]i modulation of Ca2+-regulated exocytosis in ACh-stimulated antral mucous cells of guinea pig.

    PubMed

    Shimamoto, Chikao; Umegaki, Eiji; Katsu, Ken-ichi; Kato, Masumi; Fujiwara, Shoko; Kubota, Takahiro; Nakahari, Takashi

    2007-10-01

    The effects of intracellular Cl- concentration ([Cl-]i) on acetylcholine (ACh)-stimulated exocytosis were studied in guinea pig antral mucous cells by video microscopy. ACh activated Ca2+-regulated exocytosis (an initial phase followed by a sustained phase). Bumetanide (20 microM) or a Cl- -free (NO3-) solution enhanced it; in contrast, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, a Cl- channel blocker) decreased it and eliminated the enhancement induced by bumetanide or NO3- solution. ACh and Ca2+ dose-response studies demonstrated that NO3- solution does not shift their dose-response curves, and ATP depletion studies by dinitrophenol or anoxia demonstrated that exposure of NO3- solution prior to ATP depletion induced an enhanced initial phase followed by a sustained phase, whereas exposure of NO3- solution after ATP depletion induced only a sustained phase. Intracellular Ca2+ concentration ([Ca2+]i) measurements showed that bumetanide and NO3- solution enhanced the ACh-stimulated [Ca2+]i increase. Measurements of [Cl-]i revealed that ACh decreases [Cl-]i and that bumetanide and NO3- solution decreased [Cl-]i and enhanced the ACh-evoked [Cl-]i decrease; in contrast, NPPB increased [Cl-]i and inhibited the [Cl-]i decrease induced by ACh, bumetanide, or NO3- solution. These suggest that [Cl-]i modulates [Ca2+]i increase and ATP-dependent priming. In conclusion, a decrease in [Cl-]i accelerates ATP-dependent priming and [Ca2+]i increase, which enhance Ca2+-regulated exocytosis in ACh-stimulated antral mucous cells. PMID:17673548

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

    PubMed

    Brejc, K; van Dijk, W J; Klaassen, R V; Schuurmans, M; van Der Oost, J; Smit, A B; Sixma, T K

    2001-05-17

    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, gamma-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 acetylcholine-binding protein (AChBP), a structural and functional homologue of the amino-terminal ligand-binding domain of an nAChR alpha-subunit. In the AChBP homopentamer, the protomers have an immunoglobulin-like topology. Ligand-binding sites are located at each of five subunit interfaces and contain residues contributed by biochemically determined 'loops' A to F. The subunit interfaces are highly variable within the ion-channel family, whereas the conserved residues stabilize the protomer fold. This AChBP structure is relevant for the development of drugs against, for example, Alzheimer's disease and nicotine addiction. PMID:11357122

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

    PubMed

    Fleck, Christian B; Brock, Matthias

    2009-01-01

    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

  11. A rational design of the multiwalled carbon nanotube-7,7,8,8-tetracyanoquinodimethan sensor for sensitive detection of acetylcholinesterase inhibitors.

    PubMed

    Rotariu, Lucian; Zamfir, Lucian-Gabriel; Bala, Camelia

    2012-10-20

    A new, simple and effective amperometric acetylcholinesterase biosensor was developed using screen-printed carbon electrodes modified with carbon nanotubes (MWCNTs)-7,7,8,8-tetracyanoquinodimethane (TCNQ). The design of the biosensor was based on the supramolecular arrangement resulted from the interaction of MWCNTs and TCNQ. This arrangement was confirmed by spectroscopic and electrochemical techniques. Two different supramolecular arrangements were proposed based on different MWCNTs:TCNQ ratios. The synergistic effect of MWCNTs and TCNQ was, for the first time, exploited for detection of thiocholine at low potential with high sensitivity. The biosensor developed by immobilization of acetylcholinesterase (AChE) in sol-gel allowed the detection of two reference AChE inhibitors, paraoxon-methyl and chlorpyrifos with detection limits of 30 pM (7 ppt) and 0.4 nM (0.1 ppb), respectively. Efficient enzyme reactivation was obtained by using obidoxime. PMID:23021811

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

    PubMed Central

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

    2011-01-01

    ACH-702, a novel isothiazoloquinolone (ITQ), was assessed for antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and a Neisseria sp. but was less active against members of the Enterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well as Legionella pneumophila and Mycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10× MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple. In vivo efficacy was demonstrated against S. aureus with murine sepsis and thigh infection models, with decreases in the number of CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci, and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism of action include the following: low MIC values (?0.25 ?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. PMID:21464250

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

    PubMed

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

    2011-06-01

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

  14. Isolation and Characterization of Pediocin AcH Chimeric Protein Mutants with Altered Bactericidal Activity

    PubMed Central

    Miller, Kurt W.; Schamber, Robin; Osmanagaoglu, Ozlem; Ray, Bibek

    1998-01-01

    A collection of pediocin AcH amino acid substitution mutants was generated by PCR random mutagenesis of DNA encoding the bacteriocin. Mutants were isolated by cloning mutagenized DNA into an Escherichia coli malE plasmid that directs the secretion of maltose binding protein-pediocin AcH chimeric proteins and by screening transformant colonies for bactericidal activity against Lactobacillus plantarum NCDO955 (K. W. Miller, R. Schamber, Y. Chen, and B. Ray, 1998. Appl. Environ. Microbiol. 64:14–20, 1998). In all, 17 substitution mutants were isolated at 14 of the 44 amino acids of pediocin AcH. Seven mutants (N5K, C9R, C14S, C14Y, G37E, G37R, and C44W) were completely inactive against the pediocin AcH-sensitive strains L. plantarum NCDO955, Listeria innocua Lin11, Enterococcus faecalis M1, Pediococcus acidilactici LB42, and Leuconostoc mesenteroides Ly. A C24S substitution mutant constructed by other means also was inactive against these bacteria. Nine other mutants (K1N, W18R, I26T, M31T, A34D, N41K, H42L, K43N, and K43E) retained from <1% to ?60% of wild-type activity when assayed against L. innocua Lin11. One mutant, K11E, displayed ?2.8-fold-higher activity against this indicator. About one half of the mutations mapped to amino acids that are conserved in the pediocin-like family of bacteriocins. All four cysteines were found to be required for activity, although only C9 and C14 are conserved among pediocin-like bacteriocins. Several basic amino acids as well as nonpolar amino acids located within the hydrophobic C-terminal region also were found to be important. The mutations are discussed in the context of structural models that have been proposed for the bacteriocin. PMID:9603806

  15. Metal extraction from Cetraria islandica (L.) Ach. lichen using low pH solutions

    Microsoft Academic Search

    ANA A. ?U?ULOVI?

    Extraction of metals (K, Al, Ca, Mg, Fe, Cu, Ba, Zn, Mn and Sr) from dry Cetraria islandica (L.) Ach. lichen was performed using solutions similar to acid rain (solution A - H2SO4-HNO3-(NH4)2SO4 and solution B - H2SO4- -HNO3-(NH4)2SO4-NH4NO3). The pH values of these solutions were 2.00, 2.58, 2.87, 3.28, and 3.75. Five consecutive extractions were performed with each solution.

  16. Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors.

    PubMed

    Schwarz, S; Csuk, R; Rauter, A P

    2014-04-21

    Alzheimer's disease (AD), the most common form of senile dementia, is characterized by high butyrylcholinesterase (BChE) levels in the brain in later AD stages, for which no treatment is available. Pursuing our studies on selective BChE inhibitors, that may contribute to understand the role of this enzyme in disease progression, we present now microwave-assisted synthesis and anticholinesterase activity of a new nucleoside series embodying 6-chloropurine or 2-acetamido-6-chloropurine linked to D-glucosyl, D-galactosyl and D-mannosyl residues. It was designed to assess the contribution of sugar stereochemistry, purine structure and linkage to the sugar for cholinesterase inhibition efficiency and selectivity. Compounds were subjected to Ellman's assay and their inhibition constants determined. The ?-anomers were the most active compounds, while selectivity for BChE or acetylcholinesterase (AChE) inhibition could be tuned by the purine base, by the glycosyl moiety and by N(7)-ligation. Some of the nucleosides were far more potent than the drug galantamine, and the most promising competitive and selective BChE inhibitor, the N(7)-linked 2-acetamido-?-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE. PMID:24604285

  17. Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease.

    PubMed

    Yanovsky, Inessa; Finkin-Groner, Efrat; Zaikin, Andrey; Lerman, Lena; Shalom, Hila; Zeeli, Shani; Weill, Tehilla; Ginsburg, Isaac; Nudelman, Abraham; Weinstock, Marta

    2012-12-13

    The cascade of events that occurs in Alzheimer's disease involving oxidative stress and the reduction in cholinergic transmission can be better addressed by multifunctional drugs than cholinesterase inhibitors alone. For this purpose, we prepared a large number of derivatives of indoline-3-propionic acids and esters. They showed scavenging activity against different radicals in solution and significant protection against cytotoxicity in cardiomyocytes and primary cultures of neuronal cells exposed to H2O2 species and serum deprivation at concentrations ranging from 1 nM to 10 ?M depending on the compound. For most of the indoline-3-propionic acid derivatives, introduction of N-methyl-N-ethyl or N-methyl-N-(4-methoxyphenyl) carbamate moieties at positions 4, 6, or 7 conferred both acetyl (AChE) and butyryl (BuChE) cholinesterase inhibitory activities at similar concentrations to those that showed antioxidant activity. The most potent AChE inhibitors were 120 (3-(2-aminoethyl) indolin-4-yl ethyl(methyl)carbamate dihydrochloride) and 94 (3-(3-methoxy-3-oxopropyl)-4-(((4-methoxyphenyl)(methyl) carbamoyl)oxy)indolin-1-ium hydrochloride) with IC50s of 0.4 and 1.2 ?M, respectively. PMID:23151013

  18. Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses

    PubMed Central

    Ishibashi, Masaru; Yamazaki, Yoshihiko; Miledi, Ricardo; Sumikawa, Katumi

    2014-01-01

    Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. PMID:25114227

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

    PubMed

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

    2015-01-01

    Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-?-erythroidine, and CP-601932 (a partial agonist of the ?3?4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol. PMID:26039516

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

    PubMed Central

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

    2015-01-01

    Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-?-erythroidine, and CP-601932 (a partial agonist of the ?3?4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol. PMID:26039516

  1. Perchlorate removal by quaternary amine modified reed

    Microsoft Academic Search

    Salem Baidas; Baoyu Gao; Xiaoguang Meng

    2011-01-01

    We report a kinetic and equilibrium study of perchlorate adsorption onto giant reed modified by quaternary amine (QA) functional groups in batch reactors. The effect of pH, contact time, and initial perchlorate concentration on removal was investigated. The adsorption capacity for perchlorate was 169mg\\/g on the modified reed (MR) particles ranging in size from 100 to 250?m. The isotherm results

  2. Hydration effects in quaternary amine extraction systems

    Microsoft Academic Search

    J. D. Miller; M. C. Fuerstenau

    1970-01-01

    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

  3. Palladium-catalyzed asymmetric quaternary stereocenter formation.

    PubMed

    Gottumukkala, Aditya L; Matcha, Kiran; Lutz, Martin; de Vries, Johannes G; Minnaard, Adriaan J

    2012-05-29

    An efficient palladium catalyst is presented for the formation of benzylic quaternary stereocenters by conjugate addition of arylboronic acids to a variety of ?,?-disubstituted carbocyclic, heterocyclic, and acyclic enones. The catalyst is readily prepared from PdCl(2), PhBOX, and AgSbF(6), and provides products in up to 99% enantiomeric excess, with good yields. Based on this strategy, (-)-?-cuparenone has been prepared in only two steps. PMID:22532469

  4. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...2011-07-01 false Quaternary ammonium salt of fluorinated alkylaryl amide. 721...Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl amide. ...identified generically as quaternary ammonium salt of fluorinated alkylaryl amide...

  5. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...2010-07-01 false Quaternary ammonium salt of fluorinated alkylaryl amide. 721...Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl amide. ...identified generically as quaternary ammonium salt of fluorinated alkylaryl amide...

  6. AChR deficiency due to epsilon-subunit mutations: two common mutations in the Netherlands.

    PubMed

    Faber, Catharina G; Molenaar, Peter C; Vles, Johannes S H; Bonifati, Domenic M; Verschuuren, Jan J G M; van Doorn, Pieter A; Kuks, Jan B M; Wokke, John H J; Beeson, David; De Baets, Marc

    2009-10-01

    Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) epsilon-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations epsilon1369delG and epsilonR311Q were found to be common; epsilon1369delG was present on at least one allele in seven of the nine patients, and epsilonR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of epsilonR311Q and epsilon1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for epsilonR311Q and epsilon1369delG. PMID:19544078

  7. Germination inhibitors

    Microsoft Academic Search

    Michael Evenari

    1949-01-01

    Summary  The presence of germination-inhibiting substances in plants seems to be a wide-spread phenomenon. They occur in all parts\\u000a of plants —in fruit pulp, fruit coats, endosperm, seed coat, embryo, leaves, bulbs and roots. They are non-specific in their\\u000a effects.\\u000a \\u000a Besides inhibitors, high osmotic pressure and acid pH are often partly responsible for the germination inhibition caused by\\u000a sap, juices and

  8. EXCITATORY AND INHIBITORY EFFECTS OF SECOND-GENERATION CHOLINESTERASE INHIBITORS ON RAT GASTROINTESTINAL TRANSIT

    Microsoft Academic Search

    DANIELA BRAIDA; WALTER VIRAG; FRANCESCO OTTONELLO; MARIAELVINA SALA

    2000-01-01

    We investigated the influence of increasing oral doses of second generation acetylcholinesterase inhibitors (AChEI) such as tacrine (0.25, 0.5, 1, 2, 3, 4, 10, and 20 mg kg?1), eptastigmine (0.5, 4, 8, 12, 20 and 40 mg kg?1) and E2020 (0.18, 0.25, 0.5, 1, 2, 3, 4 and 10 mg kg?1) on the distance travelled by a charcoal meal administered

  9. from an IgG1-637treated monkey induced strong AChR degradation, in contrast to serum from a

    E-print Network

    Sidow, Arend

    from an IgG1-637­treated monkey induced strong AChR degradation, in contrast to serum from a monkey injected with the IgG4 antibody (Fig. 3B). The latter serum, moreover, prevented AChR degradation by IgG1 only moderate degradation. The IgG4-637 antibody, which induced AChR degradation before injec- tion

  10. Influence of C16 Quaternary Amine on Surface Films and Polarization Resistance of Mild Steel in Carbon Dioxide-Saturated 5% Sodium Chloride

    Microsoft Academic Search

    H. Malik

    1995-01-01

    Experiments were performed to understand the behavior of a C16 quaternary amine on initially clean and precorroded surfaces in carbon dioxide-saturated brine solutions. Although the inhibitor was slow to work at pH 6.5, results indicated high efficiency could be obtained regardless of precorrosion. On initially clean surfaces, greater polarization resistances were measured at the start of the experiments with increasing

  11. In search of allosteric modulators of a7-nAChR by solvent density guided virtual screening.

    PubMed

    Dey, Raja; Chen, Lin

    2011-04-01

    Nicotinic acetylcholine receptors (nAChR) are pentameric ligand gated ion channels whose activity can be modulated by endogenous neurotransmitters as well as by synthetic ligands that bind the same or distinct sites from the natural ligand. The subtype of ?7 nAChR has been considered as a potenial therapeutic target for Alzheimer's disease, schizophrenia and other neurological and psychiatric disorders. Here we have developed a homology model of ?7 nAChR based on two high resolution crystal structures with Brookhaven Protein Data Bank (PDB) codes 2QC1 and 2WN9 for threading on one monomer and then for building a pentamer, respectively. A number of small molecule binding sites are identified using Pocket Finder (J. An, M. Tortov, and R. Abagyan, Molecular & Cellular Proteomics, 4.6, 752-761 (2005)) of Internal Coordinate Mechanics (ICM). Remarkably, these computer-identified sites match perfectly with ordered solvent densities found in the high-resolution crystal structure of ?1 nAChR, suggesting that the surface cavities in the ?7 nAChR model are likely binding sites of small molecules. A high throughput virtual screening by flexible ligand docking of 5008 small molecule compounds was performed at three potential allosteric modulator (AM) binding sites of ?7 nAChR using Molsoft ICM software (R. Abagyan, M. Tortov and D. Kuznetsov, J Comput Chem 15, 488-506, (1994)). Some experimentally verified allosteric modulators of ?7 like CCMI comp-6, LY 7082101, 5-HI, TQS, PNU-120596, genistein, and NS-1738 ranked among top 100 compounds, while the rest of the compounds in the list could guide further search for new allosteric modulators. PMID:21294583

  12. Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function ?6* nAChRs

    PubMed Central

    Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon; Grady, Sharon R.; McIntosh, J. Michael; Brunzell, Darlene H.; Cannon, Jason R.; Drenan, Ryan M.

    2014-01-01

    ?6?2* nAChRs in the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function ?6?2* nAChRs (?6L9’S mice) that are hypersensitive to nicotine and endogenous acetylcholine (ACh). Evoked extracellular dopamine (DA) levels were enhanced in ?6L9’S NAc slices compared to control, non-transgenic (nonTg) slices. Extracellular DA levels in both nonTg and ?6L9’S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing ?6?2* nAChR activation by ACh plays a role in enhancing DA levels, as ?-conotoxin MII completely abolished evoked DA release in ?6L9’S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, ?6L9’S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) compared to nonTg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE) were unchanged in ?6L9’S compared to nonTg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in ?6L9’S NAc. Overall, these results show that enhanced ?6?2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels. PMID:24266758

  13. Muscarinic ACh receptor-mediated control of thalamic activity via G(q)/G (11)-family G-proteins.

    PubMed

    Broicher, Tilman; Wettschureck, Nina; Munsch, Thomas; Coulon, Philippe; Meuth, Sven G; Kanyshkova, Tatyana; Seidenbecher, Thomas; Offermanns, Stefan; Pape, Hans-Christian; Budde, Thomas

    2008-09-01

    A genetic knock out was used to determine the specific contribution of G(q)/G(11)-family G-proteins to the function of thalamocortical relay (TC) neurons. Disruption of Galpha(q) function in a conditional forebrain-specific Galpha(q)/Galpha(11)-double-deficient mouse line (Galpha(q)/Galpha(11)(-/-) had no effects on the resting membrane potential (V (rest)) and the amplitude of the standing outward current (I (SO)). Stimulation of muscarinic acetylcholine (ACh) receptors (mAChR; muscarine, 50 microM) induced a decrease in I (SO) amplitude in wild-type mice (36 +/- 4%, n = 5), a constitutive Galpha(11)-deficient mouse line (Galpha(11)(-/-; 36 +/- 3%, n = 8), and Galpha(q)/Galpha(11)(-/-) (11 +/- 2%, n = 16). Current-clamp recordings revealed a muscarine-induced positive shift in V (rest) of 23 +/- 2 mV (n = 6), 18 +/- 5 mV (n = 5), and 2 +/- 1 mV (n = 9) in wild type, Galpha(11)(-/-), and Galpha(q)/Galpha(11)(-/-), respectively. This depolarization was associated with a change in TC neuron activity from burst to tonic firing in wild type and Galpha(11)(-/-), but not in Galpha(q)/Galpha(11)(-/-). The use of specific antibodies and of pharmacological agents with preferred affinity points to the contribution of m(1)AChR and m(3)AChR. In conclusion, we present two novel aspects of the physiology of the thalamocortical system by demonstrating that the depolarization of TC neurons, which is induced by the action of transmitters of ascending brainstem fibers, is governed roughly equally by both m(1)AChR and m(3)AChR and is transduced by Galpha(q) but not by Galpha(11). PMID:18350314

  14. NMR structures of the human ?7 nAChR transmembrane domain and associated anesthetic binding sites

    PubMed Central

    Bondarenko, Vasyl; Mowrey, David D.; Tillman, Tommy S.; Seyoum, Edom; Xu, Yan; Tang, Pei

    2014-01-01

    The ?7 nicotinic acetylcholine receptor (nAChR), assembled as homomeric pentameric ligand-gated ion channels, is one of the most abundant nAChR subtypes in the brain. Despite its importance in memory, learning and cognition, no structure has been determined for the ?7 nAChR TM domain, a target for allosteric modulators. Using solution state NMR, we determined the structure of the human ?7 nAChR TM domain (PDB ID: 2MAW) and demonstrated that the ?7 TM domain formed functional channels in Xenopus oocytes. We identified the associated binding sites for the anesthetics halothane and ketamine; the former cannot sensitively inhibit ?7 function, but latter can. The ?7 TM domain folds into the expected four-helical bundle motif, but the intra-subunit cavity at the extracellular end of the ?7 TM domain is smaller than the equivalent cavity in the ?4?2 nAChRs (PDB IDs: 2LLY; 2LM2). Neither drug binds to the extracellular end of the ?7 TM domain, but two halothane molecules or one ketamine molecule bind to the intracellular end of the ?7 TM domain. Halothane and ketamine binding sites are partially overlapped. Ketamine, but not halothane, perturbed the ?7 channel-gate residue L9?. Furthermore, halothane did not induce profound dynamics changes in the ?7 channel as observed in ?4?2. The study offers a novel high-resolution structure for the human ?7 nAChR TM domain that is invaluable for developing ?7-specific therapeutics. It also provides evidence to support the hypothesis: only when anesthetic binding perturbs the channel pore or alters the channel motion, can binding generate functional consequences. PMID:24384062

  15. Efficient Expression of Functional (?6?2)2?3 AChRs in Xenopus Oocytes from Free Subunits Using Slightly Modified ?6 Subunits

    PubMed Central

    Ley, Carson Kai-Kwong; Kuryatov, Alexander; Wang, Jingyi; Lindstrom, Jon Martin

    2014-01-01

    Human (?6?2)(?4?2)?3 nicotinic acetylcholine receptors (AChRs) are essential for addiction to nicotine and a target for drug development for smoking cessation. Expressing this complex AChR is difficult, but has been achieved using subunit concatamers. In order to determine what limits expression of ?6* AChRs and to efficiently express ?6* AChRs using free subunits, we investigated expression of the simpler (?6?2)2?3 AChR. The concatameric form of this AChR assembles well, but is transported to the cell surface inefficiently. Various chimeras of ?6 with the closely related ?3 subunit increased expression efficiency with free subunits and produced pharmacologically equivalent functional AChRs. A chimera in which the large cytoplasmic domain of ?6 was replaced with that of ?3 increased assembly with ?2 subunits and transport of AChRs to the oocyte surface. Another chimera replacing the unique methionine 211 of ?6 with leucine found at this position in transmembrane domain 1 of ?3 and other ? subunits increased assembly of mature subunits containing ?3 subunits within oocytes. Combining both ?3 sequences in an ?6 chimera increased expression of functional (?6?2)2?3 AChRs to 12-fold more than with concatamers. This is pragmatically useful, and provides insights on features of ?6 subunit structure that limit its expression in transfected cells. PMID:25068303

  16. Mus�©e Ach�©m�©nide

    NSDL National Science Digital Library

    Drawing on the expertise of a number of well-regarded institutions, the online Mus�©e Ach�©m�©nide will bring users into the world of the ancient worlds of Persia, Babylonia, and the Egyptian empire. While the graphic interfaces used throughout the site take some getting used to, there are a number of lovely features here. In the "Consultation" section, visitors can browse around through various collections, such as archival drawings and renderings from the various geographic areas covered here. They can also view objects from the ancient world and learn about their historical and cultural importance. Visitors can also move through the sections to create their own archive, which they can share with friends or colleagues. Finally, there is a "Help" section that explains how to effectively navigate the site's different areas.

  17. Surface Micellization Patterns of Quaternary Ammonium Surfactants on Mica

    E-print Network

    Aksay, Ilhan A.

    Surface Micellization Patterns of Quaternary Ammonium Surfactants on Mica Heather N. Patrick equilibrium structures of adsorbed films of quaternary ammonium surfactants on mica have been investigated never been reported on graphite. Mica is a model hydrophilic surface and has been previously used

  18. Late Quaternary history of Washington Land, North Greenland OLE BENNIKE

    E-print Network

    Ingólfsson, Ólafur

    Late Quaternary history of Washington Land, North Greenland OLE BENNIKE Bennike, O. 2002 (September): Late Quaternary history of Washington Land, North Greenland. Boreas, Vol. 31, 260­272. Oslo. ISSN 0300-9483. During the last glacial stage, Washington Land in western North Greenland was probably completely inun

  19. Uplift of quaternary shorelines in eastern Patagonia: Darwin revisited

    Microsoft Academic Search

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

    2011-01-01

    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

  20. Quaternary seismo-tectonic activity of the Polochic Fault, Guatemala

    E-print Network

    Paris-Sud XI, Université de

    Quaternary seismo-tectonic activity of the Polochic Fault, Guatemala Christine Authemayou,1 transform boundary between the North American and Caribbean plates in Guatemala and the associated seismic), Quaternary seismo-tectonic activity of the Polochic Fault, Guatemala, J. Geophys. Res., 117, B07403, doi:10

  1. Sorption and desorption of quaternary amine cations on clays

    Microsoft Academic Search

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

    1993-01-01

    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

  2. Towards a quaternary time scale*1

    NASA Astrophysics Data System (ADS)

    Berggren, W. A.; Burckle, L. H.; Cita, M. B.; Cooke, H. B. S.; Funnell, B. M.; Gartner, S.; Hays, J. D.; Kennett, J. P.; Opdyke, N. D.; Pastouret, L.; Shackleton, N. J.; Takayanagi, Y.

    1980-05-01

    Nine first-appearance datums (FADs), twenty-three last-appearance datums (LADs), and three other micropaleontological datums are related to the magnetic-reversal, oxygen-isotope, and calcite-dissolution/coarse-fraction time scales to provide a preliminary basis for subdivision of the Quaternary in deep-sea sediments. The magnetic-reversal, oxygen-isotope, and calcite-dissolution/coarse-fraction scales have been correlated by determination on the same core materials, and absolute dates applied by {40K}/{40Ar} or 14C dating of materials in known positions on one or another of these scales. FADS and LADs have been determined in cores for which either a magnetic-reversal, oxygen-isotope, or calcite-dissolution/coarse-fraction scale has also been available. Altogether 3 FADs and 5 LADs based on diatoms, 4 FADs and 5 LADs based on calcareous nannoplankton, 1 FAD and 8 LADs based on radiolarians, 1 FAD and 5 LADs based on planktonic foraminifers, 2 acme datums, and 1 ratio reversal datum have been determined, and absolute dates inferred by interpolation from known dates on the reference time scales. Some of the FADs and LADs apply or are synchronous only over limited areas of the oceans; others appear to be synchronous throughout the oceans. The base of the Quaternary is set at the top of the Olduvai event at 1.7 my. Four FADs, twelve LADs, two acme datums, and one ratio reversal datum occur above the base of the Quaternary at an average rate of about 1 per 100,000 yr. Five FADs and twelve LADs are recognized in the 0.8-my interval between the top of the Olduvai event and the Gauss/Matuyama Boundary at 2.5 my at an average incidence of about 1 per 50,000 yr.

  3. Hepatitis C virus NS5A inhibitors and drug resistance mutations.

    PubMed

    Nakamoto, Shingo; Kanda, Tatsuo; Wu, Shuang; Shirasawa, Hiroshi; Yokosuka, Osamu

    2014-03-21

    Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for "difficult-to-treat" HCV-infected patients. "First generation" HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. "Second generation" NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants. PMID:24659881

  4. Cryptotanshinone, an acetylcholinesterase inhibitor from Salvia miltiorrhiza, ameliorates scopolamine-induced amnesia in Morris water maze task.

    PubMed

    Wong, Kelvin Kin-Kwan; Ho, Michelle Tsz-Wan; Lin, Huang Quan; Lau, Kwok-Fai; Rudd, John A; Chung, Ronald Chi-Kit; Fung, Kwok-Pui; Shaw, Pang-Chui; Wan, David Chi-Cheong

    2010-02-01

    Alzheimer's disease (AD) is a common form of dementia which is characterized by the deposition of amyloids in affected neurons and a cholinergic neurotransmission deficit in the brain. The current therapeutic intervention for AD is primarily based on the inhibition of brain acetylcholinesterase (AChE) to restore the brain acetylcholine level. Cryptotanshinone (CT) is a diterpene extracted from the root of Salvia miltiorrhiza, a herb that is commonly prescribed in Chinese medicine to treat cardiovascular disease. In the present study, we demonstrated that CT is an inhibitor of both human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC(50) values of 4.09 and 6.38 microM, respectively. The IC(50) ratio of CT for BuChE:AChE was 1.56. CT inhibited human AChE in a reversible manner, and the inhibition showed the characteristics of mixed-type as both the KM and V(max) were affected by CT. The effect of CT on learning impairment in scopolamine-treated rats was also evaluated by the acquisition protocol of the Morris water maze. The task learning ability of scopolamine-treated rats was significantly reversed by CT (5 mg/kg), and the CT-fed rats were able to develop a spatial searching strategy comparable to that of the control animals. In addition, chronic CT treatment did not cause hepatotoxicity as measured by blood alanine transferase (ALT) level. Our findings demonstrate the ability of CT to improve task learning in rats with scopolamine-induced cognitive impairment. These results suggest that CT has the potential as a therapeutic drug for treating AD. PMID:19774505

  5. Quaternary vertebrates from Greenland: A review

    NASA Astrophysics Data System (ADS)

    Bennike, Ole

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

  6. New ternary and quaternary group IV tellurides

    SciTech Connect

    Keane, P.M.

    1992-01-01

    As a continuation of the interest in ternary transition-metal chalcogenides, the exploration of the ternary and quaternary Group IV tellurides, a class of compound largely unexplored, has been undertaken. For this particular system, the reactive flux method proves to be an invaluable crystallization and synthetic technique. These reactions have yielded several new phases, the majority of which represent unprecedented structure types. The compounds K[sub 4]M[sub 3]Te[sub 17] (M = Zr, Hf) contain one-dimensional [sup 1][sub [infinity

  7. Antibacterial activity of gemini quaternary ammonium salts.

    PubMed

    Ob??k, Ewa; Piecuch, Agata; Guz-Regner, Katarzyna; Dworniczek, Ewa

    2014-01-01

    A series of gemini quaternary ammonium salts (chlorides and bromides), with various hydrocarbon chain and spacer lengths, were tested. These compounds exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria and were not mutagenic. The strongest antibacterial effect was observed for TMPG-10 Cl (against Pseudomonas aeruginosa ATCC 27853) and TMPG-12 Br (against Staphylococcus aureus ATCC 6538 and Escherichia coli ATCC 11229 and clinical ESBL(+) isolate 434) surfactants. These compounds inhibited the adhesion of Staphylococcus epidermidis ATCC 35984 to a polystyrene surface and eradicated biofilm formed by P. aeruginosa PAO1. The activity of studied compounds was dependent on hydrocarbon chain length. PMID:24236547

  8. Late-quaternary shift of fagus distribution

    Microsoft Academic Search

    Matsuo Tsukada

    1982-01-01

    Based on six resolved maps of its pollen frequency (dating 13,000, 10,000, 8,000, 6,000, 3,000 and 500 yr B.P.) at 33 sites\\u000a scattered almost throughout the Japanese Archipelago,Fagus shows principally a, unidirectional late-Quaternary shift in distribution from the southwest to the northeast. The maximum\\u000a areal coverage was from 10,000 to 7,000 years ago, although northeastern populations were not fully developed

  9. Novel Complement Inhibitor Limits Severity of Experimentally Myasthenia Gravis

    PubMed Central

    Soltys, Jindrich; Kusner, Linda L.; Young, Andrew; Richmonds, Chelliah; Hatala, Denise; Gong, Bendi; Shanmugavel, Vaithesh; Kaminski, Henry J.

    2011-01-01

    Objective Complement mediated injury of the neuromuscular junction is considered a primary disease mechanism in human myasthenia gravis and animal models of experimentally acquired myasthenia gravis (EAMG). We utilized active and passive models of EAMG to investigate the efficacy of a novel C5 complement inhibitor rEV576, recombinantly produced protein derived from tick saliva, in moderating disease severity. Methods Standardized disease severity assessment, serum complement hemolytic activity, serum cytotoxicity, acetylcholine receptor (AChR) antibody concentration, IgG subclassification, and C9 deposition at the neuromuscular junction were used to assess the effect of complement inhibition on EAMG induced by administration of AChR antibody or immunization with purified AChR. Results Administration of rEV576 in passive transfer EAMG limited disease severity as evidenced by 100% survival rate and a low disease severity score. In active EAMG, rats with severe and mild EAMG were protected from worsening of disease and had limited weight loss. Serum complement activity (CH50) in severe and mild EAMG was reduced to undetectable levels during treatment, and C9 deposition at the neuromuscular junction was reduced. Treatment with rEV576 resulted in reduction of toxicity of serum from severe and mild EAMG rats. Levels of total AChR IgG, and IgG2a antibodies were similar, but unexpectedly, the concentration of complement fixing IgG1 antibodies was lower in a group of rEV576-treated animals, suggesting an effect of rEV576 on cellular immunity. Interpretation Inhibition of complement significantly reduced weakness in two models of EAMG. C5 inhibition could prove to be of significant therapeutic value in human myasthenia gravis. PMID:19194881

  10. Process of inhibiting scale formation in aqueous systems using quaternary ammonium salts of. cap alpha. -1,4-thiazine

    SciTech Connect

    Quinlan, P.M.

    1982-04-06

    Quaternary ammonium salts of ..cap alpha..-1,4-thiazine alkanephosphonic acids are described which inhibit scale formation in aqueous systems. The compounds also can be used in formation of acid corrosion inhibitors, as sequestering agents, and as microbiocides. These compounds are prepared by reacting an ..cap alpha..-1,4-thiazine alkanephosphonic acid compound with an alkylating agent in a suitable polar solvent or a mixture of polar solvents. Examples of solvents are water, mixtures of water and lower alcohols, lower alcohols, dimethyl formamide, dimethyl sulfoxide, and hexamethyulphosphorotrimide. 10 claims.

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

    PubMed

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

    2013-04-18

    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

  12. Many neurons contain both classical transmitters, such as ACh and glutamate, as well as peptide co-transmitters

    E-print Network

    Zucker, Robert S.

    Many neurons contain both classical transmitters, such as ACh and glutamate, as well as peptide co-transmitters (Kupfermann, 1991). There are some differences in the secretion of these two types of transmitters. For instance, release of classical transmitters can occur with a single AP, whereas peptide secretion often

  13. Will your direct deposit leave the U.S.? (International ACH) Will your direct deposit leave the U.S.?

    E-print Network

    Salama, Khaled

    .S.? The Electronic Payments Association (NACHA) requires all direct deposit payments that are sent outside the U traffickers, those engaged in activities related to the proliferation of weapons of mass destruction (ACH) payments, such as electronic funds transfer (EFT). Effective September 18, 2009, the Institute

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

    Microsoft Academic Search

    Katherine J. Willis; Karl J. Niklas

    2004-01-01

    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

  15. Quaternary glaciation of tibet: The geological evidence

    NASA Astrophysics Data System (ADS)

    Derbyshire, Edward; Shi Yafeng; Li Jijun; Zheng Benxing; Li Shijie; Wang Jingtai

    The question of the number and extent of Pleistocene glaciations on the Qinghai-Xizang (Tibet) Plateau remains contentious. There has been considerable research activity in Tibet by Chinese scientists since the late 1950s and their principal findings, including data on glacial and periglacial geomorphology, sedimentology, tectonics, stratigraphy and lake history, have been used to reconstruct ice margins and palaeosnowlines. Three, and in places, four distinct glaciations have been recognised, the most extensive occurring in the later Middle Pleistocene. Valley and piedmont glacial systems, with some mountain ice caps and a small ice sheet on the upper reaches of the Huang He, have been recognised but there is no evidence of a single Tibetan ice sheet. As the Plateau and the Himalaya-Karakoram underwent accelerating uplift through the Quaternary, there occurred progressive desiccation in the interior as the influx of Indian Ocean moisture was constrained. Equilibrium line elevations in the last glacial maximum were 4000 m in the south, east and northeast Plateau margins, rising to 5500 m in the northwest interior. The heat island provided by the Plateau, the progressive reduction in precipitation most marked during the glacials, and the strong southeast to northwest precipitation gradients, produced a glacier distribution pattern dominated by the trans-Tibetan mountain ranges. Tectonics and periglacial (including aeolian) processes have played an equal role with glaciation in generating the Plateau's Quaternary sedimentary succession.

  16. In situ analysis of corrosion inhibitors using a portable mass spectrometer with paper spray ionization.

    PubMed

    Jjunju, Fred P M; Li, Anyin; Badu-Tawiah, Abraham; Wei, Pu; Li, Linfan; Ouyang, Zheng; Roqan, Iman S; Cooks, R Graham

    2013-07-01

    Paper spray (PS) ambient ionization is implemented using a portable mass spectrometer and applied to the detection of alkyl quaternary ammonium salts in a complex oil matrix. These salts are commonly used as active components in the formulation of corrosion inhibitors. They were identified in oil and confirmed by their fragmentation patterns recorded using tandem mass spectrometry (MS/MS). The cations of alkyl and benzyl-substituted quaternary ammonium salts showed characteristic neutral losses of CnH2n (n carbon number of the longest chain) and C7H8, respectively. Individual quaternary ammonium compounds were detected at low concentrations (<1 ng ?L(-1)) and over a dynamic range of ?5 pg ?L(-1) to 500 pg ?L(-1) (ppb). Direct detection of these compounds in complex oil samples without prior sample preparation or pre-concentration was also demonstrated using a home-built miniature mass spectrometer at levels below 1 ng ?L(-1). PMID:23675580

  17. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and {beta}-adrenergic receptor signaling pathways

    SciTech Connect

    Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K. [Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong (Hong Kong); Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong (Hong Kong); Cho, C.H. [Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong (Hong Kong); Department of Pharmacology, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong (Hong Kong); Sung, J.J.Y. [Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong (Hong Kong); Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR (Hong Kong)], E-mail: joesung@cuhk.edu.hku

    2008-12-01

    Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor ({alpha}7 nAChR) and {beta}-adrenergic receptors. Treatment of cells with {alpha}-bungarotoxin ({alpha}-BTX, {alpha}7nAChR antagonist) or propranolol ({beta}-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE{sub 2} and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE{sub 2} induction can only be suppressed by propranolol, but not {alpha}-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis.

  18. Genotyping mutation in BmAChE3: A survey of laboratory and Mexican strains of Rhipicephalus (Boophilus) microplus that are resistant or susceptible to coumaphos

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BmAChE3 mutations I48L, I54V, R86Q, V137I, I492M, and T548A were previously identified in the organophosphate (OP) acaricide-resistant San Román strain of Rhipicephalus (Boophilus) microplus. Recombinant BmAChE3 acetylcholinesterase containing the R86Q mutation was shown to exhibit nearly 20-fold r...

  19. PSU VENDOR SET UP AND W-9/ACH (ELECTRONIC PAYMENT) PROCEDURE All vendors are established by Campus Accounting Services. To set up a vendor in Banner, a PSU

    E-print Network

    Caughman, John

    PSU VENDOR SET UP AND W-9/ACH (ELECTRONIC PAYMENT) PROCEDURE All vendors are established by Campus Accounting Services. To set up a vendor in Banner, a PSU Substitute W-9/ACH form (US entities) or an original W-8 form (foreign entities) must accompany all vendor requests. Campus Accounting is asking

  20. Inhibition of ACh release at an Aplysia synapse by neurotoxic phospholipases A2: specific receptors and mechanisms of action.

    PubMed Central

    Fossier, P; Lambeau, G; Lazdunski, M; Baux, G

    1995-01-01

    1. Monochain (OS2) and multichain (taipoxin) neurotoxic phospholipases A2 (PLA2), purified from taipan snake venom, both inhibited ACh release at a concentration of 20 nM (90% inhibition in 2 h) at an identified synapse from buccal ganglion of Aplysia californica. 2. The Na+ current was unchanged upon application of either OS2 or taipoxin. Conversely, presynaptic K+ currents (IA and IK) were increased by taipoxin but not by OS2. In addition, OS2 induced a significant decrease of the presynaptic Ca2+ current (30%) while taipoxin increased this latter current by 20-30%. 3. Bee venom PLA2, another monochain neurotoxic PLA2, also inhibited ACh release while non-toxic enzymatically active PLA2s like OS1 (also purified from taipan snake venom) or porcine pancreatic PLA2 elicited a much weaker inhibition of ACh release, suggesting a specific action of neurotoxic PLA2s versus non-toxic PLA2s on ACh release. 4. Using iodinated OS2, specific high affinity binding sites with molecular masses of 140 and 18 kDa have been identified on Aplysia ganglia. The maximal binding capacities were 55 and 300-400 fmol (mg protein)-1 for membrane preparations from whole and buccal ganglia, respectively. These binding sites are of high affinity for neurotoxic PLA2s (Kd values, 100-800 pM) and of very low affinity for non-toxic PLA2s (Kd values in the micromolar range), thus indicating that these binding sites are presumably involved in the blockade of ACh release by neurotoxic PLA2s. Images Figure 8 Figure 9 PMID:8583413

  1. Development of radiohalogenated muscarinic ligands for the in vivo imaging of m-AChR by nuclear medicine techniques

    SciTech Connect

    McPherson, D.W.; Luo, H.; Knapp, F.F. Jr.

    1994-06-01

    Alterations in the density of acetylcholinergic muscarinic receptors (m-AChR) have been observed in various dementias. This has spurred interest in the development of radiohalogenated ligands which can be used for the non-invasive in vivo detection of m-AChR by nuclear medicine techniques. We have developed a new ligand 1-azabicyclo[2.2.2]oct-3-yl ({alpha}-hydroxy-{alpha}-(1-iodo-1-propen-3-yl)-{alpha}-phenylacetate (IQNP,12) which demonstrates high affinity for the muscarinic receptor. When labeled with radioiodine it has been shown to be selective and specific for m-ACHR. Initial studies on the separation and in vivo evaluation of the various isomers of IQNP have shown that the stereochemistry of the chiral centers and the configuration around the double bond play an important role in m-AChR subtype specificity. In vivo evaluation of these stereoisomers demonstrate that E-(R,R)-IQNP has a high affinity for the M{sub 1} muscarinic subtype while Z-(R,R)-IQNP demonstrate a high affinity for M{sub 1} and M{sub 2} receptor subtypes. These data demonstrate IQNP (12) has potential for use in the non-evasive in vivo detection of m-AChR by single photon emission computed tomography (SPECT). A brominated analogue, ``BrQNP,`` in which the iodine has been replaced by a bromine atom, has also been prepared and was shown to block the in vivo uptake of IQNP in the brain and heart and therefore has potential for positron emission tomographic (PET) studies of m-AChR.

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

    PubMed

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

    2012-07-01

    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

  3. Antimicrobial Polymeric Materials with Quaternary Ammonium and Phosphonium Salts

    PubMed Central

    Xue, Yan; Xiao, Huining; Zhang, Yi

    2015-01-01

    Polymeric materials containing quaternary ammonium and/or phosphonium salts have been extensively studied and applied to a variety of antimicrobial-relevant areas. With various architectures, polymeric quaternary ammonium/phosphonium salts were prepared using different approaches, exhibiting different antimicrobial activities and potential applications. This review focuses on the state of the art of antimicrobial polymers with quaternary ammonium/phosphonium salts. In particular, it discusses the structure and synthesis method, mechanisms of antimicrobial action, and the comparison of antimicrobial performance between these two kinds of polymers. PMID:25667977

  4. A quaternary temperament model and defense cluster preferences.

    PubMed

    Kelly, Kathryn E; Tobacyk, Jerome J

    2003-10-01

    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

  5. Biocide comparison: Aldehyde versus mixture of aldehyde and quaternary amine

    SciTech Connect

    Prasad, R. [Champion Technologies, Inc., Houston, TX (United States)

    1994-12-31

    Glutaraldehyde and quaternary ammonium chloride salts are widely used biocides in oil field systems to control microbiologically influenced corrosion (MIC). These biocides and others were evaluated for their efficacy to control sessile and planktonic sulfate reducing bacteria (SRB) and aerobic bacteria. The efficacy of these biocides was then compared. In addition to laboratory evaluation, all the biocides were evaluated against SRB and acid producing bacteria in two different field waters. It was found that the blend containing aldehyde and quaternary amino was, in general, a more effective biocide than either glutaraldehyde or quaternary amine alone.

  6. Multifunctional corrosion inhibitors for protective coatings

    SciTech Connect

    Agarwala, V.S.; Fabiszewski, A.S. [Naval Air Warfare Center, Warminster, PA (United States). Aircraft Division

    1994-12-31

    A chemical system called DNBM (a mixture of quaternary ammonium salts of dichromate, nitrate, borate and molybdate) was developed to inhibit corrosion fatigue and stress corrosion cracking, as well as general corrosion, in high strength steels and Aluminum alloys. In this study, DNBM in neat Compound form was examined as a possible substitute inhibitor in standard epoxy primer coatings. The DNBM was added into a very basic epoxy coating consisting of only one relatively inert pigment and also into a clear, resin-only system in order to determine it`s isolated performance. The tests were run on 2024-T3 chromate conversion coated aluminum, bare steel, and zinc phosphated steel. Electrochemical Impedance Spectroscopy measurements were made along with salt spray and humidity exposure testing. Tests results showed that the DNBM definitely added a corrosion inhibiting effect without compromising the functional properties of the coatings.

  7. Quaternary coral reef refugia preserved fish diversity.

    PubMed

    Pellissier, Loïc; Leprieur, Fabien; Parravicini, Valeriano; Cowman, Peter F; Kulbicki, Michel; Litsios, Glenn; Olsen, Steffen M; Wisz, Mary S; Bellwood, David R; Mouillot, David

    2014-05-30

    The most prominent pattern in global marine biogeography is the biodiversity peak in the Indo-Australian Archipelago. Yet the processes that underpin this pattern are still actively debated. By reconstructing global marine paleoenvironments over the past 3 million years on the basis of sediment cores, we assessed the extent to which Quaternary climate fluctuations can explain global variation in current reef fish richness. Comparing global historical coral reef habitat availability with the present-day distribution of 6316 reef fish species, we find that distance from stable coral reef habitats during historical periods of habitat loss explains 62% of the variation in fish richness, outweighing present-day environmental factors. Our results highlight the importance of habitat persistence during periods of climate change for preserving marine biodiversity. PMID:24876495

  8. On Quaternary glaciations, observations and theories

    NASA Astrophysics Data System (ADS)

    Paillard, D.

    2015-07-01

    In a recent paper, Paillard (2015) presents a rapid overview of both major theoretical and empirical studies of Pleistocene glaciations. In particular, it is explained how, over the last 150 years, astronomical theories were confronted to observational constraints and why the "100-kyr problem" is still the major unsolved issue of Quaternary ice ages. This paper also discusses the main alternative theory, which involves changes in atmospheric carbon dioxide concentration. It is then argued that a synthesis of both theories would better account for empirical evidences, as well as for our current knowledge of climate physics. Indeed, if there is no doubt that ice ages are "paced" by the astronomy as evidenced in Hays et al. (1976), the cause of terminations, and therefore the dynamics of the 100-kyr cycles, appears to be closely linked to Southern Ocean climate and atmospheric pCO2.

  9. Antifungal activity of gemini quaternary ammonium salts.

    PubMed

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

    2013-12-14

    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

  10. Suggested terminology for Quaternary dating methods

    USGS Publications Warehouse

    Colman, Steven M.; Pierce, K.L.; Birkeland, P.W.

    1987-01-01

    Classification of Quaternary dating methods should be based on the level of quantitative information and the degree of confidence contained in the age estimates produced by the dating methods. We recommend the use of the terms numerical-age, calibrated-age, relative-age, and correlated-age to describe these levels. We also classify dating methods by type into sideral, isotopic, radiogenic, chemical and biological, geomorphic, and correlation methods. The use of "absolute" is inappropriate for most dating methods, and should be replaced by "numerical." The use of "date" should be minimized in favor of "age" or "age estimate." We recommend use of the abbreviations ka and Ma for most ages; calender dates can be used where appropriate and yr B.P. can be used for radiocarbon ages. ?? 1987.

  11. [Quaternary ammonium compounds--new occupational hazards].

    PubMed

    Lipi?ska-Ojrzanowska, Agnieszka; Walusiak-Skorupa, Jolanta

    2014-01-01

    Quaternary ammonium compounds (QACs, quats) belong to organic ionic chemical agents which display unique properties of both surfactants and disinfectants. Their wide distribution in the work environment and also in private households brings about new occupational hazards. This paper reviews reports about the health effects of QACs. QACs could play a role of sensitizers and irritants to the skin and mucous membranes. It is suspected that particular QACs can display an immunologic cross-reactivity between each other and with other chemical compounds containing ammonium ion, such as muscle relaxants widely used in anesthesia. They may promote the development of airway allergy, however, the background mechanisms are still unclear and need to be further investigated. Until now, a few cases of occupational asthma induced by QACs have been described and their involvement in contact dermatitis has been documented. The possibility of anaphylaxis due to QACs cannot be excluded as well. PMID:25812396

  12. Redefining the role of the quaternary shift in Bacillus stearothermophilus phosphofructokinase.

    PubMed

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

    2013-08-13

    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

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

    PubMed Central

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

    2013-01-01

    Bacillus stearothermophilus PFK (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 inhibitor, phosphoglycolate, bound structure, when compared to the substrate and activator bound structure of wild-type BsPFK, 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 the binding affinity for PEP, a 50-fold decrease in the binding affinity for Fru-6-P, but an inhibitory coupling comparable to wild type. Crystal structures of the apo and PEP bound forms of D12A BsPFK have been determined (Protein Data Bank ID codes 4I36 and 4I7E, respectively), and both indicate a shifted structure similar to the inhibitor-bound structure of 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 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 wild-type. In addition, the T156A BsPFK crystal structure bound to PEP is reported (Protein Data Bank ID code 4I4I), and it exhibits a shifted structure similar to D12A BsPFK and the inhibitor-bound structure of wild type. The results suggest that main role of the quaternary shift may be to influence ligand binding and not to cause the heterotropic allosteric inhibition per se. PMID:23859543

  14. Macrocyclic proteasome inhibitors.

    PubMed

    Krahn, D; Ottmann, C; Kaiser, M

    2011-01-01

    Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors. PMID:22050753

  15. The tempo of avian diversification during the Quaternary

    Microsoft Academic Search

    Robert M. Zink; John Klicka; Brian R. Barber

    2004-01-01

    It is generally assumed that the Quaternary was a period of heightened diversification in temperate ver- tebrate organisms. Previous molecular systematics studies have challenged this assertion. We re-examined this issue in north temperate birds using log-lineage plots and distributions of sister-taxon distances. Log- lineage plots support earlier conclusions that avian diversification slowed during the Quaternary. To test plots of empirical

  16. Late quaternary geologic history of the south Texas continental shelf

    E-print Network

    Pyle, Carroll Anthony

    1977-01-01

    LATE QUATERNARY GEOLOGIC HISTORY OF THE SOUTH TEXAS CONTINENTAL SHELF A Thesis CARROLL ANTHONY PYLE Submitted to the Graduate College of Texas AAM University in partial fulfillment of the requirement for the degree of MASTER OF SCIENCE... December 1977 Major Subject: Oceanography LATE QUATERNARY GEOLOGIC HISTORY OF THE SOUTH TEXAS CONTINENTAL SHELF A Thesis by CARROLL ANTHONY PYLE Approved as to style and content by: (Chairman of Comm tee) (Head of Depar nt) ember) Me ber...

  17. STRIPPING OF GOLD FROM QUATERNARY AMINE EXTRACTION SYSTEMS

    Microsoft Academic Search

    Gang Ma; Wenfei Yan; Jing Chen; Weijin Zhou; Jinguang Wu; Guangxian Xu

    2000-01-01

    A new procedure based on the use of sodium perchlorate (NaC1O4) and saturated potassium chloride (KCl) solutions for gold stripping from quaternary amine extraction systems is proposed for the first time. In this procedure, the stripping of Au(CN)2 is accomplished by the ClO4 ions in the first step, and the regeneration of quaternary amine is achieved by Cl ions in

  18. Gentamicin Blocks the ACh-Induced BK Current in Guinea Pig Type II Vestibular Hair Cells by Competing with Ca2+ at the l-Type Calcium Channel

    PubMed Central

    Yu, Hong; Guo, Chang-Kai; Wang, Yi; Zhou, Tao; Kong, Wei-Jia

    2014-01-01

    Type II vestibular hair cells (VHCs II) contain big-conductance Ca2+-dependent K+ channels (BK) and l-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh) evoked the BK current by triggering the influx of Ca2+ ions through l-type Ca2+ channels, which was mediated by M2 muscarinic ACh receptor (mAChRs). Aminoglycoside antibiotics, such as gentamicin (GM), are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage-independent, and dose-dependent with an IC50 value of 36.3 ± 7.8 ?M. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca2+ concentration ([Ca2+]o) could antagonize it. Moreover, 50 ?M GM potently blocked Ca2+ currents activated by (?)-Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca2+ at the l-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II. PMID:24758923

  19. Gentamicin blocks the ACh-induced BK current in guinea pig type II vestibular hair cells by competing with Ca²? at the L-type calcium channel.

    PubMed

    Yu, Hong; Guo, Chang-Kai; Wang, Yi; Zhou, Tao; Kong, Wei-Jia

    2014-01-01

    Type II vestibular hair cells (VHCs II) contain big-conductance Ca²?-dependent K? channels (BK) and L-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh) evoked the BK current by triggering the influx of Ca²? ions through L-type Ca²? channels, which was mediated by M2 muscarinic ACh receptor (mAChRs). Aminoglycoside antibiotics, such as gentamicin (GM), are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage-independent, and dose-dependent with an IC?? value of 36.3 ± 7.8 µM. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca²? concentration ([Ca²?]?) could antagonize it. Moreover, 50 µM GM potently blocked Ca²? currents activated by (-)-Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca²? at the L-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II. PMID:24758923

  20. Sorption and desorption of quaternary amine cations on clays

    SciTech Connect

    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

    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.

  1. Reduction of ACh-induced contraction of rat isolated ileum by coptisine, (+)-caffeoylmalic acid, Chelidonium majus, and Corydalis lutea extracts.

    PubMed

    Boegge, S C; Kesper, S; Verspohl, E J; Nahrstedt, A

    1996-04-01

    The crude extracts of Chelidonium majus and Corydalis lutea were examined for antispasmodic activity against acetylcholine (ACh)-induced contraction on isolated rat ileal smooth muscle. Further, coptisine and caffeolmalic acid as components of the alkaloid and the hydroxycinnamic acid ester fraction of both plants were similarly investigated. The ACh-induced contraction was found to be antagonized weakly by caffeolymalic acid (6.9%; 2.5 x 10(-5) g/ml/organ bath), C. majus extract (12.7%; 2.0 x 10(-4) g/ml), and a higher concentration of coptisine (16.5%; 1.0 x 10(-5) g/ml) whereas the antispasmodic activity of C.lutea extract reached 45% (2.0 x 10(-4) g/ml). Antagonism by papaverine as a positive control amounted to 83.2%. PMID:8657755

  2. Single particle tracking of alpha7 nicotinic AChR in hippocampal neurons reveals regulated confinement at glutamatergic and GABAergic perisynaptic sites.

    PubMed

    Bürli, Thomas; Baer, Kristin; Ewers, Helge; Sidler, Corinne; Fuhrer, Christian; Fritschy, Jean-Marc

    2010-01-01

    Alpha7 neuronal nicotinic acetylcholine receptors (alpha7-nAChR) form Ca(2+)-permeable homopentameric channels modulating cortical network activity and cognitive processing. They are located pre- and postsynaptically and are highly abundant in hippocampal GABAergic interneurons. It is unclear how alpha7-nAChRs are positioned in specific membrane microdomains, particularly in cultured neurons which are devoid of cholinergic synapses. To address this issue, we monitored by single particle tracking the lateral mobility of individual alpha7-nAChRs labeled with alpha-bungarotoxin linked to quantum dots in live rat cultured hippocampal interneurons. Quantitative analysis revealed different modes of lateral diffusion of alpha7-nAChR dependent on their subcellular localization. Confined receptors were found in the immediate vicinity of glutamatergic and GABAergic postsynaptic densities, as well as in extrasynaptic clusters of alpha-bungarotoxin labeling on dendrites. alpha7-nAChRs avoided entering postsynaptic densities, but exhibited reduced mobility and long dwell times at perisynaptic locations, indicative of regulated confinement. Their diffusion coefficient was lower, on average, at glutamatergic than at GABAergic perisynaptic sites, suggesting differential, synapse-specific tethering mechanisms. Disruption of the cytoskeleton affected alpha7-nAChR mobility and cell surface expression, but not their ability to form clusters. Finally, using tetrodotoxin to silence network activity, as well as exposure to a selective alpha7-nAChR agonist or antagonist, we observed that alpha7-nAChRs cell surface dynamics is modulated by chronic changes in neuronal activity. Altogether, given their high Ca(2+)-permeability, our results suggest a possible role of alpha7-nAChR on interneurons for activating Ca(2+)-dependent signaling in the vicinity of GABAergic and glutamatergic synapses. PMID:20634896

  3. Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

    PubMed Central

    2013-01-01

    Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. PMID:23659787

  4. The effects of climatic pattern on lichen productivity: Cetraria cucullata (Bell.) Ach. in the arctic tundra of northern Alaska

    Microsoft Academic Search

    Martin J. Lechowicz

    1981-01-01

    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

  5. Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands

    Microsoft Academic Search

    Peter Imming; Paul Klaperski; Milton T Stubbs; Gunther Seitz; Daniela Gündisch

    2001-01-01

    We have developed one-step syntheses of halogenated derivatives of (?)-cytisine featuring a halogen substituent at positions 3, 5 or 3 and 5 of the 2-pyridone fragment, and prepared the novel bioisosteric thiocytisine by oxygen–sulphur exchange. The affinities of these pyridone-modified analogs of (?)-cytisine for (?4)2(?2)3 and ?7* nAChRs in rat forebrain membranes were determined by competition with (±)-[3H]epibatidine and [3H]MLA,

  6. Density of ?4?2* nAChR on the surface of neurons is modulated by chronic antagonist exposure

    PubMed Central

    Zambrano, Cristian A; Short, Caitlin A; Salamander, Rakel M; Grady, Sharon R; Marks, Michael J

    2015-01-01

    The expression of high-affinity ?4?2* nicotinic acetylcholine receptors (nAChR) increases following chronic exposure to nicotinic agonists. While, nAChR antagonists can also produce upregulation, these changes are often less pronounced than achieved with agonists. It is unknown if nAChR agonists and antagonists induce receptor upregulation by the same mechanisms. In this study, primary neuronal cultures prepared from cerebral cortex, hippocampus, diencephalon, and midbrain/hindbrain of C57BL/6J mouse embryos were treated chronically with nicotine (agonist), mecamylamine (noncompetitive antagonist) or dihydro-?-erythroidine (competitive antagonist) or the combination of nicotine with each antagonist. The distribution of intracellular and surface [125I]epibatidine-binding sites were subsequently measured. Treatment with 1 ?mol/L nicotine upregulated intracellular and cell surface [125I]epibatidine binding after 96 h. Chronic dihydro-?-erythroidine (10 ?mol/L) treatment also increased [125I]epibatidine binding on the cell surface; however, mecamylamine was ineffective in upregulating receptors by itself. The combination of 1 ?mol/L nicotine plus 10 ?mol/L mecamylamine elicited a significantly higher upregulation than that achieved by treatment with nicotine alone due to an increase of [125I]epibatidine binding on the cell surface. This synergistic effect of mecamylamine and nicotine was found in neuronal cultures from all four brain regions. Chronic treatment with nicotine concentrations as low as 10 nmol/L produced upregulation of [125I]epibatidine binding. However, the effect of mecamylamine was observed only after coincubation with nicotine concentrations equal to or greater than 100 nmol/L. Vesicular trafficking was required for both nicotine and nicotine plus mecamylamine-induced upregulation. Results presented here support the idea of multiple mechanisms for nAChR upregulation. PMID:25729578

  7. Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function ?6* nAChRs.

    PubMed

    Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon; Grady, Sharon R; McIntosh, J Michael; Brunzell, Darlene H; Cannon, Jason R; Drenan, Ryan M

    2014-04-01

    ?6?2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function ?6?2* nAChRs (?6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in ?6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and ?6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing ?6?2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as ?-conotoxin MII completely abolished evoked DA release in ?6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, ?6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in ?6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in ?6L9'S NAc. Overall, these results show that enhanced ?6?2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels. PMID:24266758

  8. NMR resolved multiple anesthetic binding sites in the TM domains of the ?4?2 nAChR

    PubMed Central

    Bondarenko, Vasyl; Mowrey, David; Liu, Lu Tian; Xu, Yan; Tang, Pei

    2012-01-01

    The ?4?2 nicotinic acetylcholine receptor (nAChR) has significant roles in nervous system function and disease. It is also a molecular target of general anesthetics. Anesthetics inhibit the ?4?2 nAChR at clinically relevant concentrations, but their binding sites in ?4?2 remain unclear. The recently determined NMR structures of the ?4?2 nAChR transmembrane (TM) domains provide valuable frameworks for identifying the binding sites. In this study, we performed solution NMR experiments on the ?4?2 TM domains in the absence and presence of halothane and ketamine. Both anesthetics were found in an intra-subunit cavity near the extracellular end of the 2 transmembrane helices, homologous to a common anesthetic binding site observed in X-ray structures of anesthetic-bound GLIC (Nury, et. al. 2011). Halothane, but not ketamine, was also found in cavities adjacent to the common anesthetic site at the interface of ?4 and ?2. In addition, both anesthetics bound to cavities near the ion selectivity filter at the intracellular end of the TM domains. Anesthetic binding induced profound changes in protein conformational exchanges. A number of residues, close to or remote from the binding sites, showed resonance signal splitting from single to double peaks, signifying that anesthetics decreased conformation exchange rates. It was also evident that anesthetics shifted population of two conformations. Altogether, the study comprehensively resolved anesthetic binding sites in the ?4?2 nAChR. Furthermore, the study provided compelling experimental evidence of anesthetic-induced changes in protein dynamics, especially near regions of the hydrophobic gate and ion selectivity filter that directly regulate channel functions. PMID:23000369

  9. Heritability and fitness correlates of personality in the Ache, a natural-fertility population in Paraguay.

    PubMed

    Bailey, Drew H; Walker, Robert S; Blomquist, Gregory E; Hill, Kim R; Hurtado, A Magdalena; Geary, David C

    2013-01-01

    The current study assessed the heritability of personality in a traditional natural-fertility population, the Ache of eastern Paraguay. Self-reports (n?=?110) and other-reports (n?=?66) on the commonly used Big Five Personality Inventory (i.e., extraversion, agreeableness, conscientiousness, neuroticism, openness) were collected. Self-reports did not support the Five Factor Model developed with Western samples, and did not correlate with other-reports for three of the five measured personality factors. Heritability was assessed using factors that were consistent across self- and other-reports and factors assessed using other-reports that showed reliabilities similar to those found in Western samples. Analyses of these items in combination with a multi-generation pedigree (n?=?2,132) revealed heritability estimates similar to those found in most Western samples, although we were not able to separately estimate the influence of the common environment on these traits. We also assessed relations between personality and reproductive success (RS), allowing for a test of several mechanisms that might be maintaining heritable variation in personality. Phenotypic analyses, based largely on other-reports, revealed that extraverted men had higher RS than other men, but no other dimensions of personality predicted RS in either sex. Mothers with more agreeable children had more children, and parents mated assortatively on personality. Of the evolutionary processes proposed to maintain variation in personality, assortative mating, selective neutrality, and temporal variation in selection pressures received the most support. However, the current study does not rule out other processes affecting the evolution and maintenance of individual differences in human personality. PMID:23527163

  10. Heritability and Fitness Correlates of Personality in the Ache, a Natural-Fertility Population in Paraguay

    PubMed Central

    Bailey, Drew H.; Walker, Robert S.; Blomquist, Gregory E.; Hill, Kim R.; Hurtado, A. Magdalena; Geary, David C.

    2013-01-01

    The current study assessed the heritability of personality in a traditional natural-fertility population, the Ache of eastern Paraguay. Self-reports (n?=?110) and other-reports (n?=?66) on the commonly used Big Five Personality Inventory (i.e., extraversion, agreeableness, conscientiousness, neuroticism, openness) were collected. Self-reports did not support the Five Factor Model developed with Western samples, and did not correlate with other-reports for three of the five measured personality factors. Heritability was assessed using factors that were consistent across self- and other-reports and factors assessed using other-reports that showed reliabilities similar to those found in Western samples. Analyses of these items in combination with a multi-generation pedigree (n?=?2,132) revealed heritability estimates similar to those found in most Western samples, although we were not able to separately estimate the influence of the common environment on these traits. We also assessed relations between personality and reproductive success (RS), allowing for a test of several mechanisms that might be maintaining heritable variation in personality. Phenotypic analyses, based largely on other-reports, revealed that extraverted men had higher RS than other men, but no other dimensions of personality predicted RS in either sex. Mothers with more agreeable children had more children, and parents mated assortatively on personality. Of the evolutionary processes proposed to maintain variation in personality, assortative mating, selective neutrality, and temporal variation in selection pressures received the most support. However, the current study does not rule out other processes affecting the evolution and maintenance of individual differences in human personality. PMID:23527163

  11. Experimental investigation into Quaternary badland geomorphic development

    NASA Astrophysics Data System (ADS)

    Kasanin-Grubin, Milica; Kuhn, Nikolaus; Yair, Aaron; Bryan, Rorke; Schwanghart, Wolfgang

    2010-05-01

    Badland morphology is commonly linked to lithological properties of the bedrock. However, recent investigations indicate that the geomorphic development is sensitive to climate and in particular to precipitation characteristics. In this study, the precipitation characteristics that are critical for the Quaternary landscape development in the Dinosaur Badlands in Alberta, Canada, and Zin Valley Badlands, Negev Desert, Israel are investigated. Runoff, erosion and weathering were simulated in the field and the laboratory to determine rates for modeling different precipitation regimes. Currently, the geomorphic development in the Dinosaur badlands is characterized by weathering/supply limited conditions, leading to slope retreat independent of lithology. In the Negev, transport limited conditions cause frequent runoff discontinuity, creating a pattern of areas dominated by erosion or deposition. The results of the weathering and erosion experiments show that the balance between snowmelt induced weathering in the spring and summer rainfall and erosion determine the rate of slope retreat in the Dinosaur Badlands. In the Zin Valley, on the other hand, the magnitude of the individual rainstorms determines whether a slope section is eroded or acts as a sediment sink. The experiments illustrate that the badland slopes experienced an auto-stabilization during the Quaternary in the Zin Valley. In the Dinosaur Badlands Holocene climatic variations have not caused a permanent differentiation of patterns of erosion and deposition. Based on these results the reaction of badland slopes to changing precipitation characteristics was modeled. In their current state, both badland slope systems appear to be fairly stable against climate change in the range of those occurring during the Holocene. However, the stability is achieved in different ways. In the Dinosaur Badlands, weathering rates are low compared to erosion capacity, maintaining continuous evacuation of sediment from slopes to the flood planes of the Red Deer River system. Only a very pronounced contrast between winter weathering and drier summers would generate a colluvium and thus change slope hydrology. In the Zin Valley the development of a thick colluvium at the foot of the slopes has increased infiltration capacity, reducing runoff and sediment yield into the floodplain. Here, only an increase in rainfall magnitude would improve runoff continuity and induce the erosion of the colluvium. This would in turn reduce infiltration capacity and thus initiate a positive feedback on runoff and sediment yield into the Zin River. Overall, Holocene climate change appears to be insufficient to change the geomorphic development in both badlands. However, this stability is achieved not despite of climate, but because of the specific history of geomorphic development. In addition, the combination of erosion and weathering experiments with numerical modeling demonstrates the versatility of Experimental Geomorphology in landscape evolution studies.

  12. Cholinesterase inhibitor use is associated with increased plasma levels of anti-A? 1-42 antibodies in Alzheimer's disease patients.

    PubMed

    Conti, Elisa; Galimberti, Gloria; Tremolizzo, Lucio; Masetto, Alessandro; Cereda, Diletta; Zanchi, Clara; Piazza, Fabrizio; Casati, Marco; Isella, Valeria; Appollonio, Ildebrando; Ferrarese, Carlo

    2010-12-17

    Acetyl-cholinesterase inhibitors (AChEI) are drugs frequently prescribed for the treatment of Alzheimer's disease (AD), exerting an effect on cognition, as well as on behavioural and psychological symptoms of dementia and activities of daily living. The efficacy of AChEI may be ascribed not only to the activation of cholinergic transmission, but also to other mechanisms, among which a putative regulation of the immune response has already been hypothesized. In the present study, we evaluated, in a cross-sectional sample of 66AD patients and 48 healthy controls, the putative influence of AChEI on anti-Abeta 1-42 antibody plasma levels by ELISA assay. AD patients receiving AChEI therapy showed increased plasma levels of anti-Abeta 1-42 antibodies respect to untreated AD patients and antibodies levels similar to those of healthy controls, both before and after normalization by total IgG values. Our results support a potential role of AChEI in the modulation of the immune response against Abeta. We suggest that a strategy aimed at increasing the endogenous response against this peptide might represent an interesting therapeutic target to be further investigated. PMID:20869427

  13. The effect of thermal annealing on the structural and mechanical properties of a-C:H thin films prepared by the CFUBM magnetron sputtering method

    E-print Network

    Hong, Byungyou

    spectroscopy (XPS). Surface and mechanical properties were investigated by atomic force microscopy (AFM), nano-indentation, residual stress tester, and nano-scratch tester. We found that the mechanical properties of a-C:H films

  14. Quaternary Ammonium Biocides: Efficacy in Application

    PubMed Central

    2014-01-01

    Quaternary ammonium compounds (QACs) are among the most commonly used disinfectants. There has been concern that their widespread use will lead to the development of resistant organisms, and it has been suggested that limits should be place on their use. While increases in tolerance to QACs have been observed, there is no clear evidence to support the development of resistance to QACs. Since efflux pumps are believe to account for at least some of the increased tolerance found in bacteria, there has been concern that this will enhance the resistance of bacteria to certain antibiotics. QACs are membrane-active agents interacting with the cytoplasmic membrane of bacteria and lipids of viruses. The wide variety of chemical structures possible has seen an evolution in their effectiveness and expansion of applications over the last century, including non-lipid-containing viruses (i.e., noroviruses). Selection of formulations and methods of application have been shown to affect the efficacy of QACs. While numerous laboratory studies on the efficacy of QACs are available, relatively few studies have been conducted to assess their efficacy in practice. Better standardized tests for assessing and defining the differences between increases in tolerance versus resistance are needed. The ecological dynamics of microbial communities where QACs are a main line of defense against exposure to pathogens need to be better understood in terms of sublethal doses and antibiotic resistance. PMID:25362069

  15. When the Earth has a Belly-Ache: Young Seismologists at School

    NASA Astrophysics Data System (ADS)

    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

    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.

  16. Electrical impedance analysis of N2a neuroblastoma cells in gel matrices after ACh-receptor triggering with an impedimetric biosensor

    Microsoft Academic Search

    T. Valero; T. Jacobs; G. Moschopoulou; M. Naumann; P. Hauptmann; S. Kintzios

    2009-01-01

    In this contribution triggering of the acetylcholine receptor (AChR) in Neuro2a murine neuroblastoma (N2a) cells was studied by means of electrical impedance analysis. N2a cells were immobilized in a bactoagar gel matrix and stimulated with acetylcholine (ACh). Gel films were prepared in between the electrodes of a novel impedimetric sensor. Devices were integrated in a micro fluidic bioreactor for cell

  17. A combined molecular docking and charge density analysis is a new approach for medicinal research to understand drug-receptor interaction: curcumin-AChE model.

    PubMed

    Renuga Parameswari, A; Rajalakshmi, G; Kumaradhas, P

    2015-01-01

    In the present study, a molecular docking analysis has been performed on diketone form of curcumin molecule with acetylcholinesterase (AChE). The calculated lowest docked energy of curcumin molecule in the active site of AChE is -11.21 kcal/mol; this high negative value indicates that the molecule exhibits large binding affinity towards AChE. When the curcumin molecule present in the active site of AChE, subsequently, its conformation has altered significantly and the molecule adopts a U-shape geometry as it is linear in gas phase (before entering into the active site). This conformational transition facilitates curcumin to form strong interaction with Phe330 of acyl-binding pocket and the choline binding site with indole ring of Trp84 and Asp72. The gas phase and the active site analysis of curcumin allows to understand the conformational geometry, nature of molecular flexibility, charge density redistribution and the variation of electrostatic properties of curcumin in the active site. To obtain the gas phase structure, the curcumin molecule was optimized using Hartree-Fock and density functional methods (B3LYP) with the basis set 6-311G(??). A charge density analysis on both gas phase as well as the molecule lifted from the active site was carried out using Bader's theory of atoms in molecules (AIM). The difference in molecular electrostatic potential between the two forms of curcumin displays the difference in charge distribution. The large dipole moment of curcumin (7.54 D) in the active site reflects the charge redistribution as it is much less in the gas phase (4.34 D). PMID:25446495

  18. Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a

    E-print Network

    Barbas III, Carlos F.

    Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using-step constructions of molecules with multiple quaternary carbon stereocentres are rare. The spirooxindole structural by a novel multifunctional organocatalyst that contains tertiary and primary amines and thiourea moieties

  19. ELIC-?7 Nicotinic Acetylcholine Receptor (?7nAChR) Chimeras Reveal a Prominent Role of the Extracellular-Transmembrane Domain Interface in Allosteric Modulation*

    PubMed Central

    Tillman, Tommy S.; Seyoum, Edom; Mowrey, David D.; Xu, Yan; Tang, Pei

    2014-01-01

    The native ?7 nicotinic acetylcholine receptor (?7nAChR) is a homopentameric ligand-gated ion channel mediating fast synaptic transmission and is of pharmaceutical interest for treatment of numerous disorders. The transmembrane domain (TMD) of ?7nAChR has been identified as a target for positive allosteric modulators (PAMs), but it is unclear whether modulation occurs through changes entirely within the TMD or changes involving both the TMD and the extracellular domain (ECD)-TMD interface. In this study, we constructed multiple chimeras using the TMD of human ?7nAChR and the ECD of a prokaryotic homolog, ELIC, which is not sensitive to these modulators, and for which a high resolution structure has been solved. Functional ELIC-?7nAChR (EA) chimeras were obtained when their ECD-TMD interfaces were modified to resemble either the ELIC interface (EAELIC) or ?7nAChR interface (EA?7). Both EA?7 and EAELIC show similar activation response and desensitization characteristics, but only EA?7 retained the unique pharmacology of ?7nAChR evoked by PAMs, including potentiation by ivermectin, PNU-120596, and TQS, as well as activation by 4BP-TQS. This study suggests that PAM modulation through the TMD has a more stringent requirement at the ECD-TMD interface than agonist activation. PMID:24695730

  20. Chronic ethanol (EtOH) feeding increases muscarinic receptor (mAChR) density in esophagus without parallel change in dose response (D-R) to cholinergic agonists

    SciTech Connect

    Keshavarzian, A.; Gordon, J.H.; Urban, G.; Fields, J.Z. (Loyola Univ., Maywood (United States) VA Hospital, Hines, IL (United States))

    1991-03-11

    The mAChR/effector pathway for signal transduction is important in the physiology of esophagus and mAChR alterations are involved in EtOH induced changes in several organs. To see if EtOH-induced increases in lower esophageal sphincter pressure (LESP) are due to upregulation of mAChR, the authors evaluated mAChR binding and D-R curves for bethanechol (IV) induced increases in LESP, and compared these values to changes in LESP after acute and chronic EtOH. EtOH was given to cats acutely or chronically. The number of mAChR sites (Bmax) in esophagus was lowered by acute EtOH, withdrawal from chronic EtOH raised Bmax. Acute injection of EtOH to cats in withdrawal reversed this increase in mAChR density. These changes correlated with the earlier data on EtOH-induced changes in LESP. In contrast, the D-R curve for bethanechol shifted to the right. Thus, the withdrawal-associated increase in Bmax is more likely to be a compensatory response to deficits distal to the receptor recognition site than to proximal deficits and doesn't cause LESP hyperactivity. Also, receptor binding changes do not necessarily translate into physiological changes.

  1. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

    PubMed Central

    Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

    2015-01-01

    Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV.

  2. Quaternary Evolution of Karliova Triple Junction

    NASA Astrophysics Data System (ADS)

    Sançar, Taylan; Zabc?, Cengiz; Akyüz, H. Serdar

    2013-04-01

    The arguments to explain Quaternary evolution of Karl?ova Triple Junction (KTJ) depends upon two different analogue models. The compressional type of Prandtl Cell Model (PCM) and 60 km wide shear zone with concomitant counter clockwise block rotation used to modelled for west and east of the KTJ respectively. The data for the model of west of the KTJ acquired by extensive field studies, and quantified geomorphic features. Compressional PCM put forward that behavior of slip lines controlled by boundary faults. But the model is not enough to explain slip distribution, age relation of them. At west of the KTJ boundary faults presented by eastern most segments of the North Anatolian Fault Zone (NAFZ) and the East Anatolian Fault Zone (EAFZ). Slip lines, however, presented by Bahçeli and Toklular faults. Both field studies and morphometric analyses undisputedly set forth that there are two different fault types between the NAFZ and EAFZ. The most strain loaded fault type, which are positioned near the NAFZ, start as a strike-slip fault and when it turn to SE its sense of motion change to oblique normal due to changing orientation of principal stress axes. The new orientation of stress axes exposed in the field as a special kind of caprock -cuesta-. The younger slip lines formed very close to junction point and accommodate less slip. Even though slip trajectories started from the boundary faults in compressional PCM, at the west of KTJ, right lateral trajectories more clearly formed close the NAFZ and left lateral trajectories, relatively less strain loaded fault type, are poorly formed close the EAFZ . We think that, this differences between KTJ and compressional PCM result from the distinction of velocity of boundary faults. East of the KTJ governed by completely different mechanism. The region controlled two main fault systems. The Varto Fault Zone (VFZ), the eastern branch of the KTJ, and Murat Fault (MF) delimited the region from north and south respectively. The region also delimited at west by the EAFZ. All secondary faults between these three faults are strike slip faults. The faults which are positioned NW-SE and nearly parallel to the N70W oriented VFZ are dextral, whereas sinistral faults are N-S oriented and nearly orthogonal to NW-SE trending right lateral faults. Sinistral faults develop in the overlap area between adjacent left stepping of dextral faults which are arranged in an en echelon pattern. This configuration formed under shear zone regime with one Previous shear zone model studies proposed that right lateral faults form the 17-24 degree to principal displacement zone. Paleo-magnetic studies of Plio-Quaternary rocks, which covered the all region, show that there is a counterclockwise block rotation between 18 to 23 degree that is clearly explain position of the secondary right lateral faults.

  3. Analysis of Quaternary Amine Compounds by Hydrophilic Interaction Chromatography\\/Mass Spectrometry (HILIC\\/MS)

    Microsoft Academic Search

    Yong Guo

    2005-01-01

    Hydrophilic interaction chromatography (HILIC) was explored for the separation of selected quaternary amine compounds of biological and environmental importance, including acetylcholine, choline, betaine, chlormequat, and mepiquat. The HILIC method was successful in separating the model quaternary amine compounds without the need for ion?pairing reagents. The present study indicates that the amide phase provides much stronger retention for the quaternary amine

  4. Late Quaternary fire regimes of Australasia

    NASA Astrophysics Data System (ADS)

    Mooney, S. D.; Harrison, S. P.; Bartlein, P. J.; Daniau, A.-L.; Stevenson, J.; Brownlie, K. C.; Buckman, S.; Cupper, M.; Luly, J.; Black, M.; Colhoun, E.; D'Costa, D.; Dodson, J.; Haberle, S.; Hope, G. S.; Kershaw, P.; Kenyon, C.; McKenzie, M.; Williams, N.

    2011-01-01

    We have compiled 223 sedimentary charcoal records from Australasia in order to examine the temporal and spatial variability of fire regimes during the Late Quaternary. While some of these records cover more than a full glacial cycle, here we focus on the last 70,000 years when the number of individual records in the compilation allows more robust conclusions. On orbital time scales, fire in Australasia predominantly reflects climate, with colder periods characterized by less and warmer intervals by more biomass burning. The composite record for the region also shows considerable millennial-scale variability during the last glacial interval (73.5-14.7 ka). Within the limits of the dating uncertainties of individual records, the variability shown by the composite charcoal record is more similar to the form, number and timing of Dansgaard-Oeschger cycles as observed in Greenland ice cores than to the variability expressed in the Antarctic ice-core record. The composite charcoal record suggests increased biomass burning in the Australasian region during Greenland Interstadials and reduced burning during Greenland Stadials. Millennial-scale variability is characteristic of the composite record of the sub-tropical high pressure belt during the past 21 ka, but the tropics show a somewhat simpler pattern of variability with major peaks in biomass burning around 15 ka and 8 ka. There is no distinct change in fire regime corresponding to the arrival of humans in Australia at 50 ± 10 ka and no correlation between archaeological evidence of increased human activity during the past 40 ka and the history of biomass burning. However, changes in biomass burning in the last 200 years may have been exacerbated or influenced by humans.

  5. Tertiary and Quaternary Research with Remote Sensing Methods

    NASA Technical Reports Server (NTRS)

    Conel, J. E.

    1985-01-01

    Problems encountered in mapping the Quaternary section of the Wind River Region using remote sensing methods are discussed. Analysis of the stratigraphic section is a fundamental aspect of the geologic study of sedimentary basins. Stratigraphic analysis of post-Cretaceous rocks in the Wind River Basin encounters problems of a distinctly different character from those involved in studying the pre-Cretaceous section. The interior of the basin is predominantly covered by Tertiary and Quaternary sediments. These rocks, except on the basin margin to the north, are mostly flat lying or gently dipping. The Tertiary section consists of sandstones, siltstones, and tuffaceous sediments, some variegated, but in general poorly bedded and of great lithologic similarity. The Quaternary sediments consist of terrace, fan, and debris tongue deposits, unconsolidated alluvium occupying the bottoms of modern watercourses, deposits of eolian origin and tufa. Terrace and fan deposits are compositionally diverse and reflect the lithologic diversity of the source terranes.

  6. The tempo of avian diversification during the Quaternary.

    PubMed Central

    Zink, Robert M; Klicka, John; Barber, Brian R

    2004-01-01

    It is generally assumed that the Quaternary was a period of heightened diversification in temperate vertebrate organisms. Previous molecular systematics studies have challenged this assertion. We re-examined this issue in north temperate birds using log-lineage plots and distributions of sister-taxon distances. Log-lineage plots support earlier conclusions that avian diversification slowed during the Quaternary. To test plots of empirical sister-taxon distances we simulated three sets of phylogenies: constant speciation and extinction, a pulse of recent speciation, and a pulse of recent extinction. Previous opinions favour the model of recent speciation although our empirical dataset on 74 avian comparisons failed to reject a distribution derived from the constant and extinction models. Hence, it does not appear that the Quaternary was a period of exceptional rates of diversification, relative to the background rate. PMID:15101578

  7. Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity

    SciTech Connect

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

    1984-04-01

    The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

  8. [18F]ASEM, a radiolabeled antagonist for imaging the ?7-nicotinic acetylcholine receptor (?7-nAChR) with positron emission tomography (PET)

    PubMed Central

    Horti, Andrew G.; Gao, Yongjun; Kuwabara, Hiroto; Wang, Yuchuan; Abazyan, Sofya; Yasuda, Robert P.; Tran, Thao; Xiao, Yingxian; Sahibzada, Niaz; Holt, Daniel P.; Kellar, Kenneth J.; Pletnikov, Mikhail V.; Pomper, Martin G.; Wong, Dean F.; Dannals, Robert F.

    2014-01-01

    The ?7-nicotinic cholinergic receptor (?7-nAChR) is a key mediator of brain communication and has been implicated in a wide variety of central nervous system disorders. None of the currently available PET radioligands for ?7-nAChR are suitable for quantitative PET imaging, mostly due to insufficient specific binding. The goal of this study was to evaluate the potential of [18F]ASEM ([18F]JHU82132) as an ?7-nAChR radioligand for PET. Methods Inhibition binding assay and receptor functional properties of ASEM were assessed in vitro. The brain regional distribution of [18F]ASEM in baseline and blockade were evaluated in DISC1 mice (dissection) and baboons (PET). Results ASEM is an antagonist for the ?7-nAChR with high binding affinity (Ki = 0.3 nM). [18F]ASEM readily entered the baboon brain and specifically labeled ?7-nAChR. The in vivo specific binding of [18F]ASEM in the brain regions enriched with ?7-nAChRs was 80–90%. SSR180711, an ?7-nAChR selective partial agonist, blocked [18F]ASEM binding in the baboon brain in a dose-dependent manner, suggesting that the binding of [18F]ASEM was mediated by ?7-nAChRs and the radioligand was suitable for drug evaluation studies. In the baboon baseline studies, the brain regional volume of distribution (VT) values for [18F]ASEM were 23 (thalamus), 22 (insula), 18 (hippocampus) and 14 (cerebellum), whereas in the binding selectivity (blockade) scan, all regional VT values were reduced to less than 4. The range of regional binding potential (BPND) values in the baboon brain was from 3.9 to 6.6. In vivo cerebral binding of [18F]ASEM and ?7-nAChR expression in mutant DISC1 mice, a rodent model of schizophrenia, was significantly lower than in control animals, which is in agreement with previous post-mortem human data. Conclusion [18F]ASEM holds promise as a radiotracer with suitable imaging properties for quantification of ?7-nAChR in the human brain. PMID:24556591

  9. Desorption of 137 Cs from Cetraria islandica (L.) Ach. using solutions of acids and their salts mixtures

    Microsoft Academic Search

    ANA A. ?U?ULOVI?

    2009-01-01

    The desorption of 137 Cs from Cetraria islandica (L.) Ach. lichen was investigated using the solutions: A) H2SO4-HNO3-K2SO4, B) H2SO4-HNO3- -Na2SO4 and C) H2SO4-HNO3-(NH4)2SO4-(NH)4NO3 at pH 2.00, 2.58, 2.87, 3.28 and 3.75, similar to acid rain. After five consecutive desorptions using so- lutions A, B and C, from 44.0 % (solution B, pH 3.75) to 68.8 % (solution C, pH

  10. A geometricla error in some Computer Programs based on the Aki-Christofferson-Husebye (ACH) Method of Teleseismic Tomography

    USGS Publications Warehouse

    Julian, B.R.; Evans, J.R.; Pritchard, M.J.; Foulger, G.R.

    2000-01-01

    Some computer programs based on the Aki-Christofferson-Husebye (ACH) method of teleseismic tomography contain an error caused by identifying local grid directions with azimuths on the spherical Earth. This error, which is most severe in high latitudes, introduces systematic errors into computed ray paths and distorts inferred Earth models. It is best dealt with by explicity correcting for the difference between true and grid directions. Methods for computing these directions are presented in this article and are likely to be useful in many other kinds of regional geophysical studies that use Cartesian coordinates and flat-earth approximations.

  11. Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors

    Microsoft Academic Search

    Ming Zhou; João H. Morais-Cabral; Sabine Mann; Roderick MacKinnon

    2001-01-01

    Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by the channel's cytoplasmic amino terminus. Here we show that the central cavity

  12. Ice Age Earth: Late Quaternary geology and climate

    SciTech Connect

    Dawson, A.G.

    1992-01-01

    This book is a concise and readable account of the most important geologic records of the late Quaternary. It provides a synopsis of the major environmental changes that took place from approximately 13,000 to 7,000 years ago, highlighting the complexity and rapidity of past climate changes and the environmental responses they produced. The text is well illustrated, though some figures are rough and need more explanation. Also needed is a critical appraisal of the geochronology which places the paleoenvironmental records into the temporal domain. However, as a whole the book reaches its objective of summarizing the most important scientific findings about the nature of the late Quaternary climate changes.

  13. Toxicity assessments with Daphnia magna of Guadipyr, a new neonicotinoid insecticide and studies of its effect on acetylcholinesterase (AChE), glutathione S-transferase (GST), catalase (CAT) and chitobiase activities.

    PubMed

    Qi, Suzhen; Wang, Chen; Chen, Xiaofeng; Qin, Zhaohai; Li, Xuefeng; Wang, Chengju

    2013-12-01

    Guadipyr is a novel neonicotinoid insecticide, developed by the China Agricultural University. This work investigated its aquatic toxicity on Daphnia magna. The acute immobilization test showed that guadipyr was slightly toxic to daphnids, with a 48 h EC?? of 13.01 mg/L. In addition, guadipyr significantly enhanced the acetylcholinesterase (AChE) and glutathione S-transferase (GST) activity (per gram of protein), but had no obvious impact on catalase (CAT) activity within 48 h. The 21 d chronic exposure of D. magna to guadipyr induced a significant decrease in body growth and reproduction; both share the same lowest observed effect concentration (LOEC) at 0.10 mg/L. In the 14 d chronic test, a significant increase in chitobiase activity in test media was observed at day 8 (days to the first breeding), while a significant decrease was observed from days 10 to 14, which might be due to the endocrine imbalance resulting from guadipyr stress. These results demonstrated that guadipyr can induce notable negative ecotoxicological impacts on the aquatic system in long-term exposure at a sub-lethal dose. Further research in environmental behaviors is needed to regulate guadipyr use in the future. PMID:24075643

  14. Biochemical and functional properties of distinct nicotinic acetylcholine receptors in the superior cervical ganglion of mice with targeted deletions of nAChR subunit genes

    PubMed Central

    David, Reinhard; Ciuraszkiewicz, Anna; Simeone, Xenia; Orr-Urtreger, Avi; Papke, Roger L.; McIntosh, J. Michael; Huck, Sigismund; Scholze, Petra

    2010-01-01

    Nicotinic acetylcholine receptors (nAChR) mediate fast synaptic transmission in ganglia of the autonomic nervous system. Here, we have determined the subunit composition of hetero-pentameric nAChRs in the mouse superior cervical ganglion (SCG), the function of distinct receptors (obtained by deletions of nAChR subunit genes), and mechanisms at the level of nAChRs that might compensate for the loss of subunits. As shown by immunoprecipitation and Western blots, wild type (WT) mice expressed (%): ?3?4 (55), ?3?4?5 (24), and ?3?4?2 (21) nAChRs. nAChRs in ?4 knockout (KO) mice were reduced to less than 15 % of controls and no longer contained the ?5 subunit. Compound action potentials, recorded from the postganglionic (internal carotid) nerve and induced by preganglionic nerve stimulation, did not differ between ?5?4 KO and WT, suggesting that the reduced number of receptors in the KO did not impair transganglionic transmission. Deletions of ?5 or ?2 did not affect the overall number of receptors and we found no evidence that the two subunits substitute for each other. In addition, dual KOs allowed us to study the functional properties of distinct ?3?4 and ?3?2 receptors that have previously only been investigated in heterologous expression systems. The two receptors strikingly differed in the decay of macroscopic currents, the efficacy of cytisine, and their responses to the ?-conotoxins AuIB and MII. Our data - based on biochemical and functional experiments and several mouse KO models - clarifies and significantly extends previous observations on the function of nAChRs in heterologous system and the SCG. PMID:20377613

  15. CC4, a dimer of cytisine, is a selective partial agonist at ?4?2/?6?2 nAChR with improved selectivity for tobacco smoking cessation

    PubMed Central

    Sala, Mariaelvina; Braida, Daniela; Pucci, Luca; Manfredi, Irene; Marks, Michael J; Wageman, Charles R; Grady, Sharon R; Loi, Barbara; Fucile, Sergio; Fasoli, Francesca; Zoli, Michele; Tasso, Bruno; Sparatore, Fabio; Clementi, Francesco; Gotti, Cecilia

    2013-01-01

    Background and Purpose Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4). Experimental Approach The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours. Key Results When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal ?4?2, ?3?4, ?7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through ?4?2 and ?6?2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the ?3?4 and ?7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose–response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions. Conclusion and Implications Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for ?2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation. PMID:22957729

  16. Receiver architectures and aperiodic correlation parameters for direct-sequence spread spectrum with quaternary complex spreading sequences

    Microsoft Academic Search

    Thomas G. Macdonald; Michael B. Pursley

    1998-01-01

    Results on quaternary complex sequences have provided quaternary sequences that have better periodic correlation properties than binary sequences. In this paper we examine a receiver architecture that takes advantage of the superior periodic correlation properties of these quaternary sequences, and we investigate the aperiodic correlation properties that permit quaternary direct-sequence spread spectrum to discriminate against multipath and provide multiple-access capability

  17. Biosorption of Au (III) and Cu (II) from aqueous solution by a non-living Cetraria islandica (L.) Ach.

    PubMed

    Ekinci Dogan, Canan; Turhan, Kadir; Akcin, Göksel; Aslan, Ali

    2006-01-01

    Biosorption of Au(III) and Cu(II) from dilute aqueous solutions was investigated by biomass of the non-living Cetraria islandica (L.) Ach. The removal and recovery of gold and copper were studied by applying batch technique. The experimental parameters such as the pH of the solution, contact time, the amount of Cetraria islandica (L.) Ach. (dried lichen), the concentration of metals on retention and eluents kind and amount have been investigated. Au(III) and Cu(II) were adsorbed on the dried lichen at pH 3 and pH 8, respectively. Quantitative retention (> or = 90%) was obtained within 60 minutes for metals. Maximum capacity of 1.0 g of dried lichen for biosorption of Au(III) and Cu(II) were found as 7.4 mg of Au(III) and 19.2 mg of Cu(II). It was seen that the adsorption equilibrium data conformed well to the Langmuir model and Freundlich equation for Au(III) and only Freundlich equation for Cu(II). The method proposed in this study was applied to spiked mineral water analysis and metals adsorbed on the lichens were quantitatively (> or = 90%) recovered from mineral water samples by using 0.5 mol L(-1) HCl. PMID:16836256

  18. Acetylcholinesterase inhibitors from the twigs of Vaccinium oldhami Miquel.

    PubMed

    Lee, Jae Hyeok; Lee, Ki Taek; Yang, Jae Heon; Baek, Nam In; Kim, Dae Keun

    2004-01-01

    In the course of finding Korean natural products with acetylcholinesterase (AChE) inhibitory activity, we found that a methanolic extract of the twigs of Vaccinium oldhami significantly inhibited AChE. Bioassay-guided fractionation of the methanolic extract resulted in the isolation of two compounds, taraxerol (1) and scopoletin (2), as active constituents. These compounds inhibited AChE activity in a dose-dependent manner, and the IC50 values of compounds 1 and 2 were 33.6 (79 microM) and 10.0 (52 microM) microg/mL, respectively. PMID:14969339

  19. Quaternary fossil fauna of South Canterbury, South Island, New Zealand

    Microsoft Academic Search

    T. H. Worthy

    1997-01-01

    This study documents the Late Quaternary fossil fauna from 59 fossil sites in the South Canterbury downlands, South Island, New Zealand. Twenty?seven sites were predator accumulations attributed to laughing owls, two were accumulated by falcons, two were swamp sites, and the rest were pitfalls or rockshelter deposits. A total of 60 indigenous species of birds, one bat, three rodents, one

  20. Quaternary research in Poland: selected achievements and prospects

    Microsoft Academic Search

    Leszek Marks

    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

  1. Synthesis and antimicrobial properties of polymerizable quaternary ammoniums

    Microsoft Academic Search

    Laurent Caillier; Elisabeth Taffin de Givenchy; Richard Levy; Yves Vandenberghe; Serge Géribaldi; Frédéric Guittard

    2009-01-01

    Introduction of biocide monomers during the process of polymerization is a promising approach in the development of new permanent non leaching biocide materials. Two series of surfactants monomers, with a quaternary ammonium group as polar head and an acrylic function as the polymerizable moiety, were synthesized and tested to evaluate their surface active properties alongside with their antibacterial and antifungal

  2. Study on antibacterial behavior of insoluble quaternary ammonium

    Microsoft Academic Search

    Shan Jiang; Li Wang; Haojie Yu; Ying Chen; Quan Shi

    2006-01-01

    Insoluble crosslinked polystyrenes (PS) grafted with different quaternary ammonium groups were synthesized as antibacterial agents. Their antibacterial activ- ities against Staphylococcus aureus were investigated by a colony count method. It was found that when the concen- tration of the insoluble antibacterial agent was low, the antibacterial activity was different from that of the typical soluble antibacterial agent. The antibacterial activity

  3. Antibacterial Nanocomposite with Calcium Phosphate and Quaternary Ammonium

    Microsoft Academic Search

    L. Cheng; M. D. Weir; K. Zhang; S. M. Xu; Q. Chen; X. Zhou; H. H. K. Xu

    2012-01-01

    Secondary caries is a frequent reason for restoration failure, resulting from acidogenic bacteria and their biofilms. The objectives of this study were to: (1) develop a novel nanocomposite containing nanoparticles of amorphous calcium phosphate (NACP) and quaternary ammonium dimethacrylate (QADM); and (2) investigate its mechanical and antibacterial durability. A spray-drying technique yielded NACP with particle size of 116 nm. The

  4. Historical distribution of Sundaland's Dipterocarp rainforests at Quaternary glacial maxima

    E-print Network

    Slik, Ferry

    Historical distribution of Sundaland's Dipterocarp rainforests at Quaternary glacial maxima Niels, 2014 (received for review February 21, 2014) The extent of Dipterocarp rainforests on the emergent the rainforests of Sundaland, and their distributions serve as a proxy for rainforest extent. We used species

  5. Effects of Quaternary Sea Level Cycles on Strontium in Seawater

    Microsoft Academic Search

    Heather M Stoll; Daniel P Schrag

    1998-01-01

    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

  6. Quaternary Glacial Mapping in Western Wisconsin Using Soil Survey Information

    ERIC Educational Resources Information Center

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

    2011-01-01

    The majority of soils in the western Wisconsin have developed from glacial sediments deposited during the Quaternary Period (2.6 million years before present). In many regions, multiple advances and retreats have left a complex landscape of diverse glacial sediments and landforms. The soils that have developed on these deposits reflect the nature…

  7. LATE QUATERNARY GLACIATION OF THE ERCIYES VOLCANO, CENTRAL TURKEY

    E-print Network

    Zreda, Marek

    LATE QUATERNARY GLACIATION OF THE ERCIYES VOLCANO, CENTRAL TURKEY SARIKAYA, M. Akif1, ÇINER, Attila, Turkey, aciner@hun.edu.tr, (2) Hydrology and Water Resources, Univ of Arizona, Tucson, AZ 85721 Mount Erciyes (3917 m), highest stratovolcano of Central Turkey, is located in the northeastern part

  8. Hydroclimatic interpretation of Quaternary shorelines on South Australian playas

    Microsoft Academic Search

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

    1998-01-01

    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

  9. Application of quaternary phase diagrams to compound semiconductor processing

    SciTech Connect

    Sinclair, R.

    1994-10-01

    Isobaric, isothermal phase diagrams are a molar representation of condensed phases in equilibrium with each other at a fixed temperature, pressure, and composition. Since three or four elements are usually involved at a fabricated interface in a semiconductor device, knowledge of the appropriate ternary or quaternary phase diagram is important for optimizing the processing parameters and designing long term stability of devices. While the use of phase diagrams is well-established in the fields of metallurgy, ceramics and mineralogy, only recently have phase diagrams been employed to provide a framework for understanding thin film reactions on a substrate, encountered in semiconductor processing. Even though there are many examples of applications of ternary phase diagrams in the semiconductor literature (for instance, metallization of GaAs, the use of refractory metal silicides for metallization layers in VLSI devices and oxidation of III-V compounds), the same is not true for quaternary phase diagrams. To date, the only application is oxidation of mercury cadmium telluride. This lack of examples is not warranted, as four elements are often involved at a critical interface in compound semiconductor processing and devices. This paper reports on the progress made to remedy this situation by considering the application of quaternary phase diagrams to understanding and predicting the behavior of II-VI thin film interfaces in photovoltaic devices under annealing conditions. Moreover, for the first time, solid solubility is taken into account for quaternary phase diagrams of semiconductor systems.

  10. Modeling of Ion-Pairing Extraction with Quaternary Amines

    Microsoft Academic Search

    I. M. Coelhoso; J. P. S. G. Crespo; M. J. T. Carrondo

    1996-01-01

    The objective of this work is to present a general methodology and to describe the modeling of ion-pairing extraction of organic acids, including amino acids, with quaternary amines, allowing for the prediction of equilibrium concentrations with different operating conditions. The model takes into account the hydration of the organic phase, thus making it also valid for any organic phase used.

  11. Solvent Extraction of Organomercury Compound with Quaternary Amines

    Microsoft Academic Search

    F. L. Moore

    1975-01-01

    Methylmercuric chloride and phenylmercuric acetate extract very efficiently with quaternary amines dissolved in diethylbenzene or other simple solvents. The extraction is effective from either alkaline or acidic solution. The technique considerably extends the scope of conventional solvent extraction practice to permit the extraction and concentration of total mercury in environmental and biological matrices.

  12. Reaction of 2-arylazobenzimidazolium quaternary salts with amines

    Microsoft Academic Search

    R. A. Sogomonova; A. M. Simonov; L. N. Divaeva; S. N. Kolodyazhnaya

    1982-01-01

    Different behaviors of aromatic and nonaromatic amines with respect to a change in the structure of the salt and variations in the reaction conditions were revealed in a study of the reaction of 2-arylazobenzimidazolium quaternary salts with amines. Aliphatic and secondary cyclic amines react at comparable rates via pathways involving cleavage of the azo group and replacement of the hydrogen

  13. Quaternary Ammonium Polysaccharides for Gene Delivery Ira Yudovin-Farber,

    E-print Network

    Linial, Michal

    Quaternary Ammonium Polysaccharides for Gene Delivery Ira Yudovin-Farber, Chava Yanay, Tony Azzam by conjugation of various monoquaternary (MQ) ammonium oligoamines to oxidized dextran by reductive amination that contain primary, secondary, or tertiary amines (11). Under physiological conditions, polyamines become

  14. AREAL DISTRIBUTION OF THE VARIOUS COMBINATIONS OF QUATERNARY CLIMATES

    Microsoft Academic Search

    Stuart A. HARRIS

    Palseoclimates hâve recently been recognized as a major influence in controlling the type of Iandscape, soil and végétation found in diverse areas of the world. Their methods of récognition hâve been discussed and their effects are well known. Most of thèse phenomena hâve been produced in Tertiary and Quaternary times. In this paper, the apparent extent of various simple com-

  15. LARGE-SCALE QUATERNARY DETACHMENTS IN VENTURA BASIN, SOUTHERN CALIFORNIA

    Microsoft Academic Search

    Robert S. Yeats

    1983-01-01

    The Ventura basin is an east-north- east trending trough in the California Transverse Ranges which records major Quaternary detachment faulting at three levels. The earliest thrusting occurred along weak siltstone interbeds in a sequence dominated by competent basin-plain tur- bidite sandstone. Because sedimentation contin- ued during thrusting, the age, rate, and direc- tion of thrusting can be worked out. Faulting

  16. Application of Analytic Geometry to Ternary and Quaternary Diagrams.

    ERIC Educational Resources Information Center

    MacCarthy, Patrick

    1986-01-01

    Advantages of representing ternary and quaternary composition diagrams by means of rectangular coordinates were pointed out in a previous paper (EJ 288 693). A further advantage of that approach is that analytic geometry, based on rectangular coordinates, is directly applicable as demonstrated by the examples presented. (JN)

  17. ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway

    PubMed Central

    1996-01-01

    AChR-inducing activity (ARIA)/heregulin, a ligand for erbB receptor tyrosine kinases (RTKs), is likely to be one nerve-supplied signal that induces expression of acetylcholine receptor (AChR) genes at the developing neuromuscular junction. Since some RTKs act through Ras and phosphatidylinositol 3-kinase (PI3K), we investigated the role of these pathways in ARIA signaling. Expression of activated Ras or Raf mimicked ARIA-induction of AChR epsilon subunit genes in muscle cells; whereas dominant negative Ras or Raf blocked the effect of ARIA. ARIA rapidly activated erk1 and erk2 and inhibition of both erks also abolished the effect of ARIA. ARIA stimulated association of PI3K with erbB3, expression of an activated PI3K led to ARIA-independent AChR epsilon subunit expression, and inhibition of PI3K abolished the action of ARIA. Thus, synaptic induction of AChR genes requires activation of both Ras/MAPK and PI3K signal transduction pathways. PMID:8707830

  18. Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal ?7 from Muscle ?12??? nAChRs.

    PubMed

    Bourne, Yves; Sulzenbacher, Gerlind; Radi?, Zoran; Aráoz, Rómulo; Reynaud, Morgane; Benoit, Evelyne; Zakarian, Armen; Servent, Denis; Molgó, Jordi; Taylor, Palmer; Marchot, Pascale

    2015-06-01

    Pinnatoxins are macrocyclic imine phycotoxins associated with algal blooms and shellfish toxicity. Functional analysis of pinnatoxin A and pinnatoxin G by binding and voltage-clamp electrophysiology on membrane-embedded neuronal ?7, ?4?2, ?3?2, and muscle-type ?12??? nicotinic acetylcholine receptors (nAChRs) reveals high-affinity binding and potent antagonism for the ?7 and ?12??? subtypes. The toxins also bind to the nAChR surrogate, acetylcholine-binding protein (AChBP), with low Kd values reflecting slow dissociation. Crystal structures of pinnatoxin-AChBP complexes (1.9-2.2 Å resolution) show the multiple anchoring points of the hydrophobic portion, the cyclic imine, and the substituted bis-spiroketal and cyclohexene ring systems of the pinnatoxins that dictate tight binding between the opposing loops C and F at the receptor subunit interface, as observed for the 13-desmethyl-spirolide C and gymnodimine A congeners. Uniquely, however, the bulky bridged EF-ketal ring specific to the pinnatoxins extends radially from the interfacial-binding pocket to interact with the sequence-variable loop F and govern nAChR subtype selectivity and central neurotoxicity. PMID:26004441

  19. Production of Active Chimeric Pediocin AcH in Escherichia coli in the Absence of Processing and Secretion Genes from the Pediococcus pap Operon†

    PubMed Central

    Miller, Kurt W.; Schamber, Robin; Chen, Yanling; Ray, Bibek

    1998-01-01

    Minimum requirements have been determined for synthesis and secretion of the Pediococcus antimicrobial peptide, pediocin AcH, in Escherichia coli. The functional mature domain of pediocin AcH (Lys+1 to Cys+44) is targeted into the E. coli sec machinery and secreted to the periplasm in active form when fused in frame to the COOH terminus of the secretory protein maltose-binding protein (MBP). The PapC-PapD specialized secretion machinery is not required for secretion of the MBP-pediocin AcH chimeric protein, indicating that in Pediococcus, PapC and PapD probably are required for recognition and processing of the leader peptide rather than for translocation of the mature pediocin AcH domain across the cytoplasmic membrane. The chimeric protein displays bactericidal activity, suggesting that the NH2 terminus of pediocin AcH does not span the phospholipid bilayer in the membrane-interactive form of the molecule. However, the conserved Lys+1-Tyr-Tyr-Gly-Asn-Gly-Val+7-sequence at the NH2 terminus is important because deletion of this sequence abolishes activity. The secreted chimeric protein is released into the culture medium when expressed in a periplasmic leaky E. coli host. The MBP fusion-periplasmic leaky expression system should be generally advantageous for production and screening of the activity of bioactive peptides. PMID:9435056

  20. Gibberellin: inhibitor of an inhibitor of...?

    PubMed

    Harberd, N P; King, K E; Carol, P; Cowling, R J; Peng, J; Richards, D E

    1998-12-01

    Gibberellin is an endogenous plant growth regulator. Here, we describe our present understanding of how gibberellin regulates plant growth, using recent results gained from studies of gibberellin-signalling mutants of Arabidopsis. These results show that a signalling pathway represses plant growth and that gibberellin releases this repression. In consequence, the well-known growth-promoting properties of gibberellin are due to its activity as an "inhibitor of an inhibitor" [Brian Pw. Sym Soc. Exp Bio 1957; 11:166-182 (Ref. 1)] of plant growth. PMID:10048300

  1. The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors

    SciTech Connect

    Grandi?, Marjana [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia); Aráoz, Romulo; Molgó, Jordi [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Turk, Tom; Sep?i?, Kristina [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia)] [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia); Benoit, Evelyne [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Frangež, Robert, E-mail: robert.frangez@vf.uni-lj.si [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)

    2012-12-01

    APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve–hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC{sub 50} = 0.74 ?M), without affecting directly-elicited twitch tension up to 2.72 ?M. The compound (0.007–3.40 ?M) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 ?M, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC{sub 50} = 0.36 ?M) without significant change in the resting membrane potential of the muscle fibers up to 3.40 ?M. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (?1{sub 2}?1??) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC{sub 50} = 0.0005 ?M), indicating a higher affinity of the compound for Torpedo (?1{sub 2}?1??) than for the mouse (?1{sub 2}?1??) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction. -- Highlights: ? APS12-2 produces concentration-dependent inhibition of nerve-evoked muscle contraction in vitro. ? APS12-2 blocks MEPPs and EPPs at the neuromuscular junction. APS12-2 blocks ACh-activated current in Xenopus oocytes incorporated with Torpedo nAChRs.

  2. Low toxicity corrosion inhibitors

    SciTech Connect

    Prince, P.; Naraghi, A.R.; Saffer, C.E. [Champion Technologies, Inc., Fresno, TX (United States)

    1996-12-01

    This paper discusses the design and testing of low toxicity corrosion inhibitors. New chemistries have been investigated with respect to corrosion protection and impact on the marine environment. The resulting chemicals, while they are effective corrosion inhibitors, present significant improvements in terms of environmental properties over current products. The discussion includes results of the corrosion inhibition, toxicity, biodegradability and partitioning studies.

  3. Rustling up corrosion inhibitors

    SciTech Connect

    Hairston, D.W.

    1996-03-01

    New corrosion inhibitors have replaced heavy metals in water treatment chemicals and protective coatings due to regulatory actions of the US Environmental Protection Agency. The paper discusses inhibitors for cooling towers, suppressing zinc corrosion, new protective coatings, and novel products for scale, corrosion, and algae inhibition.

  4. Experimental and computational studies on the inhibition of acetylcholinesterase by curcumin and some of its derivatives.

    PubMed

    Tello-Franco, Veronica; Lozada-García, Maria Concepcion; Soriano-García, Manuel

    2013-06-01

    Recent studies have demonstrated several biological activities of curcumin with therapeutic potential against Alzheimer's disease, among them the inhibition of the enzyme acetylcholinesterase (AChE). Aiming at identifying the chemical features relevant for this activity, the inhibition of curcumin and a set of 7 derivatives against AChE of E. electricus was measured. These derivatives presented lower activity than curcumin, allowing for the identification of possible unfavorable enzyme-inhibitor interactions. Our computational approach was to dock the molecules to the active site of AChE, followed by an analysis of hydrogen bonds and close contacts to relevant aromatic amino acid residues. To account for inhibitory activity, we sought to define the common structural features between known acetylcholinesterase inhibitors and the tested derivatives. A pharmacophore model was generated, which consisted of two hydrophobic, one aromatic and one hydrogen bond acceptor features. We conclude that the presence of two aromatic rings and the distance between them, allows curcumin and its derivatives to favorably interact with both the quaternary and peripheral sites of AChE. Hydrogen bonds can be formed with the quaternary and acyl sites, which should further stabilize the complex. The acylation of the hydroxyl groups and the reduction of the conjugated double bonds lowered the inhibitory activity, pointing to the modification of the keto-enol moiety as the best alternative for the design of more potent curcumin derivatives as acetylcholinesterase inhibitors. PMID:23106780

  5. Influence of C16 quaternary amine on surface films and polarization resistance of mild steel in carbon dioxide-saturated 5% sodium chloride

    SciTech Connect

    Malik, H. [UMIST, Manchester (United Kingdom). Corrosion and Protection Centre

    1995-04-01

    Experiments were performed to understand the behavior of a C16 quaternary amine on initially clean and precorroded surfaces in carbon dioxide-saturated brine solutions. Although the inhibitor was slow to work at pH 6.5, results indicated high efficiency could be obtained regardless of precorrosion. On initially clean surfaces, greater polarization resistances were measured at the start of the experiments with increasing inhibitor concentration. Once the surface was covered by visible iron carbonate, the lower concentrations tended to perform better than higher concentrations. This point was confirmed in experiments under conditions of increasing precorrosion. Scanning electron micrographs revealed that coinciding with improved inhibition was a transformation in the surface structure of FeCO{sub 3}, from that of voids and grain boundaries under blank conditions to a fine dispersion-type particulate structure, as a consequence of inhibitor action. To develop this change, local FeCO{sub 3} supersaturation was believed to be required. This was achieved by the alkyl chains of the inhibitor leading to ferrous iron entrapment at the metal-solution interface. The rate of FeCO{sub 3} deposition was thought to have become dependent on the passage of carbonate past the alkyl chains, which in turn was affected by inhibitor concentration, to regions locally saturated in Fe{sup 2+}.

  6. Discovery of Isoxazole Analogs of Sazetidine-A as Selective ?4?2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists for the Treatment of Depression

    PubMed Central

    Liu, Jianhua; Yu, Li-Fang; Eaton, J. Brek; Caldarone, Barbara; Cavino, Katie; Ruiz, Christina; Terry, Matthew; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Lowe, David A.; Brunner, Dani; Lukas, Ronald J.; Kozikowski, Alan P.

    2011-01-01

    Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with ?4?2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the ?4?2 subtype of nAChR over ?3?4-nAChRs are partial agonists at the ?4?2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary ADMET studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450 related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline. PMID:21905669

  7. Determination of imidazoline and amido-amine type corrosion inhibitors in both crude oil and produced brine from oilfield production

    SciTech Connect

    Matherly, R.M.; Jiao, J. [Baker Performance Chemicals, Houston, TX (United States); Blumer, D.J. [ARCO Alaska Inc., Anchorage, AK (United States); Ryman, J.S. [Baker Performance Chemicals, Anchorage, AK (United States)

    1995-12-01

    The classical method for the determination of corrosion inhibitors in oilfield brines is the dye transfer method. Within this method are many variations which the analyst may use to determine the amount of corrosion inhibitor in either water or crude oil. These methods, however, suffer from many interferences which result in both false positive and negatives for corrosion inhibitor content. These methods essentially detect all amines as corrosion inhibitors. Improved high pressure liquid chromatography (HPLC) methods have been developed for the analysis of quaternary salt type corrosion inhibitors in brine waters, however, these methods do not appear to work in crude oil or for other forms of corrosion inhibitors such as the imidazolines, and amido-amines. This paper presents a method for the quantitative analysis of the imidazoline and amido-amine type corrosion inhibitors in both oilfield water and crude oil samples by HPLC. The corrosion inhibitor of interest is first separated from the matrix on a small column, then derivatized to form a product which is both sensitive and selective on a fluorescence detector. Detection limits for imidazolines are around 0.2 mg/L, amides and amines are similar. The advantage of this procedure is it can be used to determine the amount of corrosion inhibitor in both oil and brine water phases as well as on solid surfaces.

  8. Different pharmacology of N-desmethylclozapine at human and rat M2 and M 4 mAChRs in neocortex.

    PubMed

    Gigout, S; Wierschke, S; Dehnicke, C; Deisz, R A

    2015-05-01

    Cholinergic transmission plays a pivotal role in learning, memory and cognition, and disturbances of cholinergic transmission have been implicated in neurological disorders including Alzheimer's disease, epilepsy and schizophrenia. Pharmacological alleviation of these diseases by drugs including N-desmethylclozapine (NDMC), promising in animal models, often fails in patients. We therefore compared the effects of NDMC on glutamatergic and GABAergic transmission in slices from rat and human neocortex. We used carbachol (CCh; an established agonist at metabotropic muscarinic acetylcholine (ACh) receptors (mAChRs)) as a reference. Standard electrophysiological methods including intracellular and field potential recordings were used. In the rat neocortex, NDMC prevented the CCh-induced decrease of GABAA and GABAB receptor-mediated responses but not the CCh-induced increase of the paired-pulse depression. NDMC reduced neither the amplitude of the excitatory postsynaptic potentials (EPSP) nor antagonized the CCh-induced depression of EPSP. In the human neocortex, however, NDMC failed to prevent CCh-induced decrease of the GABAB responses and directly reduced the amplitude of EPSP. These data suggest distinct effects of NDMC in rat and human at M2 and M4 mAChRs underlying presynaptic modulation of GABA and glutamate release, respectively. In particular, NDMC might be a M2 mAChR antagonist in the rat but has no activity at this receptor in human neocortex. However, NDMC has an agonistic effect at M4 mAChR in the human but no such effect in the rat neocortex. The present study confirms that pharmacology at mAChRs can differ between species and emphasizes the need of studies in human tissue. PMID:25592256

  9. Ovariectomy combined with amyloid ? 1-42 impairs memory by decreasing acetylcholine release and ?7nAChR Expression without induction of apoptosis in the hippocampus CA1 neurons of rats

    Microsoft Academic Search

    Katsunori Iwasaki; Izzettin Hatip-Al-Khatib; Nobuaki Egashira; Yuki Akiyoshi; Takashi Arai; Kenichi Mishima; Yuki Takagaki; Keiichiro Inui; Michihiro Fujiwara

    2004-01-01

    In this study, the effect of ovariectomy and amyloid P1-42 (A?1-42)on eight-armed radial maze performance, acetylcholine (ACh) release, ?7nACh receptor (?7nAChR), glyceraldehyde 3-phosphate\\u000a dehydrogenase (GAPDH) expression, and apoptosis of CA1 neurons in the dorsal hippocampus were investigated in rat. The results\\u000a showed that the dorsal hippocampus of sham rats contains 136.7 ± 16.7 to 160.4 ± 21.1 fmol\\/?l ACh, and

  10. Drug binding to the acetylcholine receptor: Nitroxide analogs of phencyclidine and a local anesthetic

    Microsoft Academic Search

    Palma

    1988-01-01

    The interaction of noncompetitive inhibitors (NCIs) with Torpedo californica native nicotinic acetylcholine receptor (nAChR) membranes was examined primarily by the technique of electron paramagnetic resonance (EPR) spectroscopy. The goal of this work being to define some of the physical characteristics for the site(s) of association between an NCI and the nAChR membrane. A nitroxide labeled analog of a quaternary amine

  11. Why renin inhibitors?

    PubMed

    Haber, E

    1989-04-01

    Angiotensin converting enzyme inhibitors are widely used in the treatment of hypertension and congestive heart failure. They are potent drugs and have few side effects. The search for potent and orally absorbable agents that either block the angiotensin II receptor or inhibit the catalytic action of renin has not been so successful. This paper reviews present efforts to develop renin inhibitors. Most of the work has been based on the design of peptide analogues of angiotensinogen, many of which contain the unusual amino acid statine (or one of its variants) in place of the scissile bond (the peptide bond that renin cleaves in angiotensinogen). Substitutions at other sites in the molecule determine potency and species selectivity; for example, substitutions at the carboxyl terminus permit the construction of potent renin inhibitors that contain fewer amino acid residues. Peptide analogues of the prorenin segment of the enzyme, however, are but weak inhibitors and show little promise. Progress has also been slow in efforts to understand the principles required in the synthesis of potent renin inhibitors with significant bioavailability after oral administration. Finally, the question of whether renin inhibitors will offer a clinical advantage over converting enzyme inhibitors has not been answered. PMID:2666619

  12. Aches, pains and headache: an unusual combination of hypothyroidism, vitamin D deficiency, cervical radiculopathy and cortical vein sinus thrombosis.

    PubMed

    Ittyachen, Abraham M; Vijayan, Anuroopa; Kottam, Pratheep; Jose, Appu

    2015-01-01

    A young obese woman was admitted with vague aches and pains, including a headache. At first a provisional diagnosis of depression/myofacial pain syndrome was considered. Later, on evaluation, she was diagnosed to have hypothyroidism and vitamin D deficiency. One week into treatment, her neck pain and headache got worse. Examination of the fundus showed tortuous vessels, papilloedema and intraretinal haemorrhages. MR venogram of the brain was performed, which revealed the presence of thrombosis in the left transverse sinus, left sigmoid sinus and left internal jugular vein. This report is an unusual presentation of neuropsychiatric symptoms in a patient where overlapping diagnoses confound the clinical picture and test the clinical acumen of the physician. A careful history followed by a focused clinical examination and evaluation will help to delineate potential confounders. The report further highlights the importance of clinical medicine even in this era of 'investigative medicine'. PMID:26156835

  13. The effect of seasonal changes on the selection of biocide inhibitors for Arabian Gulf seawater for water injection purposes

    SciTech Connect

    Al-Hashem, A.; Salman, M.; Al-Muhanna, K.; Al-Bazzaz, W. [Kuwait Inst. for Scientific Research, Safat (Kuwait)

    1997-08-01

    This investigation was carried out to determine the most effective biocide inhibitor for Northern Arabian Gulf Seawater. This seawater will be used for water injection purposes for some oil fields in Kuwait. Arabian Gulf Seawater is known to be very saline during the summer months and less saline during the rainy season of spring. The biocide inhibitors were tested in a rig with six side streams biofouling monitoring tubes (SBMT). Bacterial nutrients were added to the system and carbon steel studs were placed along the tubes of the biocide evaluation test rig (BETR). After a month, a thin, slimy, and black deposit was formed on the carbon steel studs. The deposit contained 107 general aerobic bacteria (GAB), 107 general anaerobic bacteria (GAnB) and 105 sulfate reducing bacteria (SRB). The most effective biocide inhibitor was found to be a fatty amine aryl quaternary inhibitor at 50% dosage.

  14. On the behavior of acetylcholinesterase immobilized on carbon nanotubes in the presence of inhibitors.

    PubMed

    Cabral, Murilo F; Sgobbi, Lívia F; Kataoka, Erica M; Machado, Sergio A S

    2013-11-01

    The behavior of acetylcholinesterase before and after click-chemistry reaction on carbon nanotubes was evaluated by kinetic parameters from Michaelis-Menten equation. These data were obtained by means of UV-vis absorption for the enzyme in solution and attached to MWCNTs under two experimental conditions involving the presence or absence of enzyme inhibitors (chlorpyrifos and paraoxon pesticides). After the immobilization step it was possible to obtain, from Michaelis-Menten equation, Km values comparable to those for free enzyme, suggesting that the immobilization procedure does not affect the enzyme-substrate interaction. On the other hand, the Vmax value decreased about 45-fold, pointing out that enzyme activity is slowed by immobilization on MWCNTs. We were able to demonstrate that this is caused by competition between the MWCNTs and acetylthiocholine for the active sites of AChE. In the presence of inhibitors some change was observed in terms of mechanistic aspects. These results are important to improve understanding of the potential of enzyme-carbon nanotube complexes to expand the biological, medical, and environmental applications of CNT materials. PMID:23777789

  15. Chemistry of corrosion inhibitors

    Microsoft Academic Search

    James M. Gaidis

    2004-01-01

    In the last quarter century, it has become feasible to extend the life of reinforced concrete structures by inhibiting chloride-induced corrosion of steel. Chemical interactions can occur between the concrete system and the inhibitor-steel-chloride system. The chemical reactions of the corrosion process in concrete and of the most commonly used inhibitors are discussed, with special attention to test procedures and

  16. Multifunctional organic corrosion inhibitor

    Microsoft Academic Search

    Charles K. Nmai

    2004-01-01

    In this paper, the multi-functional benefits of the water-based organic corrosion inhibitor are presented and discussed, with regard to the corrosion protection of embedded steel and resistance to chemical attack; specifically, the resistance of concrete to sulfate attack and deterioration due to sulfuric acid exposure. The organic corrosion inhibitor consists of amines and fatty-acid esters and the mechanisms by which

  17. Luminescence dating of quaternary deposits in geology in Brazil.

    PubMed

    Tatumi, Sonia Hatsue; Gozzi, Giuliano; Yee, Márcio; de Oliveira, Victor Inácio; Sallun, Alethéa Ernandes Martins; Suguio, Kenitiro

    2006-01-01

    In the present work, systematic dating by luminescence methods has been done on 50 Quaternary geological samples within the study area of São Paulo State, Brazil. Bleaching experiments showed that residual TL intensity of 375 degrees C peak, of the quartz, was obtained after 10 h of sunlight exposition. Intensities decays of the 325 and 375 degrees C TL peaks can be fitted using second order exponential equation. Paleodose values were evaluated using regeneration methods with multiple aliquots. Samples dated indicate preliminary ages varying from 9 +/- 1 to 935 +/- 130 ka for colluvio-elluvial deposits, and from 17 +/- 2 to 215 +/- 30 ka for alluvial deposits of the study area. They cover four peneplained surfaces shaped during the Quaternary: I (1000-400 ka), II (400-120 ka), III (120-10 ka) and IV (10 ka until today), in decreasing order. PMID:16782979

  18. 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.

  19. Community ecology in a changing environment: Perspectives from the Quaternary

    PubMed Central

    Jackson, Stephen T.; Blois, Jessica L.

    2015-01-01

    Community ecology and paleoecology are both concerned with the composition and structure of biotic assemblages but are largely disconnected. Community ecology focuses on existing species assemblages and recently has begun to integrate history (phylogeny and continental or intercontinental dispersal) to constrain community processes. This division has left a “missing middle”: Ecological and environmental processes occurring on timescales from decades to millennia are not yet fully incorporated into community ecology. Quaternary paleoecology has a wealth of data documenting ecological dynamics at these timescales, and both fields can benefit from greater interaction and articulation. We discuss ecological insights revealed by Quaternary terrestrial records, suggest foundations for bridging between the disciplines, and identify topics where the disciplines can engage to mutual benefit. PMID:25901314

  20. Community ecology in a changing environment: Perspectives from the Quaternary.

    PubMed

    Jackson, Stephen T; Blois, Jessica L

    2015-04-21

    Community ecology and paleoecology are both concerned with the composition and structure of biotic assemblages but are largely disconnected. Community ecology focuses on existing species assemblages and recently has begun to integrate history (phylogeny and continental or intercontinental dispersal) to constrain community processes. This division has left a "missing middle": Ecological and environmental processes occurring on timescales from decades to millennia are not yet fully incorporated into community ecology. Quaternary paleoecology has a wealth of data documenting ecological dynamics at these timescales, and both fields can benefit from greater interaction and articulation. We discuss ecological insights revealed by Quaternary terrestrial records, suggest foundations for bridging between the disciplines, and identify topics where the disciplines can engage to mutual benefit. PMID:25901314

  1. Helix Bundle Quaternary Structure from [alpha]/[beta]-Peptide Foldamers

    SciTech Connect

    Horne, W. Seth; Price, Joshua L.; Keck, James L.; Gellman, Samuel H. (UW-MED)

    2008-11-18

    The function of a protein generally depends on adoption of a specific folding pattern, which in turn is determined by the side chain sequence along the polypeptide backbone. Here we show that the sequence-encoded structural information in peptides derived from yeast transcriptional activator GCN4 can be used to prepare hybrid {alpha}/{beta}-peptide foldamers that adopt helix bundle quaternary structures. Crystal structures of two hybrid {alpha}/{beta}-peptides are reported along with detailed structural comparison to {alpha}-peptides of analogous side chain sequence. There is considerable homology between {alpha}- and {alpha}/{beta}-peptides at the level of helical secondary structure, with modest but significant differences in the association geometry of helices in the quaternary structure.

  2. ?-CD assisted dissolution of quaternary ammonium permanganates in aqueous medium.

    PubMed

    Bank, Suraj Prakash; Guru, Partha Sarathi; Dash, Sukalyan

    2014-10-13

    The non-polar internal cavity of ?-cyclodextrin (?-CD) has been exploited for the entrapment of the hydrophobic tails of two water insoluble quaternary ammonium permanganates (QAPs): cetyltrimethylammonium permanganate (CTAP) and tetrabutylammonium permanganate (TBAP), for solubilization in aqueous medium. The solubilization and organizational behavior of the QAPs in aqueous ?-CD solution have been determined from the comparison of their rates of self-oxidation in presence and in absence of ?-CD. Effect of QAP concentration on their observed rate constants (k(obs)) at a fixed ?-CD concentration, phase solubility analysis in varying ?-CD concentration, impact of quaternary ammonium bromides (QABs) on the kobs values of CTAP and TBAP at fixed QAP and ?-CD concentrations, and the temperature effect have been reported. A scheme to explain the solvation of QAPs in aqueous ?-CD has been proposed based on dynamic light scattering (DLS) analysis of the samples. PMID:25037419

  3. A new spin gapless semiconductors family: Quaternary Heusler compounds

    NASA Astrophysics Data System (ADS)

    Xu, G. Z.; Liu, E. K.; Du, Y.; Li, G. J.; Liu, G. D.; Wang, W. H.; Wu, G. H.

    2013-04-01

    By using first-principles calculations, we investigate the band structures of a series of quaternary LiMgPdSn-type Heusler compounds. Our calculation results show that five compounds, CoFeMnSi, CoFeCrAl, CoMnCrSi, CoFeVSi and FeMnCrSb, possess unique electronic structures characterized by a half-metallic gap in one spin direction while they have a zero-width gap in the other spin direction showing a spin gapless semiconducting behavior. We further analyse the electronic and magnetic properties of all quaternary Heusler alloys involved, and reveal a semi-empirical general rule (the total valence electrons number should be 26 or 28) for indentifying spin gapless semiconductors in Heusler compounds. The influences of lattice distortion and main-group element change have also been discussed.

  4. Humidity sensor using epoxy resin containing quaternary ammonium salts

    Microsoft Academic Search

    Chil-Won Lee; Hee-Woo Rhee; Myoung-Seon Gong

    2001-01-01

    Humidity-sensitive epoxy monomer, glycidyl trimethyl ammonium chloride (GTMAC) was selected as the humidity-sensing resin. Polypropylene glycol diglycidyl ether (PPGDGE) and methyl tetrahydrophthalic anhydride (MTPHA) were used as a comonomer and a curing agent, respectively. The humidity-sensitive membranes were composed of GTMAC, PPGDGE and MTPHA. When impedance characteristics of the epoxy resins containing quaternary ammonium salts were measured, the impedance decreased

  5. Antibacterial activity of quaternary ammonium salt grafted cotton

    Microsoft Academic Search

    N. Ladhari; M. H. V. Baouab; Abdelbasset Ben Dekhil; Amina Bakhrouf; P. Niquette

    2007-01-01

    Cotton having good antibacterial activity can be obtained without the need for a binding chemical as a cross linker or the need for chemically pre-treated antibacterial agent. The procedure of synthesis consists in grafting an alkali-cellulose fibre by a quaternary ammonium salt: Epoxy propyltrimethylammonium chloride (EPTMAC). The characterization of grafted cotton (EPTMAC-Cotton) has been targeted on the nitrogen and the

  6. Quaternary fluvial archives: achievements of the Fluvial Archives Group

    NASA Astrophysics Data System (ADS)

    Bridgland, David; Cordier, Stephane; Herget, Juergen; Mather, Ann; Vandenberghe, Jef; Maddy, Darrel

    2013-04-01

    In their geomorphological and sedimentary records, rivers provide valuable archives of environments and environmental change, at local to global scales. In particular, fluvial sediments represent databanks of palaeoenvironment and palaeoclimatic (for example) of fossils (micro- and macro-), sedimentary and post-depositional features and buried soils. Well-dated sequences are of the most value, with dating provided by a wide range of methods, from radiometric (numerical) techniques to included fossils (biostratigraphy) and/or archaeological material. Thus Quaternary fluvial archives can also provide important data for studies of Quaternary biotic evolution and early human occupation. In addition, the physical disposition of fluvial sequences, be it as fragmented terrace remnants or as stacked basin-fills, provides valuable information about geomorphological and crustal evolution. Since rivers are long-term persistent features in the landscape, their sedimentary archives can represent important frameworks for regional Quaternary stratigraphy. Fluvial archives are distributed globally, being represented on all continents and across all climatic zones, with the exception of the frozen polar regions and the driest deserts. In 1999 the Fluvial Archives Group (FLAG) was established, as a working group of the Quaternary Research Association (UK), aimed at bringing together those interested in such archives. This has evolved into an informal organization that has held regular biennial combined conference and field-trip meetings, has co-sponsored other meetings and conference sessions, and has presided over two International Geoscience Programme (IGCP) projects: IGCP 449 (2000-2004) 'Global Correlation of Late Cenozoic Fluvial Deposits' and IGCP 518 (2005-2007) 'Fluvial sequences as evidence for landscape and climatic evolution in the Late Cenozoic'. Through these various activities a sequence of FLAG publications has appeared, including special issues in a variety of journals, amassing a substantial volume of information on fluvial archives worldwide. This presentation will highlight some of these data and will describe important patterns observed and interpretations arising therefrom.

  7. Quaternary TL Surveys: A Guide to Thermoluminescence (TL) Date Measurement

    NSDL National Science Digital Library

    Quaternary TL Surveys, a company that provides date measurement services to archaeologists and geologists, offers this comprehensive tutorial on archaeometric dating techniques. The tutorial contains a general overview as well as specific information on dating flint and stone, stalagmitic calcite, sediments, and methods of interpreting and using TL dates. For ease of use, portions of the guide are marked to alert users to their relative importance.

  8. Vegetation ecotone dynamics in Southwest Alaska during the Late Quaternary

    Microsoft Academic Search

    Linda B. Brubaker; Patricia M. Anderson; Feng Sheng Hu

    2001-01-01

    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

  9. Low Sensitivity of Listeria monocytogenes to Quaternary Ammonium Compounds

    Microsoft Academic Search

    L. Mereghetti; R. Quentin; N. Marquet-Van Der Mee; A. Audurier

    2000-01-01

    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

  10. Precise timing and rate of massive late Quaternary soil denudation

    Microsoft Academic Search

    M. Jennifer Cooke; Libby A. Stern; Jay L. Banner; Lawrence E. Mack; Thomas W. Stafford; Rickard S. Toomey

    2003-01-01

    Strontium isotopes are a unique tool to study soil-erosion dynamics. Changes in Sr isotope ratios (87Sr\\/86Sr) provide a record of late Quaternary landscape denudation of the Edwards Plateau of central Texas, United States. The use of Sr isotopes as a tracer for soil erosion is based on the observation that, in central Texas, the 87Sr\\/86Sr ratio of soil correlates with

  11. Primary biodegradation of amine oxide and quaternary ammonium amphiphiles.

    PubMed

    Cupková, V; Sirotková, L; Mlynarcík, D; Devínsky, F; Lacko, I; Kovacková, Z

    1993-01-01

    Biodegradation of two amphiphilic "soft" antimicrobially active derivatives of lauric (dodecanoic) acid, a quaternary ammonium salt and an amine oxide bearing an amide or ester group, was followed using microorganisms from activated sludge. Primary biodegradation was determined by ion-selective electrodes, total biodegradation as the chemical oxygen demand. Though organic ammonium salts quickly undergo primary biodegradation, the rest of the molecule is difficult to destroy. In contrast, amine oxides are easily biodegradable. PMID:8500780

  12. Composite aromatic boxes for enzymatic transformations of quaternary ammonium substrates.

    PubMed

    Nagy, Gergely N; Marton, Lívia; Contet, Alicia; Ozohanics, Olivér; Ardelean, Laura-Mihaela; Révész, Agnes; Vékey, Károly; Irimie, Florin Dan; Vial, Henri; Cerdan, Rachel; Vértessy, Beáta G

    2014-12-01

    Cation-? interactions to cognate ligands in enzymes have key roles in ligand binding and enzymatic catalysis. We have deciphered the key functional role of both charged and aromatic residues within the choline binding subsite of CTP:phosphocholine cytidylyltransferase and choline kinase from Plasmodium falciparum. Comparison of quaternary ammonium binding site structures revealed a general composite aromatic box pattern of enzyme recognition sites, well distinguished from the aromatic box recognition site of receptors. PMID:25283789

  13. Analytical 13 C NMR spectroscopy of fatty quaternary amines

    Microsoft Academic Search

    E. H. Fairchild

    1982-01-01

    Natural abundance13C nuclear magnetic resonance spectroscopy (CMR) has been used for the rapid, nondestructive analysis of fatty quaternary ammonium\\u000a compounds. Quantitative analysis of mixtures of mono-, di-and tri-fatty ammonium chlorides can be accommpublished under conditions\\u000a that do not involve heat or extremes of pH and that are independent of solvent present. In order to determine optimal conditions\\u000a for quantitative studies,

  14. Activity of an insoluble antimicrobial quaternary amine complex in plastics

    Microsoft Academic Search

    D. L. Price; A. D. Sawant; D. G. Ahearn

    1991-01-01

    Summary Growth and survival ofStaphylococcus aureus, Pseudomonas aeruginosa., Klebsiella pneumoniae andAspergillus niger were reduced by a low-solubility polysubstituted.-quaternary amine complex (InterseptR) processed into the matrices of ethylene vinyl acetate, polystyrene and polyethylene., Recoveries of challenge microorganisms from agar film overlays and determination of the effects of the complex on radiolabelled-leucine transport by adhered cells and bacterial biofilms were more suitable

  15. Large-scale quaternary detachments in Ventura basin, southern California

    Microsoft Academic Search

    Robert S. Yeats

    1983-01-01

    The Ventura basin is an east-north-east trending trough in the California Transverse Ranges which records major Quaternary detachment faulting at three levels. The earliest thrusting occurred along weak siltstone interbeds in a sequence dominated by competent basin-plain turbidite sandstone. Because sedimentation continued during thrusting, the age, rate, and direction of thrusting can be worked out. Faulting began 1.3 m.y. ago

  16. NMR enantiodifferentiation of quaternary ammonium salts of Tröger base.

    PubMed

    Michon, Christophe; Gonçalves-Farbos, Maria-Héléna; Lacour, Jérôme

    2009-10-01

    Hexacoordinated phosphorus BINPHAT anion 1 is an efficient NMR chiral solvating agent for quaternary ammonium cations (quats) derived from Tröger base leading to large separations of the proton signals of the enantiomers and even in polar solvent media such as CD(3)CN (Delta Delta delta up to 0.12 ppm). Quite surprisingly, this efficacy in the NMR split efficiency is not translated into a supramolecular stereocontrol (Pfeiffer effect) of the cation configuration by the anion. PMID:19161219

  17. Efficient formation of benzylic quaternary centers via palladium catalysis.

    PubMed

    Gottumukkala, Aditya L; Suljagic, Jasmin; Matcha, Kiran; de Vries, Johannes G; Minnaard, Adriaan J

    2013-09-01

    Four's a crowd: An efficient protocol for the formation of benzylic quaternary centers via arylation of enones using a catalyst made from Pd(O2 CCF3 )2 and 2,2'-bipyridine is developed. For cyclic substrates, catalyst loadings as low as 1 mol % Pd are enough to afford excellent yields (>90%) using a variety of arylboronic acids. In case of acyclic substrates, the addition of KSbF6 was found to improve conversions and yields. PMID:23821532

  18. Analysis of Human Dopamine D3 Receptor Quaternary Structure*

    PubMed Central

    Marsango, Sara; Caltabiano, Gianluigi; Pou, Chantevy; Varela Liste, María José; Milligan, Graeme

    2015-01-01

    The dopamine D3 receptor is a class A, rhodopsin-like G protein-coupled receptor that can form dimers and/or higher order oligomers. However, the molecular basis for production of these complexes is not well defined. Using combinations of molecular modeling, site-directed mutagenesis, and homogenous time-resolved FRET, the interfaces that allow dopamine D3 receptor monomers to interact were defined and used to describe likely quaternary arrangements of the receptor. These were then compared with published crystal structures of dimeric ?1-adrenoreceptor, ?-opioid, and CXCR4 receptors. The data indicate important contributions of residues from within each of transmembrane domains I, II, IV, V, VI, and VII as well as the intracellular helix VIII in the formation of D3-D3 receptor interfaces within homo-oligomers and are consistent with the D3 receptor adopting a ?1-adrenoreceptor-like quaternary arrangement. Specifically, results suggest that D3 protomers can interact with each other via at least two distinct interfaces: the first one comprising residues from transmembrane domains I and II along with those from helix VIII and a second one involving transmembrane domains IV and V. Moreover, rather than existing only as distinct dimeric species, the results are consistent with the D3 receptor also assuming a quaternary structure in which two transmembrane domain I-II-helix VIII dimers interact to form a ”rhombic” tetramer via an interface involving residues from transmembrane domains VI and VII. In addition, the results also provide insights into the potential contribution of molecules of cholesterol to the overall organization and potential stability of the D3 receptor and possibly other GPCR quaternary structures. PMID:25931118

  19. Protein flexibility facilitates quaternary structure assembly and evolution.

    PubMed

    Marsh, Joseph A; Teichmann, Sarah A

    2014-05-01

    The intrinsic flexibility of proteins allows them to undergo large conformational fluctuations in solution or upon interaction with other molecules. Proteins also commonly assemble into complexes with diverse quaternary structure arrangements. Here we investigate how the flexibility of individual protein chains influences the assembly and evolution of protein complexes. We find that flexibility appears to be particularly conducive to the formation of heterologous (i.e., asymmetric) intersubunit interfaces. This leads to a strong association between subunit flexibility and homomeric complexes with cyclic and asymmetric quaternary structure topologies. Similarly, we also observe that the more nonhomologous subunits that assemble together within a complex, the more flexible those subunits tend to be. Importantly, these findings suggest that subunit flexibility should be closely related to the evolutionary history of a complex. We confirm this by showing that evolutionarily more recent subunits are generally more flexible than evolutionarily older subunits. Finally, we investigate the very different explorations of quaternary structure space that have occurred in different evolutionary lineages. In particular, the increased flexibility of eukaryotic proteins appears to enable the assembly of heteromeric complexes with more unique components. PMID:24866000

  20. NOTES ON THREE NEW IMMIGRANT SPECIES OF SPILANTHES JACQ. (ASTERACEAE) IN INDIA AND THE IDENTITY OF THE COMMON ‘TOOTH – ACHE PLANT’

    PubMed Central

    Sivarajan, V. V.; Mathew, Philip

    1984-01-01

    Three new immigrant species of Spilanthes Jacq. (Asteraceae) is described for the first time from India. Their current nomenclature and an artificial key for the identification of the 5 Indian species are provided. The identity of the commonly used ‘tooth-ache’ plant is also discussed. PMID:22557401

  1. Sharing the Vision, Leading the Way: Continuing Educators in the New Millennium. ACHE Proceedings (62nd, Myrtle Beach, South Carolina, October 14-17, 2000).

    ERIC Educational Resources Information Center

    Barrineau, Irene T., Ed.

    This document presents the proceedings of the 2000 annual meeting of the Association for Continuing Higher Education (ACHE). Part 1 contains the text of the presidential address, "Building Solid Communities within Higher Education" (Nancy Thomason), as well as summaries of the following addresses: "Riding the Rapids of Change: Survival Tactics for…

  2. Effects of acetylcholine (ACh) and norepinephrine (NE) on phosphatidylinositol 4,5-bisphosphate (PIP/sub 2/) turnover in rabbit cornea

    SciTech Connect

    Akhtar, R.A.; Abdel-Latif, A.A.

    1986-05-01

    Muscarinic cholinergic and ..cap alpha../sub 1/-adrenergic agonists provoke hydrolysis of PIP/sub 2/ into diacylglycerol (DG) and inositol trisphosphate (IP/sub 3/) in a wide variety of tissue. Recently, IP/sub 3/ has been shown to mobilize Ca/sup 2 +/ from ER in several permeabilized tissue preparations. Although rabbit cornea is enriched in ACh and NE, the physiological function of these neurotransmitters is unclear. The present studies were initiated to determine the effects of cholinergic and adrenergic agonists on PIP/sub 2/ turnover in the cornea. Addition of ACh or NE (50 ..mu..M each) to the /sup 32/P-labeled corneas for 10 min decreased the radioactivity in PIP/sub 2/ by 33 and 36%, and increased the radioactivity in phosphatidic acid by 72 and 52%, respectively. When the corneas were labeled with myo-(/sup 3/H)inositol, ACh and NE increased the accumulation of IP/sub 3/ by 92 and 48%, respectively. The effects of ACh and NE on phospholipid labeling and IP/sub 3/ accumulation were specifically inhibited by atropine (10 ..mu..M) and prazosin (10 ..mu..M), respectively. The data suggest the presence of muscarinic cholinergic and ..cap alpha../sub 1/-adrenergic receptors in the rabbit cornea. Furthermore, activation of these receptors leads to cleavage of PIP/sub 2/ into DG and IP/sub 3/ which may function as second messengers in this tissue.

  3. Population diversity and distinct haplotype frequencies associated with ACHE and BCHE genes of Israeli Jews from trans-caucasian Georgia and from Europe

    SciTech Connect

    Ehrlich, G.; Ginzberg, D.; Loewenstein, Y. [Hebrew Univ., Jerusalem (Israel)] [and others] [Hebrew Univ., Jerusalem (Israel); and others

    1994-07-15

    Variant alleles of the butyrylcholinesterase gene, BCHE, have often been used to trace the genetic histories of populations. The D70G substitution in BCHE causes prolonged postanesthesia apnea ({open_quotes}atypical{close_quotes} phenotype); H322N substitution in the closely related acetylcholinesterase gene, ACHE, is the basis of the mutually incompatible YT blood groups. In both genes, additional point mutations were reported to be linked to these phenotypically evident ones. To examine whether the intragenic linkage reported for the ACHE and BCHE mutations in Americans is universal, the authors studied frequencies of these mutations in trans-Caucasian Georgian Jews, a population that has remained relatively isolated for 1500 years. To this end they employed PCR amplification followed by DNA sequencing and enzymatic restriction and compared the frequencies found to corresponding reported phenotype data. Georgian Jews` N322 ACHE was a rather low 7.0% and was totally linked to a P446 mutation, in agreement with a recent report. In BCHE, however, G70 was a relatively high 5.8%, and the V497 and T539 mutations were not found, either in Georgian or in Ashkenazi Jews, in contrast to reported findings in Americans. The findings reveal distinct displays of ACHE and BCHE haplotypes in Georgian Jews and suggest different founder effects, genetic drifts, and/or selection pressures in the evolution of each of these genes. 29 refs., 3 figs., 2 tabs.

  4. A.S. Tijsseling A.C.H. Kruisbrink A. Pereira da Silva Dept. of Civii Engineering industriai Techn. Division Dept. of Civil Engineering

    E-print Network

    Tijsseling, A.S.

    A.S. Tijsseling A.C.H. Kruisbrink A. Pereira da Silva Dept. of Civii Engineering industriai Techn Dundee DDl 4HN P.O.Box 177, 2600 MH Delft 1096 Lisbon United Kingdom The Netherlands Portugal a of waterhammer measurementsin asteelpipeline fitted with aninternal air-filled tube of rectangular cross

  5. Comparisons of G and its Stability The combination of some data and an aching desire for an answer does not ensure

    E-print Network

    Walsh, Bruce

    36 Comparisons of G and its Stability The combination of some data and an aching desire (1986) Version 26 June 2014 As shown in the previous chapter, theory offers some hints that parts of G (its orientation) may be somewhat stable over modest amounts of time, but also suggests the G can dra

  6. Comparisons of G and its Stability The combination of some data and an aching desire for an answer does not ensure

    E-print Network

    Walsh, Bruce

    32 Comparisons of G and its Stability The combination of some data and an aching desire of G (its orientation) may be somewhat stable over modest amounts of time, but also suggests the G can dra- matically change over short periods of time. Hence, the stability of G remains foremost

  7. Database and Map of Quaternary Faults and Folds in Peru and its Offshore Region

    USGS Publications Warehouse

    Machare, Jose; Fenton, Clark H.; Machette, Michael N.; Lavenu, Alain; Costa, Carlos; Dart, Richard L.

    2003-01-01

    This publication consists of a main map of Quaternary faults and fiolds of Peru, a table of Quaternary fault data, a region inset map showing relative plate motion, and a second inset map of an enlarged area of interest in southern Peru. These maps and data compilation show evidence for activity of Quaternary faults and folds in Peru and its offshore regions of the Pacific Ocean. The maps show the locations, ages, and activity rates of major earthquake-related features such as faults and fault-related folds. These data are accompanied by text databases that describe these features and document current information on their activity in the Quaternary.

  8. Quaternary ammonium salts and lubricating oil containing said salts as dispersants

    SciTech Connect

    Chafetz, H.; Lee, G. D.

    1981-02-03

    Quaternary ammonium salts prepared by reacting an alkenylsuccinimide with a monocarboxylic acid ester provide improved dispersancy in lubricating oils, as compared with the starting alkenylsuccinimides.

  9. Effect of a nicotine vaccine on nicotine binding to the beta2-nAChRs in vivo in human tobacco smokers

    PubMed Central

    Esterlis, Irina; Hannestad, Jonas O.; Perkins, Evgenia; Bois, Frederic; D’Souza, D. Cyril; Tyndale, Rachel F.; Seibyl, John P.; Hatsukami, Dorothy M.; Cosgrove, Kelly P.; O’Malley, Stephanie S.

    2013-01-01

    Objective Nicotine acts in the brain to promote smoking in part by binding to the beta2-containing nicotinic acetylcholine receptors (?2*-nAChRs) and acting in the mesolimbic reward pathway. The effects of nicotine from smoking one tobacco cigarette are significant (80% of ?2*-nAChRs occupied for >6h). This likely contributes to the maintenance of smoking dependence and low cessation outcomes. Development of nicotine vaccines provides potential for alternative treatments. We used [123I]5IA-85380 SPECT to evaluate the effect of 3?-AmNic-rEPA on the amount of nicotine that binds to the ?2*-nAChRs in the cortical and subcortical regions in smokers. Method Eleven smokers (36years (SD=13); 19cig/day (SD=11) for 10years (SD=7) who were dependent on nicotine (Fagerström Test of Nicotine Dependence score =5.5 (SD=3); plasma nicotine 9.1 ng/mL (SD=5)) participated in 2 SPECT scan days: before and after immunization with 4–400?g doses of 3?-AmNic-rEPA. On SPECT scan days, 3 30-min baseline emission scans were obtained, followed by administration of IV nicotine (1.5mg/70kg) and up to 9 30-min emission scans. Results ?2*-nAChR availability was quantified as VT/fP and nicotine binding was derived using the Lassen plot approach. Immunization led to a 12.5% reduction in nicotine binding (F=5.19, df=1,10, p=0.05). Significant positive correlations were observed between nicotine bound to ?2*-nAChRs and nicotine injected before but not after vaccination (p=0.05 vs. p=0.98). There was a significant reduction in the daily number of cigarettes and desire for a cigarette (p=.01 and p=.04, respectively). Conclusions This proof-of-concept study demonstrates that immunization with nicotine vaccine can reduce the amount of nicotine binding to ?2*-nAChRs and disrupt the relationship between nicotine administered vs. nicotine available to occupy ?2*-nAChRs. PMID:23429725

  10. Polycationic antimicrobial dendrimers: a comparison of alkyl pyridinium,quaternary ammonium, quaternary phosphonium and tertiary sulfonium salts

    NASA Astrophysics Data System (ADS)

    Chen, Chris; Cooper, Stuart

    2000-03-01

    Polycationic biocides usually kill bacteria through the interactions of the positively charged head groups with negatively charged bacteria and the interactions of the hydrophobic segments with phospholipid cell membranes, which implies that high local charge densities and a large number of hydrophobic groups would lead to enhanced biocidal potency. The advent of dendrimers offers us the first-ever opportunity to achieve the desired high local density. We have demonstrated that dimethyl dodecyl ammonium chloride functionalized polypropylene imine dendrimers are over 100 times more potent than their small molecule ounterparts. In this study, quaternary ammonium, quaternary phosphonium, alkyl pyridinium and tertiary sulfonium salts based on polypropylene imine dendrimers have been synthesized and characterized. Their antimicrobial properties have been quantified with a novel bioluminescence method. The structure-activity relationship of these polycationic dendrimers has also been investigated to elucidate the molecular mechanism for the enhanced antimicrobial effects.

  11. Quaternary extension in southern Tibet: Field observations and tectonic implications

    NASA Astrophysics Data System (ADS)

    Armijo, Rolando; Tapponnier, Paul; Mercier, J. L.; Han, Tong-Lin

    1986-12-01

    We summarize evidence for Quaternary and active faulting collected in the field during three Sino-French expeditions to southeastern Tibet (1980-1982). Detailed mapping of Quaternary and active faults as well as microtectonic measurements indicate that normal faulting has been the dominant tectonic regime north of the Himalayas in the last 2 ± 0.5 m.y. The maximum horizontal principal stress in south Tibet appears to be only the intermediate principal stress ?2, ?1 being vertical. South of the "chord" joining the eastern and western syntaxes of the Himalayan arc, extensional strains are principally localized within seven regularly spaced rift zones, three of which have been studied in some detail. The extension direction is determined to be N96° E ± 7° mainly from statistical averaging of strikes of newly formed normal faults. Throw rates on normal faults are evaluated for different time spans (2 ± 0.5 m.y., 60 ± 40 kyr, and 10 ± 2 kyr B.P.), using structural and topographic reliefs, as well as synglacial and postglacial vertical offsets. The rate of Quaternary extension is about 1% m.y.-1 along an 1100-km-long ESE traverse across south Tibet. This corresponds to a "spreading" rate of 1 ± 0.6 cm/yr. This rate and the divergent horizontal projections of slip vectors of earthquakes along the Himalayan front constrain the rate at which rigid India underthrusts southern Tibet to be 2 ± 1 cm/yr. Although most of the normal faults appear to be independent of, and nearly orthogonal to, the ?E-W Mesozoic-Tertiary tectonic fabric, the Yadong-Gulu rift appears to be guided for over 130 km by the older, oblique (?NE-SW) Nyainqentanglha range and fault zones along it. This reactivated zone is the most prominent left-lateral strike-slip fault system in SE Tibet. Excepting this zone, and the vicinity of the SE extremity of the Karakorum fault, Quaternary strike-slip faulting is rare in south Tibet, i.e., south of the chord between the syntaxes of the Himalayan arc. North of the chord, the tectonic style is different. There minor conjugate strike-slip faulting is widespread and appears to control Quaternary normal faulting, which is more diffuse and subdued than in south Tibet. Along the chord, the presence of a major zone of active right-lateral, en échelon strike-slip faults (Karakorum-Jiali fault zone) probably reflects the greater facility of eastward extrusion in north central Tibet, in response to the northward push of India. The eastern Himalayan syntaxis may be an obstacle to such extrusion movements south of the chord.

  12. Quaternary coastal evolution of Oman (Arabian Peninsula) - a quantitative approach

    NASA Astrophysics Data System (ADS)

    Hoffmann, G.; Rupprechter, M.; Roepert, A.; Quraishi, K. Al; Balushi, N. Al; Grützner, C.; Reicherter, K.

    2012-04-01

    The paper reviews the Quaternary coastal evolution of Oman. Emphasise is put on quantifying the different forcing factors. The plate tectonic setting, the Quaternary climate evolution, the sea-level history and the impact of natural hazards are identified as key factors of coastal evolution. The Arabian Plate is characterized by a northward movement forming a continent-continent collision zone in the west and the Makran Subduction Zone in the east. As a result differential land movement is observable in Oman. The Quaternary climate evolution is well understood. Besides other proxies notably spelothems and aeolian deposits allow to draw a consistent picture. It is understood that changes in the position of the intertropical convergence zone result in intensity-changes of the summer monsoon. These changes are related to global atmospheric circulation patterns. Data on the sea-level history are sparse; despite general assumptions of a sea-level lowstand, correlating with the last glacial maximum, resulting in terrestrial conditions within the Arabian Gulf. Furthermore, a mid-Holocene sea level highstand in the range of +2m is documented in several locations. The coastlines of Oman are affected by tsunami and hurricanes. However, almost no instrumental or historical data on the impact of such natural hazards are available due to the isolation of the country in the past. Several Quaternary deposits have been investigated in a reconnaissance survey. There is sound geological evidence for a tsunami to have affected the coastline in 1945, with the possibility of older tsunami events being also recorded in the geological record. There is strong evidence of differential land movement along the coastline; locally indicated by marine terraces in elevations of up to 400m (Rupprechter at al. 2012). By quantifying the differential land movement for numerous sites, the sea-level history will be revealed. Ultimately the data will be utilized to form the base of a modeling approach. Furthermore, a sedimentary archive of past precipitation events is documented which will allow reconstructing frequency and intensity of precipitation events and may indicate the impact of past hurricanes. It is concluded that the geological archives are suitable to quantify the forcing factors of Quaternary coastal evolution on different time scales and that the recurrence intervals of natural hazards will be revealed. Proxy data will be gained in subsequent investigations. This allows a scientific based holistic approach for an integrated coastal zone management that helps to formulate adaptation strategies with regard to global warming and expected environmental changes.

  13. Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs

    PubMed Central

    Neveu, Cedric; Cabaret, Jacques; Cortet, Jacques; Peineau, Nicolas; Abongwa, Melanie; Courtot, Elise; Robertson, Alan P.; Martin, Richard J.

    2014-01-01

    Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important “classical” anthelmintics like levamisole and pyrantel, as well as “novel” anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms. PMID:24497826

  14. Investigation of acetylcholine receptor diversity in a nematode parasite leads to characterization of tribendimidine- and derquantel-sensitive nAChRs.

    PubMed

    Buxton, Samuel K; Charvet, Claude L; Neveu, Cedric; Cabaret, Jacques; Cortet, Jacques; Peineau, Nicolas; Abongwa, Melanie; Courtot, Elise; Robertson, Alan P; Martin, Richard J

    2014-01-01

    Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important "classical" anthelmintics like levamisole and pyrantel, as well as "novel" anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms. PMID:24497826

  15. Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of A?PP via M1 mAChRs

    PubMed Central

    Nelson, Amy R.; Kolasa, Krystyna; McMahon, Lori L.

    2014-01-01

    Alzheimer’s disease (AD) is characterized by amyloid-beta (A?) plaques, hyperphosphorylated tau neurofibrillary tangles (NFTs) and cholinergic dysfunction. Cholinergic degeneration can be mimicked in rats by lesioning cholinergic neurons in medial septum. Hippocampal cholinergic denervation disrupts retrograde transport of nerve growth factor (NGF), leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Previously we reported that coincident with noradrenergic sprouting is the partial reinnervation of hippocampus with cholinergic fibers, and the maintenance of a M1 mAChR dependent long-term depression at CA3-CA1 synapses that is lost in the absence of sprouting. These findings suggest that sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. Interestingly, noradrenergic sympathetic and cholinergic sprouting have been demonstrated in AD postmortem human brain. Furthermore, M1 mAChRs have been a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid beta-protein precursor (A?PP). Here we tested the hypothesis that noradrenergic sympathetic sprouting and the associated increase in cholinergic innervation maintains non-amyloidogenic A?PP processing that is dependent upon M1 mAChRs. Also, we investigated the effect of intrahippocampal A?42 infusion on noradrenergic sympathetic and cholinergic sprouting. We found that A?42 is not only toxic to central cholinergic fibers innervating hippocampus but prevents and reverses noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation. These findings reiterate the clinical implications of sprouting as an innate compensatory mechanism and emphasize the importance of M1 mAChRs as an AD therapeutic target. PMID:24081376

  16. Nicotine induces the up-regulation of the ?7-nicotinic receptor (?7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA protein pathway.

    PubMed

    Brown, Kathleen C; Perry, Haley E; Lau, Jamie K; Jones, Dennie V; Pulliam, Joseph F; Thornhill, Brent A; Crabtree, Clayton M; Luo, Haitao; Chen, Yi Charlie; Dasgupta, Piyali

    2013-11-15

    Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the ?7-nicotinic acetylcholine receptor (?7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on ?7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased ?7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of ?7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of ?7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of ?7-nAChR mRNA and ?7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of ?7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the ?7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of ?7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking. PMID:24089524

  17. A Novel Route to Recognizing Quaternary Ammonium Cations Using Electrospray Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Shackman, Holly M.; Ding, Wei; Bolgar, Mark S.

    2015-01-01

    Characterizing and elucidating structures is a commonplace and necessary activity in the pharmaceutical industry with mass spectrometry and NMR being the primary tools for analysis. Although many functional groups are readily identifiable, quaternary ammonium cations have proven to be difficult to unequivocally identify using these techniques. Due to the lack of an N-H bond, quaternary ammonium groups can only be detected in the 1H NMR spectra by weak signals generated from long-range 14N-H coupling, which by themselves are inconclusive evidence of a quaternary ammonium functional group. Due to their low intensity, these signals are frequently not detected. Additionally, ions cannot be differentiated in a mass spectrum as an M+ or [M + H]+ ion without prior knowledge of the compound's structure. In order to utilize mass spectrometry as a tool for determining this functionality, ion cluster formation of quaternary ammonium cations and non-quaternary amines was studied using electrospray ionization. Several mobile phase modifiers were compared; however, the addition of small amounts of trifluoroacetic acid proved superior in producing characteristic and intense [M +2TFA]- clusters for compounds containing quaternary ammonium cations when using negative electrospray. By fragmenting this characteristic ion using CID, nearly all compounds studied could be unambiguously identified as containing a quaternary ammonium cation or a non-quaternary amine attributable to the presence (non-quaternary amine) or absence (quaternary ammonium cation) of the resulting [2TFA + H]- ion in the product spectra. This method of analysis provides a rapid, novel, and reliable technique for indicating the presence of quaternary ammonium cations in order to aid in structural elucidation.

  18. A novel route to recognizing quaternary ammonium cations using electrospray mass spectrometry.

    PubMed

    Shackman, Holly M; Ding, Wei; Bolgar, Mark S

    2015-01-01

    Characterizing and elucidating structures is a commonplace and necessary activity in the pharmaceutical industry with mass spectrometry and NMR being the primary tools for analysis. Although many functional groups are readily identifiable, quaternary ammonium cations have proven to be difficult to unequivocally identify using these techniques. Due to the lack of an N-H bond, quaternary ammonium groups can only be detected in the (1)H NMR spectra by weak signals generated from long-range (14)N-H coupling, which by themselves are inconclusive evidence of a quaternary ammonium functional group. Due to their low intensity, these signals are frequently not detected. Additionally, ions cannot be differentiated in a mass spectrum as an M(+) or [M + H](+) ion without prior knowledge of the compound's structure. In order to utilize mass spectrometry as a tool for determining this functionality, ion cluster formation of quaternary ammonium cations and non-quaternary amines was studied using electrospray ionization. Several mobile phase modifiers were compared; however, the addition of small amounts of trifluoroacetic acid proved superior in producing characteristic and intense [M +2TFA](-) clusters for compounds containing quaternary ammonium cations when using negative electrospray. By fragmenting this characteristic ion using CID, nearly all compounds studied could be unambiguously identified as containing a quaternary ammonium cation or a non-quaternary amine attributable to the presence (non-quaternary amine) or absence (quaternary ammonium cation) of the resulting [2TFA + H](-) ion in the product spectra. This method of analysis provides a rapid, novel, and reliable technique for indicating the presence of quaternary ammonium cations in order to aid in structural elucidation. PMID:25391726

  19. Using ACE inhibitors appropriately.

    PubMed

    Bicket, Daphne P

    2002-08-01

    When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction. altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and nonfatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications. (Am Fam Physician 2002;66:473.) PMID:12182524

  20. Chiral Kinase Inhibitors

    PubMed Central

    Jiang, Jian-kang; Shen, Min; Thomas, Craig J.; Boxer, Mathew B.

    2011-01-01

    Small molecule kinase inhibitors are important tools for studying cellular signaling pathways, phenotypes and are, occasionally, useful clinical agents. With stereochemistry pervasive throughout the molecules of life it is no surprise that a single stereocenter can bestow a ligand with distinct binding affinities to various protein targets. While the majority of small molecule kinase inhibitors reported to date are achiral, a number of asymmetric compounds show great utility as tools for probing kinase-associated biomolecular events as well as promising therapeutic leads. The mechanism by which chirality is introduced varies but includes screening of chiral libraries, incorporation of chiral centers during optimization efforts and the rational installation of a chiral moiety as guided by structural and modeling efforts. Here we discuss several advanced chiral small molecule kinase inhibitors where stereochemistry plays an important role in terms of potency and selectivity. PMID:21291394

  1. Combined QSAR studies of inhibitor properties of O-phosphorylated oximes toward serine esterases involved in neurotoxicity, drug metabolism and Alzheimer's disease.

    PubMed

    Makhaeva, G F; Radchenko, E V; Baskin, I I; Palyulin, V A; Richardson, R J; Zefirov, N S

    2012-10-01

    Oxime reactivation of serine esterases (EOHs) inhibited by organophosphorus (OP) compounds can produce O-phosphorylated oximes (POXs). Such oxime derivatives are of interest, because some of them can have greater anti-EOH potencies than the OP inhibitors from which they were derived. Accordingly, inhibitor properties of 58 POXs against four EOHs, along with pair-wise selectivities between them, have been analysed using different QSAR approaches. EOHs (with their abbreviations and consequences of inhibition in parentheses) comprised acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity). QSAR techniques encompassed linear regression and backpropagation neural networks in conjunction with fragmental descriptors containing labelled atoms, Molecular Field Topology Analysis (MFTA), Comparative Molecular Similarity Index Analysis (CoMSIA), and molecular modelling. All methods provided mostly consistent and complementary information, and they revealed structural features controlling the 'esterase profiles', i.e. patterns of anti-EOH activities and selectivities of the compounds of interest. In addition, MFTA models were used to design a library of compounds having a cognition-enhancement esterase profile suitable for potential application to the treatment of Alzheimer's disease. PMID:22587543

  2. Optical Characterization of Amorphous Hydrogenated Carbon (a-C:H) Thin Films Prepared by Single RF Plasma Method

    NASA Astrophysics Data System (ADS)

    Dogan, Mansuroglu; Kadir, Goksen; Sinan, Bilikmen

    2015-06-01

    Methane (CH4) plasma was used to produce amorphous hydrogenated carbon (a-C:H) films by a single capacitively coupled radio frequency (RF) powered plasma system. The system consists of two parallel electrodes: the upper electrode is connected to 13.56 MHz RF power and the lower one is connected to the ground. Thin films were deposited on glass slides with different sizes and on silicon wafers. The influence of the plasma species on film characteristics was studied by changing the plasma parameters. The changes of plasma species during the deposition were investigated by optical emission spectroscopy (OES). The structural and optical properties were analyzed via Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and UV-visible spectroscopy, and the thicknesses of the samples were measured by a profilometer. The sp3/sp2 ratio and the existing H atoms play a significant role in the determination of the chemical properties of thin films in the plasma. The film quality and deposition rate were both increased by raising the power and the flow rate.

  3. Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review

    PubMed Central

    Farrimond, Lucy E; Roberts, Emmert

    2012-01-01

    Background Memantine is licensed for moderate-to-severe Alzheimer's disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI)). The underpinning meta-analysis was disputed by the manufacturer. Objectives To compare the efficacy of AChEI monotherapy with combination memantine and AChEI therapy in patients with moderate-to-severe AD and to examine the impact of including unpublished data on the results. Design Systematic review and meta-analysis of randomised controlled trials. Data sources The Cochrane Dementia Group trial register, ALOIS, searched for the last time on 3 May 2011. Data synthesis Data from four domains (clinical global, cognition, function, behaviour and mood) were pooled. Sensitivity analyses examined the impact on the NICE-commissioned meta-analysis of restricting data to patients with moderate-to-severe AD and of including an unpublished trial of an extended release preparation of memantine. Results Pooled data from the trials, which were included in the NICE-commissioned meta-analysis but which were restricted to moderate-to-severe AD only, showed a small effect of combination therapy on cognition (standardised mean difference (SMD)=?0.29, 95% CI ?0.45 to ?0.14). Adding data from an unpublished trial of an extended release memantine (total three trials, 1317 participants) showed a small benefit of combination therapy on global scores (SMD=?0.20, 95% CI ?0.31 to ?0.09), cognition (SMD=?0.25, 95% CI ?0.36 to ?0.14) and behaviour and mood (SMD=?0.17, 95% CI ?0.32 to ?0.03) but not on function (SMD=?0.04, 95% CI ?0.21 to 0.13) at 6?months. No clinical data have been reported from a 1-year trial, although this found ‘no significant benefit’ on any clinical measures at 1?year. Conclusions These results suggest that there may be a small benefit at 6?months of adding memantine to AChEIs. However, the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, so its clinical relevance is not robustly demonstrated. Currently available information from randomised controlled trails indicates no benefit of combination therapy over monotherapy at 1?year. Legislation on the form and content of registry posted results is needed in Europe. PMID:22689908

  4. Design, synthesis and evaluation of 3,4-dihydroxybenzoic acid derivatives as antioxidants, bio-metal chelating agents and acetylcholinesterase inhibitors.

    PubMed

    Friggeri, Laura; De Vita, Daniela; Pandolfi, Fabiana; Tortorella, Silvano; Costi, Roberta; Di Santo, Roberto; Scipione, Luigi

    2015-02-01

    Metal ions, especially copper, zinc and iron, play an important role in the neurodegeneration process because they can affect protein misfolding, leading to the formation of the amyloid deposits and oxidative stress leading to reactive oxygen species (ROS). Here we report the synthesis and evaluation as antioxidant and metal chelating agents of 3,4-dihydroxybenzoic acid derivatives. Synthesized compounds were tested by the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method showing a radical scavenging ability (EC50=0.093-0.118 ?M) higher than Trolox used as reference. Furthermore, these compounds were able to bind both iron and copper, especially the iron (III), by the formation of hexa-coordinated complexes. Synthesized compounds were tested to evaluate their ability to inhibit acetyl- and butyryl-cholinesterase; the obtained results have demonstrated that they are selective inhibitors of AChE (Ki=1.5-18.9 ?M) and result weakly active versus butyrylcholinesterase (BChE). PMID:24517367

  5. A comparison of lignin and stable carbon isotope compositions in quaternary marine sediments

    Microsoft Academic Search

    JOHN I. HEDGES; ALEXANDER VAN GEEN

    1982-01-01

    Heges, J.I. and van Geen, A., 1982. A comparison of lignin and stable carbon isotope compositions in quaternary marine sediments. Mar. Chem., 11: 43--53. Organic matter in four Quaternary sediment cores from the Gulf of Mexico and one core from the Washington State coast have been analyzed for lignin and stable carbon isotope compositions. Holocene sequences of all five cores

  6. 182 28th ANNUAL eMS Sorption and Desorption of Quaternary Amine Cations on Clays

    E-print Network

    Sparks, Donald L.

    182 28th ANNUAL eMS Sorption and Desorption of Quaternary Amine Cations on Clays Z. Z. Zhang and D? The present study was conducted to investigate the sorption and desorption of several quaternary amines on Na of amines was conducted at an ionic strength of 0.01 M, and desorption of amines was studied by adding

  7. Multiplexed global internal standard technique (mGIST) using a quaternary amine coding agent

    Microsoft Academic Search

    Cathy S Sioma

    2003-01-01

    The goal of this research was to investigate the use of a quaternary amine coding agent for the use in Multiplexed Global Internal Standard Technology (mGIST). ^ The work reported here began with the search for a reagent that would improve on the limitations of current GIST reagents. Literature reviews and initial studies indicated that a quaternary amine coding agent

  8. Antistatic Wool. Part II: Quaternary Polyethoxylated Amines As Antistatic Agents for Wool

    Microsoft Academic Search

    Donna M. Brown; M. T. Pailthorpe

    1988-01-01

    An investigation is reported that describes the effects of quaternary polyethoxylated amines on the antistatic properties of wool.The ethoxylated amines reported in previous work were quaternized with benzyl chloride, and the products were found to be very effective in reducing the electrical resistance of wool. The antistatic effect observed for the quaternary ethoxylated amines was not dependent on time, alkyl–chain

  9. A review of Quaternary range shifts in European aquatic Coleopterageb_572 87..100

    E-print Network

    Murcia, Universidad de

    of the Quaternary fossil record of Euro- pean water beetles to evaluate their geographical and temporal coverage compiled Quaternary water beetle records from public databases and published references. We included of the species. Results Our final data set included over 9000 records for 259 water beetle species. Fossil

  10. Late Quaternary variability of sedimentary nitrogen isotopes in the eastern South Pacific Ocean

    E-print Network

    Demouchy, Sylvie

    Late Quaternary variability of sedimentary nitrogen isotopes in the eastern South Pacific Ocean), Late Quaternary variability of sedimentary nitrogen isotopes in the eastern South Pacific Ocean) in the water columns of the Arabian Sea (AS) and the eastern North and South Pacific oceans (ENP; ESP) holds

  11. Late-Quaternary diminution and abundance of prehistoric bison (Bison sp.) in eastern Washington state, USA

    Microsoft Academic Search

    R. Lee Lyman

    Bison (Bison spp.) occurred in eastern Washington state during the late Quaternary. This area is considered to be peripheral to the center of this taxon's natural range. Bison in the plains east of the Rocky Mountains, the heart of this range, underwent diminution during the late Quaternary, and apparently also did so in other, peripheral areas. A ratio diagram of

  12. Environ. Sci. Technol. 1993, 27, 1625-1631 Sorptlon and Desorption of Quaternary Amine Cations on Clays

    E-print Network

    Sparks, Donald L.

    Environ. Sci. Technol. 1993, 27, 1625-1631 Sorptlon and Desorption of Quaternary Amine Cations 19714 We have studied the sorption and desorption of three quaternary amines, namely-montmorillonite using a titration procedure. More than 99% of all three of the quaternary amine cations studied were

  13. An aminostratigraphy for the British Quaternary based on Bithynia opercula

    PubMed Central

    Penkman, Kirsty E.H.; Preece, Richard C.; Bridgland, David R.; Keen, David H.; Meijer, Tom; Parfitt, Simon A.; White, Tom S.; Collins, Matthew J.

    2013-01-01

    Aminostratigraphies of Quaternary non-marine deposits in Europe have been previously based on the racemization of a single amino acid in aragonitic shells from land and freshwater molluscs. The value of analysing multiple amino acids from the opercula of the freshwater gastropod Bithynia, which are composed of calcite, has been demonstrated. The protocol used for the isolation of intra-crystalline proteins from shells has been applied to these calcitic opercula, which have been shown to more closely approximate a closed system for indigenous protein residues. Original amino acids are even preserved in bithyniid opercula from the Eocene, showing persistence of indigenous organics for over 30 million years. Geochronological data from opercula are superior to those from shells in two respects: first, in showing less natural variability, and second, in the far better preservation of the intra-crystalline proteins, possibly resulting from the greater stability of calcite. These features allow greater temporal resolution and an extension of the dating range beyond the early Middle Pleistocene. Here we provide full details of the analyses for 480 samples from 100 horizons (75 sites), ranging from Late Pliocene to modern. These show that the dating technique is applicable to the entire Quaternary. Data are provided from all the stratotypes from British stages to have yielded opercula, which are shown to be clearly separable using this revised method. Further checks on the data are provided by reference to other type-sites for different stages (including some not formally defined). Additional tests are provided by sites with independent geochronology, or which can be associated with a terrace stratigraphy or biostratigraphy. This new aminostratigraphy for the non-marine Quaternary deposits of southern Britain provides a framework for understanding the regional geological and archaeological record. Comparison with reference to sites yielding independent geochronology, in combination with other lines of evidence, allows tentative correlation with the marine oxygen isotope record. PMID:23396683

  14. Arctic-alpine blockfields in northern Sweden: Quaternary not Neogene

    NASA Astrophysics Data System (ADS)

    Goodfellow, B. W.; Stroeven, A. P.; Fabel, D.; Fredin, O.; Derron, M.-H.; Bintanja, R.; Caffee, M. W.

    2014-02-01

    Slowly-eroding, blockfield-mantled, non-glacial surface remnants may serve as markers against which to determine Quaternary glacial erosion volumes in high latitude mountain settings. To investigate this potential utility of these surfaces, chemical weathering, erosion rates, and origins of mountain blockfields are investigated in northern Sweden. This is done, firstly, by assessing the intensity of regolith chemical weathering along altitudinal transects descending from three blockfield-mantled summits. Clay/silt ratios, secondary mineral assemblages determined through X-ray diffraction, and the presence of chemically weathered grains visible on scanning electron microscopy, in fine matrix samples collected from pits excavated along the transects are each used for this purpose. Secondly, erosion rates and total surface histories of two of the summits are inferred from concentrations of in situ-produced cosmogenic 10Be and 26Al in quartz at the blockfield surface. An interpretative model is adopted that includes temporal variations in nuclide production rates through surface burial by glacial ice and glacial isostasy-induced elevation changes of the blockfield surfaces. Together, our data indicate that these blockfields are not derived from remnants of intensely weathered Neogene weathering profiles, as is commonly considered. Evidence for this interpretation includes minor chemical weathering in each of the three examined blockfields, despite some differences according to slope position. In addition, average erosion rates of ∼16.2 mm ka-1 and ∼6.7 mm ka-1, calculated for two blockfield-mantled summits, are low but of sufficient magnitude to remove present blockfield mantles, of up to a few meters in thickness, within a late-Quaternary timeframe. Hence, blockfield mantles appear to be replenished by regolith formation through, primarily physical, weathering processes that have operated during the Quaternary. Erosion rates remain low enough, however, for blockfield-mantled, non-glacial surface remnants to provide reasonable landscape markers against which to contrast Quaternary erosion volumes in surrounding glacial landscape elements. The persistence of blockfield mantles over a number of glacial-interglacial cycles and an apparently low likelihood that they can re-establish on glacially eroded bedrock, also discounts the operation of a "glacial buzz-saw" on surface remnants that are presently perceived as non-glacial. These interpretations are tempered though by outstanding questions concerning the composition of preceding Neogene regoliths and why they have apparently been comprehensively removed from these remnant non-glacial surfaces. It remains possible that periglacial erosion of perhaps more intensely weathered Neogene regoliths was high during the Pliocene-Pleistocene transition to colder conditions and that periglacial processes reshaped non-glacial surface remnants largely before the formation of blockfield armours.

  15. 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.

  16. Synthesis and antibacterial activities of quaternary ammonium salt of chitosan

    Microsoft Academic Search

    Zhishen Jia; Dongfeng shen; Weiliang Xu

    2001-01-01

    Chitosan derivatives with quaternary ammonium salt, such as N,N,N-trimethyl chitosan, N–N-propyl-N,N-dimethyl chitosan and N-furfuryl-N,N-dimethyl chitosan were prepared using different 96% deacetylated chitosan of Mv 2.14×105, 1.9×104, 7.8×103. Amino groups on chitosan react with aldehydes to from a Schiff base intermediate. Quaternized chitosan were obtained by reaction of a Schiff base with methyl iodide. The yields, degree of quaternization and water-solubility

  17. 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.

  18. Cyclic explosive activity of the Iceland plume in the quaternary

    NASA Astrophysics Data System (ADS)

    Eroshenko, D. V.; Kharin, G. S.

    2014-02-01

    Data on the volcanic ash layers in 70 DSDP and ODP Sites and 100 cores obtained during cruises of the R/V Akademik Kurchatov and Mikhail Lomonosov were used for compiling tephrostratigraphic scale and schematic distribution maps of the pyroclastic material in the Quaternary sediments of the North Atlantic and Norwegian-Greenland Basin. It is revealed that the distribution of pyroclastic material through this region is characterized by cyclic and spatially irregular patterns. Based on their petrochemical and geochemical properties, these ashes are compared with the volcanics of Iceland and the Jan Mayen islands. The relations between the extreme climatic and cyclic explosive events are discussed.

  19. Extraction of actinides by quaternary amines from hydrochloric acid medium

    Microsoft Academic Search

    V. R. Bhandiwad; Rajendra Swarup; S. K. Patil

    1979-01-01

    The extraction of Np(IV), Pu(IV) and U(VI) from aqueous hydrochloric acid into quaternary amines has been studied. The dependence\\u000a of the distribution coefficient on amine concentration suggests that the actinide ions extracted are NpCl\\u000a 6\\u000a 2?\\u000a PuCl\\u000a 6\\u000a 2?\\u000a and UO2Cl\\u000a 4\\u000a 2?\\u000a . This is further supported by the absorption spectra of the amine extracts of these actinide ions.

  20. Corrosion inhibitors used in acidizing

    SciTech Connect

    Cizek, A. (Baker Performance Chemicals Inc., Houston, TX (United States). Aquaness Chemical Division)

    1994-01-01

    The history of the development of oil well acidizing and acid corrosion inhibitors used by this industry is reviewed. As deeper and hotter wells were drilled, stimulation acids were exposed to hotter conditions and the organic inhibitors required intensifiers. High-temperature acid corrosion inhibitors are also discussed.

  1. Impaired terrestrial and arboreal locomotor performance in the western fence lizard (Sceloporus occidentalis) after exposure to an AChE-inhibiting pesticide.

    PubMed

    DuRant, Sarah E; Hopkins, William A; Talent, Larry G

    2007-09-01

    We examined the effects of a commonly used AChE-inhibiting pesticide on terrestrial and arboreal sprint performance, important traits for predator avoidance and prey capture, in the western fence lizard (Sceloporus occidentalis). Lizards were exposed to carbaryl (2.5, 25, and 250 microg/g) and were raced before and 4, 24, and 96 h after dosing. In the terrestrial setting, exposure to low concentrations of carbaryl had stimulatory effects on performance, but exposure to the highest concentration was inhibitory. No stimulatory effects of carbaryl were noted in the arboreal environment and performance in lizards was reduced after exposure to both the medium and highest dose of carbaryl. Our findings suggest that acute exposure to high concentrations of carbaryl can have important sublethal consequences on fitness-related traits in reptiles and that arboreal locomotor performance is a more sensitive indicator of AChE-inhibiting pesticide poisoning than terrestrial locomotor performance. PMID:17360091

  2. The Frequency of Calcium Oscillations Induced by 5-HT, ACH, and KCl Determine the Contraction of Smooth Muscle Cells of Intrapulmonary Bronchioles

    PubMed Central

    Perez, Jose F.; Sanderson, Michael J.

    2005-01-01

    Increased resistance of airways or blood vessels within the lung is associated with asthma or pulmonary hypertension and results from contraction of smooth muscle cells (SMCs). To study the mechanisms regulating these contractions, we developed a mouse lung slice preparation containing bronchioles and arterioles and used phase-contrast and confocal microscopy to correlate the contractile responses with changes in [Ca2+]i of the SMCs. The airways are the focus of this study. The agonists, 5-hydroxytrypamine (5-HT) and acetylcholine (ACH) induced a concentration-dependent contraction of the airways. High concentrations of KCl induced twitching of the airway SMCs but had little effect on airway size. 5-HT and ACH induced asynchronous oscillations in [Ca2+]i that propagated as Ca2+ waves within the airway SMCs. The frequency of the Ca2+ oscillations was dependent on the agonist concentration and correlated with the extent of sustained airway contraction. In the absence of extracellular Ca2+ or in the presence of Ni2+, the frequency of the Ca2+ oscillations declined and the airway relaxed. By contrast, KCl induced low frequency Ca2+ oscillations that were associated with SMC twitching. Each KCl-induced Ca2+ oscillation consisted of a large Ca2+ wave that was preceded by multiple localized Ca2+ transients. KCl-induced responses were resistant to neurotransmitter blockers but were abolished by Ni2+ or nifedipine and the absence of extracellular Ca2+. Caffeine abolished the contractile effects of 5-HT, ACH, and KCl. These results indicate that (a) 5-HT and ACH induce airway SMC contraction by initiating Ca2+ oscillations, (b) KCl induces Ca2+ transients and twitching by overloading and releasing Ca2+ from intracellular stores, (c) a sustained, Ni2+-sensitive, influx of Ca2+ mediates the refilling of stores to maintain Ca2+ oscillations and, in turn, SMC contraction, and (d) the magnitude of sustained airway SMC contraction is regulated by the frequency of Ca2+ oscillations. PMID:15928401

  3. Molecular size effect in the chemical sputtering of aC:H thin films by low energy H +, H 2 + , and H 3 + ions

    Microsoft Academic Search

    Peter R Harris; Fred W Meyer; W. Jacob; T. Schwarz-Selinger; U. von Toussaint

    2011-01-01

    We have experimentally determined total carbon yields per incident H atom in the energy range 36–300eV\\/H for H+, H2+, and H3+ projectiles incident normally on ?60nm thick a-C:H films, using 2-D ellipsometry determination of erosion crater volumes ex vacuo, the separately characterized thin film carbon density, and the incident beam current integration accumulated on target during the crater evolution. During

  4. Molecular size effect in the chemical sputtering of aC:H thin films by low energy H+, H2+, and H3+ ions

    Microsoft Academic Search

    P. R. Harris; F. W. Meyer; W. Jacob; T. Schwarz-Selinger; U. von Toussaint

    2011-01-01

    We have experimentally determined total carbon yields per incident H atom in the energy range 36-300 eV\\/H for H+, H2+, and H3+ projectiles incident normally on ˜60 nm thick a-C:H films, using 2-D ellipsometry determination of erosion crater volumes ex vacuo, the separately characterized thin film carbon density, and the incident beam current integration accumulated on target during the crater

  5. Additional acetylcholine (ACh) binding site at alpha4/alpha4 interface of (alpha4beta2)2alpha4 nicotinic receptor influences agonist sensitivity.

    PubMed

    Mazzaferro, Simone; Benallegue, Naïl; Carbone, Anna; Gasparri, Federica; Vijayan, Ranjit; Biggin, Philip C; Moroni, Mirko; Bermudez, Isabel

    2011-09-01

    Nicotinic acetylcholine receptor (nAChR) ?4 and ?2 subunits assemble in two alternate stoichiometries to produce (?4?2)(2)?4 and (?4?2)(2)?2, which display different agonist sensitivities. Functionally relevant agonist binding sites are thought to be located at ?4(+)/?2(-) subunit interfaces, but because these interfaces are present in both receptor isoforms, it is unlikely that they account for differences in agonist sensitivities. In contrast, incorporation of either ?4 or ?2 as auxiliary subunits produces isoform-specific ?4(+)/?4(-) or ?2(+)/?2(-) interfaces. Using fully concatenated (?4?2)(2)?4 nAChRs in conjunction with structural modeling, chimeric receptors, and functional mutagenesis, we have identified an additional site at the ?4(+)/?4(-) interface that accounts for isoform-specific agonist sensitivity of the (?4?2)(2)?4 nAChR. The additional site resides in a region that also contains a potentiating Zn(2+) site but is engaged by agonists to contribute to receptor activation. By engineering ?4 subunits to provide a free cysteine in loop C at the ?4(+)?4(-) interface, we demonstrated that the acetylcholine responses of the mutated receptors are attenuated or enhanced, respectively, following treatment with the sulfhydryl reagent [2-(trimethylammonium)ethyl]methanethiosulfonate or aminoethyl methanethiosulfonate. The findings suggest that agonist occupation of the site at the ?4(+)/(?4(-) interface leads to channel gating through a coupling mechanism involving loop C. Overall, we propose that the additional agonist site at the ?4(+)/?4(-) interface, when occupied by agonist, contributes to receptor activation and that this additional contribution underlies the agonist sensitivity signature of (?4?2)(2)?4 nAChRs. PMID:21757735

  6. Coupled effects of bombarding ions energy on the microstructure and stress level of RFPECVD aC:H films: correlation with Raman spectroscopy

    Microsoft Academic Search

    E. Tomasella; L. Thomas; C. Meunier; M. Nadal; S. Mikhailov

    2003-01-01

    In this work a-C:H films have been prepared in a capacitively coupled RF-PECVD device (?=13.56 MHz) from methane as the gas source. By the use of ERDA, IRTF and X-Ray reflectometry techniques, we have first investigated the structural evolutions of the films as a function of the ion energy. In the second part, we have measured mechanical properties (hardness and

  7. Impaired terrestrial and arboreal locomotor performance in the western fence lizard ( Sceloporus occidentalis) after exposure to an AChE-inhibiting pesticide

    Microsoft Academic Search

    Sarah E. DuRant; William A. Hopkins; Larry G. Talent

    2007-01-01

    We examined the effects of a commonly used AChE-inhibiting pesticide on terrestrial and arboreal sprint performance, important traits for predator avoidance and prey capture, in the western fence lizard (Sceloporus occidentalis). Lizards were exposed to carbaryl (2.5, 25, and 250?g\\/g) and were raced before and 4, 24, and 96h after dosing. In the terrestrial setting, exposure to low concentrations of

  8. Separation of a mixture of paraconic acids from Cetraria islandica (L.) Ach. employing a fluorous tag—catch and release strategy

    Microsoft Academic Search

    David Horhant; Anne-Cécile Le Lamer; Joël Boustie; Philippe Uriac; Nicolas Gouault

    2007-01-01

    A light-fluorous catch and release approach application has been designed to the separation of a mixture of three paraconic acids extracted from the Island moss (Cetraria islandica (L.) Ach.). The (+)-protolichesterinic acid was caught and released via a Michaël\\/retro-Michaël addition sequence with a fluorous thiol, while the resulting two other compounds were classically separated, allowing the isolation of (+)-roccellaric acid

  9. Population diversity and distinct haplotype frequencies associated with ACHE and BCHE genes of Israeli Jews from trans-caucasian Georgia and from Europe

    Microsoft Academic Search

    G. Ehrlich; D. Ginzberg; Y. Loewenstein

    1994-01-01

    Variant alleles of the butyrylcholinesterase gene, BCHE, have often been used to trace the genetic histories of populations. The D70G substitution in BCHE causes prolonged postanesthesia apnea ({open_quotes}atypical{close_quotes} phenotype); H322N substitution in the closely related acetylcholinesterase gene, ACHE, is the basis of the mutually incompatible YT blood groups. In both genes, additional point mutations were reported to be linked to

  10. Activation of the ?7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT1a receptor antagonist

    PubMed Central

    Pandya, Anshul A.; Yakel, Jerrel L.

    2013-01-01

    The ?7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the ?7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both ?7 and non-?7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the ?7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamine-induced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT1a receptor antagonist WAY-100135. However the ?7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that ?7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the ?7 receptors. PMID:23321689

  11. Non-noxious skin stimulation activates the nucleus basalis of Meynert and promotes NGF secretion in the parietal cortex via nicotinic ACh receptors.

    PubMed

    Hotta, Harumi; Watanabe, Nobuhiro; Piché, Mathieu; Hara, Sanae; Yokawa, Takashi; Uchida, Sae

    2014-07-01

    The effects of non-noxious skin stimulation on nerve growth factor (NGF) secretion in the parietal cortex were examined in anesthetized rats. Innocuous skin stimulation was delivered to the left hindlimb with a soft-hair brush. Extracellular NGF in the right parietal cortex was collected by microdialysis methods using a protein-permeable probe and was measured using an enzyme-linked immune-sorbent assay. Brushing produced a significant increase in extracellular NGF levels. This NGF response was not observed in rats pretreated with a nicotinic ACh receptor (nAChR) antagonist mecamylamine. We further examined whether brushing could activate the basal forebrain nucleus (nucleus basalis of Meynert, NBM), which is the main source of cholinergic fibers in the cerebral cortex, by means of functional MRI. The blood oxygen level-dependent signal in the right NBM was significantly higher during brushing compared to baseline. The results suggest that non-noxious skin stimulation activates NBM and promotes NGF secretion in the parietal cortex via nAChRs. PMID:24801530

  12. Induction of long-term oscillations in the ? frequency band by nAChR activation in rat hippocampal CA3 area.

    PubMed

    Zhang, X; Ge, X Y; Wang, J G; Wang, Y L; Wang, Y; Yu, Y; Li, P P; Lu, C B

    2015-08-20

    The hippocampal neuronal network oscillation at ? frequency band (? oscillation) is generated by the precise interaction between interneurons and principle cells. ? oscillation is associated with attention, learning and memory and is impaired in the diseased conditions such as Alzheimer's disease (AD) and schizophrenia. Nicotinic acetylcholine receptor (nAChR) plays an important role in the regulation of hippocampal neurotransmission and network activity. It is not known whether nicotine modulates plasticity of network activity at ? oscillations in the hippocampus. In this study we investigated the effects of nicotine on the long-term changes of KA-induced ? oscillations. We found that hippocampal ? oscillations can be enhanced by a low concentration of nicotine (1?M), such an enhancement lasts for hours after washing out of nicotine, suggesting a form of synaptic plasticity, named as long-term oscillation at ? frequency band (LTO?). Nicotine-induced LTO? was mimicked by the selective ?4?2 but not by ?7 nAChR agonist and was involved in N-methyl-d-aspartate (NMDA) receptor activation as well as depended on excitatory and inhibitory neurotransmission. Our results indicate that nAChR activation induced plasticity in ? oscillation, which may be beneficial for the improvement of cognitive deficiency in AD and schizophrenia. PMID:26049144

  13. Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor

    Microsoft Academic Search

    Hugo Rubén Arias

    1998-01-01

    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

  14. Notes Bull. Korean Chem. Soc. 2005, Vol. 26, No. 1 175 Synthesis of Novel Biodegradable Quaternary Amine-based Cross-linked

    E-print Network

    Park, Jong-Sang

    , 2004 Key Words : Cross-linked polymer, Quaternary amine, Biodegradability, Gene delivery In recent to linear type carriers.4 Several quaternary amine-based polymeric gene delivery carriers were reported amines.9 Because quaternary amines have no nucleophilicity, quaternary amine-based biodegradable

  15. Late Quaternary terrestrial vertebrate coprolites from New Zealand

    NASA Astrophysics Data System (ADS)

    Wood, Jamie R.; Wilmshurst, Janet M.

    2014-08-01

    Over the past decade, concerted efforts to find and study Late Quaternary terrestrial vertebrate coprolites in New Zealand have revealed new insights into the diets and ecologies of New Zealand's prehistoric birds. Here, we provide a broader review of the coprolites found in natural (non-archaeological) Late Quaternary deposits from New Zealand. We summarise the morphological diversity of the coprolites, and discuss the taphonomy of the sites in which they are found. Since the 1870s more than 2000 coprolites have been discovered from 30 localities, all restricted to the South Island. The distribution of coprolite localities appears to reflect the presence of geological and climatic factors that enhance the potential for coprolite preservation; coprolites require dry conditions for preservation, and have been found on the ground surface within drafting cave entrances and at shallow (<300 mm) depths beneath rock overhangs with a northerly aspect. We classify the coprolites into eleven morphotypes, each of which may represent a range of different bird and/or reptile species. A review of genetically identified specimens shows that coprolites of different bird species overlap in size and morphology, reinforcing the need for identifications to be based on ancient DNA analysis.

  16. Late quaternary environments, Denali National Park and Preserve, Alaska

    USGS Publications Warehouse

    Elias, S.A.; Short, S.K.; Waythomas, C.F.

    1996-01-01

    Late Quaternary pollen, plant macrofossils, and insect fossils were studied from sites along three rivers in the foothills north of the Alaska Range in Denali National Park and Preserve. The aim was to carry out a reconaissance of late Quaternary organic sediments in the region, emphasizing the mid-Wisconsin, or Boutellier interstadial interval. Samples of probable early- to mid-Boutellier age (ca. 60 000 to 40 000 B.P.) from Unit 2 at the Toklat High Bluffs site indicate open boreal woodland with dense alder shrub vegetation. Organic Unit 1 at the Foraker River Slump site indicates open taiga with shrubs of probable Boutellier age. Fossil evidence from the youngest horizon in this unit indicates graminoid tundra environments, marking the transition from interstadial to late Wisconsin glacial environments. Early Holocene samples from the Foraker exposures suggest birch shrub tundra; coniferous forest apparently became established only alter 6500 B.P. Local variations in forest composition at the Foraker and Sushana sites were probably the result of disturbances, such as fire.

  17. Historical distribution of Sundaland's Dipterocarp rainforests at Quaternary glacial maxima.

    PubMed

    Raes, Niels; Cannon, Charles H; Hijmans, Robert J; Piessens, Thomas; Saw, Leng Guan; van Welzen, Peter C; Slik, J W Ferry

    2014-11-25

    The extent of Dipterocarp rainforests on the emergent Sundaland landmass in Southeast Asia during Quaternary glaciations remains a key question. A better understanding of the biogeographic history of Sundaland could help explain current patterns of biodiversity and support the development of effective forest conservation strategies. Dipterocarpaceae trees dominate the rainforests of Sundaland, and their distributions serve as a proxy for rainforest extent. We used species distribution models (SDMs) of 317 Dipterocarp species to estimate the geographic extent of appropriate climatic conditions for rainforest on Sundaland at the last glacial maximum (LGM). The SDMs suggest that the climate of central Sundaland at the LGM was suitable to sustain Dipterocarp rainforest, and that the presence of a previously suggested transequatorial savannah corridor at that time is unlikely. Our findings are supported by palynologic evidence, dynamic vegetation models, extant mammal and termite communities, vascular plant fatty acid stable isotopic compositions, and stable carbon isotopic compositions of cave guano profiles. Although Dipterocarp species richness was generally lower at the LGM, areas of high species richness were mostly found off the current islands and on the emergent Sunda Shelf, indicating substantial species migration and mixing during the transitions between the Quaternary glacial maxima and warm periods such as the present. PMID:25385612

  18. Distribution and metabolism of quaternary amines in salt marshes

    NASA Technical Reports Server (NTRS)

    King, Gary M.

    1985-01-01

    Quaternary amines such as glycine betaine (GBT) are common osmotically active solutes in much of the marine biota. GBT is accumulated by various bacteria, algae, higher plants, invertebrates, and vertebrates in response to salinity or water stresses; in some species, GBT occurs at tens to hundreds of millimolar concentrations and can account for a significant fraction of total nitrogen. Initial studies suggest that GBT is readily converted to two potential methane precursors, trimethylamine (TMA) and acetate, in anoxic sediments. TMA is apparently the most important methane precursor in surface sediments containing sulfate reducing bacteria. In salt marshes, the bulk of the methane formed may be due to the metabolism of TMA rather than other substrates. Current research is focussed on testing this hypothesis and on determining the role of quaternary amino osmoregulatory solutes in methane fluxes from marine environments. Preliminary studies have dealt with several problems: (1) determination of GBT concentrations in the dominant flora and fauna of salt marshes; (2) synthesis of radiolabelled GBT for metabolic studies; and (3) determination of fates of BGT in marine sediments using radiotracers. Both GC and HPLC techniques have been used to assay GBT concentrations in plant and animal tissues. S. alterniflora is probably the only significant source of GBT (and indirectly of methane) since the biomass and distribution of most other species is limited. Current estimates suggest that S. alterniflora GBT could account for most of the methane efflux from salt marshes.

  19. Actinobacterial enzyme inhibitors - A review.

    PubMed

    Manivasagan, Panchanathan; Venkatesan, Jayachandran; Sivakumar, Kannan; Kim, Se-Kwon

    2015-06-01

    Actinobacteria have potential as important new sources of enzyme inhibitors. Enzyme inhibitors have great demand in medicine, agriculture and biotechnology. In medicine, enzyme inhibitors can be used as therapeutic agents for bacterial, fungal, viral and parasitic diseases as well as treating cancer, neurodegenerative, immunological and cardiovascular diseases. Enzyme inhibitors are also valuable for the control of carbohydrate-dependent diseases such as diabetes, obesity and hyperlipidemia and melanogenesis in skin. They can be also involved in crop protection against plant pathogens, herbivorous pests and abiotic stresses such as drought. In this review, we discuss about several actinobacterial enzyme inhibitors with various industrial uses and biotechnological applications. PMID:24495095

  20. Highly efficient, selective and sensitive molecular screening of acetylcholinesterase inhibitors of natural origin by solid-phase extraction-liquid chromatography/electrospray ionisation-octopole-orthogonal acceleration time-of-flight-mass spectrometry and novel thin-layer chromatography-based bioautography.

    PubMed

    Mroczek, Tomasz

    2009-03-20

    Highly efficient, selective and sensitive molecular screening of natural acetylcholinesterase (AChE) inhibitors was developed and comprised optimized pressurized liquid extraction (PLE) of plant materials followed by highly selective solid-phase extraction (SPE) using Oasis HLB cartridges. Pure alkaloidal fractions were analyzed by a newly developed high-performance liquid-chromatography (HPLC) on a 3 microm Atlantis HILIC silica stationary phase combined with recently introduced electrospray ionisation (ESI) octopole-orthogonal acceleration time-of-flight (oa TOF)-mass spectrometry (MS) with high mass accuracy (about 2 ppm) and high sensitivity (absolute limit of detection (LOD) for galanthamine was about 43 fg at signal-to-noise 13:1). Moreover, a newly developed and validated TLC-bioautography permit galanthamine sensitivities at pg levels. In this way, more potent than galanthamine AChE inhibitor namely 1,2-dihydrogalanthamine in Narcissus jonquilla 'Pipit' extract could be found (with IC(50) value 0.19 microM lower of about 42% than that of galanthamine). PMID:19203760

  1. PARP inhibitors and more.

    PubMed

    Bose, Chinmoy K; Basu, Nirban

    2015-01-01

    Polyadenosine diphosphate (ADP) ribose polymerase (PARP) lends a panoramic view to the inner mystery of protection of integrity of deoxyribonucleic acid (DNA) in a cell genome. They are a balancing part of an even more dynamic equilibrium of normalcy against daily assaults. PARP finds its companion candidates in other tumor suppressors, with the most prominent and glaring one being breast cancer (BRCA) 1 and 2. The strength of both is split by PARP inhibitors, inculcating the synthetic lethality of tumor cell, which is now in the market for ovarian cancer treatment. There are many reasons for the resistance of such inhibitors, which are now becoming clinically important. These are seen along with other damage repair approaches. PMID:26097394

  2. PARP inhibitors and more

    PubMed Central

    Bose, Chinmoy K.; Basu, Nirban

    2015-01-01

    Polyadenosine diphosphate (ADP) ribose polymerase (PARP) lends a panoramic view to the inner mystery of protection of integrity of deoxyribonucleic acid (DNA) in a cell genome. They are a balancing part of an even more dynamic equilibrium of normalcy against daily assaults. PARP finds its companion candidates in other tumor suppressors, with the most prominent and glaring one being breast cancer (BRCA) 1 and 2. The strength of both is split by PARP inhibitors, inculcating the synthetic lethality of tumor cell, which is now in the market for ovarian cancer treatment. There are many reasons for the resistance of such inhibitors, which are now becoming clinically important. These are seen along with other damage repair approaches.

  3. Coal cleaning employing quaternary salts: Final report, July 1, 1985-February 28, 1986

    SciTech Connect

    Hippo, E.J.; Murdie, N.

    1986-05-01

    Investigation into a novel approach to coal desulfurization has continued. This approach is envisioned to include a treatment step to swell coal in quaternary salt solution, followed by physical separation, chemical reaction to desulfurize the coal, and recovery of the quaternary salt. The objective of the first step of the program was to define conditions under which complete exchange of quaternary salts with coal hydroxy groups occurs, define the extent of coal swelling and changes in coal properties as a function of amount of exchange, and determine the effect of process variation on swelling rate and coal properties. Results of this reaction have demonstrated that substantial coal swelling occurs in the presence of quaternary salts. The amount of quaternary exchange is a small portion of the total OH groups present in the coal. Swelling was found to depend on the concentration of quaternary salts, ratio of solution to coal, time of exchange (less than one hour), type and amount of solvent, pH, and coal composition, but was independent of particle size (<-60 mesh), temperature, and soak time < one hour. Recent data have shown that pyrite and inertinite can be concentrated after quaternary salt treatment. Excessive swelling with little exchange indicates that changes occur in the surface chemistry of the coal during reaction. Thus, oil agglomeration and froth flotation should be improved when coals are treated with quaternary salt. Optical microscopic analysis of the treated coals indicates that swelling and exchange are maceral dependent. In addition, swelling causes liberation of pyrite and inertinite which become isolated or exposed at edge/crack sites. Work is now concentrating on the development of mineral separation from coal and recovery of quaternary salt. 12 refs., 13 figs., 17 tabs.

  4. Classification of acetylcholinesterase inhibitors and decoys by a support vector machine.

    PubMed

    Wang, Kai; Hu, Xiaoying; Wang, Zhi; Yan, Aixia

    2012-07-01

    Acetylcholinesterase has long been considered as a target for Alzheimer disease therapy. In this work, several classification models were built for the purpose of distinguishing acetylcholinesterase inhibitors (AChEIs) and decoys. Each molecule was initially represented by 211 ADRIANA.Code and 334 MOE descriptors. Correlation analysis, F-score and attribute selection methods in Weka were used to find the best reduced set of descriptors, respectively. Additionally, models were built using a Support Vector Machine and evaluated by 5-, 10-fold and leave-one-out cross-validation. The best model gave a Matthews Correlation Coefficient (MCC) of 0.99 and a prediction accuracy (Q) of 99.66% for the test set. The best model also gave good result on an external test set of 86 compounds (Q=96.51%, MCC=0.93). The descriptors selected by our models suggest that H-bond and hydrophobicity interactions are important for the classification of AChEIs and decoys. PMID:22263859

  5. Excitatory and inhibitory effects of second-generation cholinesterase inhibitors on rat gastrointestinal transit.

    PubMed

    Braida, D; Virag, W; Ottonello, F; Sala, M

    2000-06-01

    We investigated the influence of increasing oral doses of second generation acetylcholinesterase inhibitors (AChEI) such as tacrine (0.25, 0.5, 1, 2, 3, 4, 10, and 20 mg kg(-1)), eptastigmine (0.5, 4, 8, 12, 20 and 40 mg kg(-1)) and E2020 (0.18, 0.25, 0.5, 1, 2, 3, 4 and 10 mg kg(-1)) on the distance travelled by a charcoal meal administered 30 min after each compound, in comparison with physostigmine (0.5, 1, 2, 4, 8 and 12 mg kg(-1)). An inverted U regression was observed with a significant parabola between the centimetres travelled and the log of the doses for all AChEI. The maximal stimulating doses (mg kg(-1)) were 2 for physostigmine, 4 for eptastigmine, 3 for tacrine and E2020, while the inhibitory doses were 12 for physostigmine, 40 for eptastigmine, 20 for tacrine and 10 for E2020. The stimulating and inhibiting effects on gastrointestinal propulsion were significantly reversed by 0.25 mg kg(-1)of scopolamine hydrobromide. A dose of scopolamine hydrobromide (0.06 mg kg(-1)) or methylbromide (0.25 mg kg(-1)), pirenzepine dihydrochloride (0.25 mg kg(-1)) and mecamylamine hydrochloride (0.5 mg kg(-1)), which per se did not affect gastrointestinal propulsion, antagonized both the stimulating and inhibitory effect of eptastigmine. Thus, the biphasic effect is peripherally mediated through both muscarinic (at least M(1)) and nicotinic receptors. PMID:10816338

  6. Multitarget-directed tricyclic pyridazinones as g?protein-coupled receptor ligands and cholinesterase inhibitors.

    PubMed

    Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

    2015-06-01

    By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G?protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A , adrenergic ?1A , and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of ?1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. PMID:25924828

  7. Selection of quaternary ammonium bromides for use in zinc/bromine cells

    NASA Astrophysics Data System (ADS)

    Cathro, K. J.; Cedzynska, K.; Constable, D. C.; Hoobin, P. M.

    Various cyclic and aliphatic quaternary ammonium bromides have been tested for use in zinc/bromine battery electrolytes. No single compound can be used over the temperature range 0-50°C due to crystallization of solid materials from either the polybromide or the aqueous phases. Electrolytes containing mixtures of quaternary ammonium bromides can avoid this problem of crystallization, and electrolytes containing 1:1 mixtures of N-methyl- N-ethylpyrrolidinium bromide with either N-methyl- N-ethylmorpholinium bromide or dimethylethylpropylammonium bromide have proved acceptable. The performance of a small zinc/bromine cell using electrolytes prepared from various quaternary ammonium bromides is described.

  8. Gene Name Gene Symbol Variant ID# Assay Type cholinergic receptor, nicotinic, alpha 7 AchR (CHRNA7) 2bp repeat d15s1360 gel http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=3757792

    E-print Network

    Oliver, Douglas L.

    ) 2bp repeat d15s1360 gel http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=3757792 cholinergic receptor, nicotinic, alpha 7 AchR (CHRNA7) 2bp repeat d15s1010 gel http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=1234700 cholinergic receptor, nicotinic, alpha 7 AchR (CHRNA7) 2bp repeat d15s1031 gel http://www.ncbi.nlm.nih.gov

  9. Site of Action of Certain Antibacterial Heterocyclic Quaternary Ammonium Compounds

    PubMed Central

    Cox, W. A.

    1965-01-01

    The site of action of related mono- and bis-quinaldinium compounds was investigated in Staphylococcus aureus and Bacillus megaterium. The effects of these compounds on cell morphology and on protoplast formation and fragility were studied, and the distribution of C14-labeled quinaldinium compound in cell fractions was measured. The latter studies showed that a major part of the quaternary compound penetrates the cell, leaving a very small quantity associated with the cell wall. Similar antibacterial effects were seen with both the mono- and bis-quinaldinium compounds studied, and these effects were comparable with antibacterial properties of known cationic surface-active antibacterial agents. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:4956041

  10. Evidences for Neogene-Quaternary tectonics in Svalbard

    NASA Astrophysics Data System (ADS)

    Cianfarra, Paola; Salvini, Francesco

    2013-04-01

    Svalbard locates along the De Geer Transform Fault that separates the kinematics of North Atlantic and Arctic Ocean and are a continental rise along the North Atlantic portion of this transform. A fold and thrust belt of Paleogene age boards the Western margin of the Spitsbergen with a NNW-SSE trend. In the '60s the West - Spitsbergen fold and trust belt was related to the relative movements between Laurentia and Eurasia. Specifically, it was regarded to be a transpressive orogen developed at the intra-continental De Geer Transform margin between the Barents and the Greenland Shelves. This setting was suggested by the necessity of a continental transform off the western margin of Svalbard needed to restore the relative openings of the North Atlantic-Arctic Ocean basins, and the Paleogene age of the fold-belt. Later structural studies in other areas of Svalbard suggested that convergent tectonics have been prevailing during much of the fold and thrust development. However this belt can hardly be regarded as a classical orogen resulting from an active continental margin for the lack of evidence for subduction, synorogenic magmatism, metamorphism or a thickened crust. On the other hand, it would be difficult to merely relate this fold and thrust belt to the De Geer Transform Fault. According to Authors a transform fault should produce structures with vergence away from the fault on both sides, whereas the found direction of tectonic transport in North Greenland is the same as in Spitsbergen, i.e. to the E and NE. In this way the transform separation of North-Greenland and Spitsbergen should postdate the formation of the Tertiary North-Greenland and Spitsbergen fold and trust belt. This rises the question on possible Neogene-Quaternary tectonics in Spitsbergen. Evidence for this younger tectonics includes the occurrence of Quaternary volcanism and thermal springs in the northern part of Spitsbergen and the moderate seismicity in Nordaustlandet. Other clues supporting a recent tectonics derive from the analysis of satellite images and air photos, including the glacier and fluvial drainage suggesting a strong tectonic control. Moreover some authors have found in Ny Alesund an uplift rate from GPS measurements higher than those predicted by postglacial rebound models, again suggesting a tectonic contribution. Preliminary results from field work in the Brogger peninsula confirmed the presence of Neogene-Quaternary tectonics. Marine terraces and fluvio-glacial deposits show several N-S elongated steps along the northern projection of N-S trending faults cutting the Meso-Cenozoic rocks. N-S trending faults have been systematically found in Devonian to Tertiary rocks. These faults are characterised by right-lateral, strike-slip movements and the presence of near surface to sub aerial mineralizations on their surfaces, including kinematic indicators. N-S faults with the same kinematics show the presence of deformed Quaternary clastic, unconsolidated deposits within their shear zones. All the found brittle deformation evidence are compatible with the kinematics of the recent activity of the De Geer Transform Fault.

  11. Late Quaternary folding of coral reef terraces, Barbados

    NASA Astrophysics Data System (ADS)

    Taylor, Frederick W.; Mann, Paul

    1991-02-01

    Uplifted late Ouaternary coral reefs on the island of Barbados record folding of the emergent crest of the Lesser Antilles accretionary prism (Barbados Ridge complex) since ca. 1 Ma. Three northeast striking folds are defined by systematic changes in altitudes in the crest of First High Cliff, a mostly constructional reef terrace about 125 ka, and Second High Cliff, a partially erosional reef terrace about 500 ka. The folds have wavelengths of 6 to 8 km and fold axes extend about 10 km. The largest anticline rises to the northeast, where it has been breached by erosion exposing highly deformed Eocene to lower Miocene rocks of the Scotland District. Uplift rates based on heights of the last interglacial First High Cliff range from 0.07 to 0.44 mm/yr. Quaternary folding on Barbados indicates that the crest of the accretionary prism continues to be an active fold belt undergoing northwestsoutheast shortening.

  12. Programmed pore architectures in modular quaternary metal-organic frameworks.

    PubMed

    Liu, Lujia; Konstas, Kristina; Hill, Matthew R; Telfer, Shane G

    2013-11-27

    To generate metal-organic frameworks (MOFs) that are complex and modular yet well ordered, we present a strategy employing a family of three topologically distinct linkers that codes for the assembly of a highly porous quaternary MOF. By introducing substituted analogues of the ligands, a set of eight isoreticular frameworks is delivered, with the MOF structure systematically varied while the topology is maintained. To combat randomness and disorder, the substitution patterns of the ligands are designed to be compatible with their crystallographic site symmetries. MOFs produced in this way feature "programmed pores"--multiple functional groups compartmentalized in a predetermined array within a periodic lattice--and are capable of complex functional behavior. In these examples unconventional CO2 sorption trends, including capacity enhancements close to 100%, emerge from synergistic effects. Future PP-MOFs may be capable of enzyme-like heterogeneous catalysis and ultraselective adsorption. PMID:24180695

  13. Quaternary prevention, an answer of family doctors to overmedicalization.

    PubMed

    Jamoulle, Marc

    2015-02-01

    In response to the questioning of Health Policy and Management (HPAM) by colleagues on the role of rank and file family physicians in the same journal, the author, a family physician in Belgium, is trying to highlight the complexity and depth of the work of his colleagues and their contribution to the understanding of the organization and economy of healthcare. It addresses, in particular, the management of health elements throughout the ongoing relationship of the family doctor with his/her patients. It shows how the three dimensions of prevention, clearly included in the daily work, are complemented with the fourth dimension, quaternary prevention or prevention of medicine itself, whose understanding could help to control the economic and human costs of healthcare. PMID:25674569

  14. Neogene-Quaternary Middle Atlas basaltic province (Morocco): Isotope constraints

    NASA Astrophysics Data System (ADS)

    Bosch, D.; Maury, R.; El Azzouzi, M.; Parat, F.; Bellon, H.

    2012-04-01

    The Middle Atlas basaltic province is the largest and youngest volcanic field in Morocco. A hundred well-preserved strombolian cones and maars emitted numerous mafic lava flows which cover a surface of ca. 960 km2 and range in composition from nephelinites to subalkaline basalts through basanites and alkali basalts. We have investigated the Sr, Nd and Pb isotopic compositions and trace element features of these mafic lavas. Nephelinites represent only 1.2 % of the total surface of volcanic units; they form small monogenic volcanoes built during the Middle and Late Miocene (16.25 - 5.87 Ma) and the Plio-Quaternary (3.92 - 0.67 Ma). The three other types are exclusively Plio-Quaternary (3.77 - 0.60 Ma). Basanites cover 22.5 % of the volcanic field area, and generally overlie the more widespread alkali basaltic flows (68.5 % of the plateau surface). Finally, subalkaline basalts form the El Koudiate cone and associated flows (7.8 % of the surface of the volcanic units) and their petrographic, trace element and isotopic features suggest that they derive from the contamination of alkali basaltic magmas by the upper continental crust. Nephelinites, basanites and alkali basalts have a distinct HIMU flavour (206Pb/204Pb up to 20.44) which is similar to that of metasomatic clinopyroxenes from associated spinel-facies peridotite xenoliths (Wittig et al., 2010). Most nephelinites have rather unradiogenic 87Sr/86Sr ratios close to 0.7032, which do not change through time. Those of the other types are slightly higher (up to 0.7037) and tend to increase temporally, and also from basanites to alkali basalts. These geochemical features allow us to discuss the relative contributions of the African continental crust and lithospheric mantle and that of the underlying asthenosphere to the genesis of the Middle Atlas magmas.

  15. Late Quaternary slip on the Santa Cruz Island fault, California

    USGS Publications Warehouse

    Pinter, N.; Lueddecke, S.B.; Keller, E.A.; Simmons, K.R.

    1998-01-01

    The style, timing, and pattern of slip on the Santa Cruz Island fault were investigated by trenching the fault and by analysis of offset late Quaternary landforms. A trench excavated across the fault at Christi Beach, on the western coast of the island, exposed deformation of latest Pleistocene to Holocene sediments and pre-Quaternary rocks, recording repeated large-magnitude rupture events. The most recent earthquake at this site occurred ca. 5 ka. Coastal terraces preserved on western Santa Cruz Island have been dated using the uranium-series technique and by extrapolation using terrace elevations and the eustatic record. Offset of terraces and other landforms indicates that the Santa Cruz Island fault is predominantly left lateral, having a horizontal slip rate of not more than 1.1 mm/yr and probably about 0.8 mm/yr. The fault also has a smaller reverse component, slipping at a rate of between 0.1 and 0.2 mm/yr. Combined with measurements of slip per event, this information suggests a long-term average recurrence interval of at least 2.7 k.y. and probably 4-5 k.y., and average earthquake magnitudes of Mw 7.2-7.5. Sense of slip, recurrence interval, and earthquake magnitudes calculated here for the Santa Cruz Island fault are very similar to recent results for other faults along the southern margin of the western Transverse Range, including the Malibu Coast fault, the Santa Monica fault, the Hollywood fault, and the Raymond fault, supporting the contention that these faults constitute a continuous and linked fault system, which is characterized by large but relatively infrequent earthquakes.

  16. Quaternary incised valleys in southern Brazil coastal zone

    NASA Astrophysics Data System (ADS)

    Weschenfelder, Jair; Baitelli, Ricardo; Corrêa, Iran C. S.; Bortolin, Eduardo C.; dos Santos, Cristiane B.

    2014-11-01

    High-resolution seismic records obtained in the Rio Grande do Sul coastal zone, southern Brazil, revealed that prominent valleys and channels developed in the area before the installation of actual coastal plain. Landwards, the paleoincisions can be linked with the present courses of the main river dissecting the area. Oceanwards, they can be linked with related features previously recognized in the continental shelf and slope by means of seismic and morphostructural studies. Based mainly on seismic, core data and geologic reasoning, it can be inferred that the coastal valleys were incised during forced regression events into the coastal prism deposited during previous sea level highstand events of the Quaternary. Seismic data has revealed paleovalleys up to 10 km wide and, in some places, infilled with up to 40 m thick of sediments. The results indicated two distinct periods of cut-and-fill events in the Patos Lagoon area. The filling of the younger incision system is mainly Holocene and its onset is related to the last main regressive event of the Pleistocene, when the sea level fell about 130 m below the actual position. The older incision and filling event is related to the previous regressive-transgressive events of the Middle and Late Pleistocene. The fluvial discharge fed delta systems on the shelf edge during the sea level lowstands. The subsequent transgressions drowned the incised drainage, infilling it and closing the inlets formerly connecting the coastal river to the ocean. The incised features may have played a significant role on the basin-margin architecture, facies distribution and accommodation space during the multitude of up and down sea level events of the Quaternary.

  17. Are seawater Sr/Ca variations preserved in Quaternary foraminifera?

    SciTech Connect

    Stoll, H.M.; Schrag, D.P.; Clemens, S.C.

    1999-11-01

    High precision measurements of Sr/Ca in planktonic foraminifera for the last 150 ka reveal Sr/Ca variations of up to 12% on glacial/interglacial time scales. Although records showing the largest variations appear to be strongly influenced by selective dissolution, other records show Sr/Ca variations of 3--5% that do not covary with indicators of dissolution intensity and that are reproduced in sites of contrasting Quaternary dissolution histories. These systematic variations are characterized by high Sr/Ca ratios during glacial maxima, followed by steep decreases during deglaciation and gradual increases through interstadial periods, closely following {delta}{sup 18}O curves. Foraminiferal Sr/Ca variations may reflect changes in the Sr/Ca ratio of seawater, or they may be due to kinetically or biologically induced changes in Sr partitioning. Coupled numerical models of the Sr and Ca budgets of the ocean reveal that sea level changes, together with large changes in river fluxes and carbonate accumulation rates, can produce seawater Sr/Ca variations that approximate both the shape and amplitude of foraminiferal Sr/Ca variations. However, such extreme changes in river and carbonate fluxes conflict with existing data on carbonate accumulation rates and Sr isotopic constraints on the magnitude of variations in the river flux. Smaller variations (1--3%) in the Sr/Ca ratio of seawater likely characterize Quaternary glacial cycles. Changes in Sr partitioning due to glacial-interglacial changes in the carbonate ion concentration and other environmental factors likely produce additional variation in the Sr/Ca record of planktonic foraminifera.

  18. Toxicity of checkpoint inhibitors.

    PubMed

    Schmerling, Rafael Aron

    2014-09-01

    Immunologic checkpoint inhibitor is a new class of antineoplastic drugs which mechanism of action depends on the interaction with the immune system. The first in class was ipilimumab, anti-CTLA4, and soon the anti-PD1 (Programmed Death 1) and anti-PDL1 are expected to be available. Although the profile of adverse events is unique, they are predictable and, by complying with the guidelines available, the management of these drugs is safe in the great majority of patients. Here, it is provided a review of adverse events and their management. PMID:25841457

  19. CASPASE SUBSTRATES AND INHIBITORS

    PubMed Central

    Por?ba, Marcin; Strózyk, Aleksandra; Salvesen, Guy S.; Drag, Marcin

    2014-01-01

    Caspases are proteases at the heart of networks that govern apoptosis and inflammation. The past decade has seen huge leaps in understanding the biology and chemistry of the caspases, largely through the development of synthetic substrates and inhibitors. Such agents are used to define the role of caspases in transmitting life and death signals, in imaging caspases in situ and in vivo, and in deconvoluting the networks that govern cell behavior. Additionally, focused proteomics methods have begun to reveal the natural substrates of caspases in the thousands. Together, these chemical and proteomics technologies are setting the scene for designing and implementing control of caspase activity as appropriate targets for disease therapy. PMID:23788633

  20. HIV-1 Entry Inhibitor

    Cancer.gov

    Soluble forms (sCD4) of human CD4, the HIV-1 primary receptor, are potent HIV-1 entry inhibitors. Both four-domain (D1-4) and two-domain (D1D2) sCD4 and their fusion proteins have been tested as candidate therapeutics in animal models and in human clinical trials and were well tolerated by patients with no significant clinical or immunologic toxicities and exhibited significant inhibitory activities. However, their activities were transient and the virus rapidly rebound.

  1. High performance oilfield scale inhibitors

    SciTech Connect

    Duccini, Y.; Dufour, A. [NorsoHaas S.A., Verneuil en Hallatte (France); Hann, W.M.; Sanders, T.W.; Weinstein, B. [Rohm and Haas Co., Spring House, PA (United States)

    1997-08-01

    Sea water often reacts with the formation water in offshore fields to produce barium, calcium and strontium sulfate deposits that hinder oil production. Newer fields often have more difficult to control scale problems than older ones, and current technology scale inhibitors are not able to control the deposits as well as needed. In addition, ever more stringent regulations designed to minimize the impact of inhibitors on the environment are being enacted. Three new inhibitors are presented that overcome many of the problems of older technology scale inhibitors.

  2. Corrosion inhibitors in hydrocarbon systems

    SciTech Connect

    Jayaraman, A.; Saxena, R.C. [Indian Inst. of Petroleum, Dehra Dun (India)

    1996-08-01

    An attempt has been made to provide directions to select the various corrosion inhibitors for different areas of petroleum industry based on their available structure-activity relationship. The present review highlights the utility of most of the inhibitors (used in production, handling, and distillation of crude oils) which are either N-containing compounds or their derivatives. The action of specific corrosion inhibitors used in oil well acidizing, refining units handling naphthenic acid crudes, and amine gas absorbers has been explained. Emphasis has been laid on the dependence of the inhibitor performance on the type of the test method used for its evaluation. 54 refs., 6 figs., 5 tabs.

  3. Antibacterial properties of poly(quaternary ammonium) modified gold and titanium dioxide nanoparticles.

    PubMed

    Wan, Weijie; Yeow, John T W

    2012-06-01

    We report excellent antibacterial effect induced by amine-functionalized gold and titanium dioxide nanoparticles without external excitations. The idea originates from the excellent antibacterial property of quaternary ammonium salts. The effects of poly(quaternary ammonium) and polyacrylate sodium functional groups as nanoparticle surfactants are compared to show that poly(quaternary ammonium) functional groups are the main cause of the induced antibacterial effect. 99.999% of E. coli can be destructed in 10 minutes by simply mixing bacteria with nanoparticle dispersions. The effect of nanoparticle concentrations on the antibacterial property is evaluated. Time required to significantly suppress bacteria growth is studied. The result indicates that the excellent antibacterial property can be introduced to any nanomaterials by using poly(quaternary ammonium) functional groups as surfactants. The engineered nanoparticles can find enormous applications such as self-cleaning surfaces, waste water treatment, Lab-on-a-Chip devices and many more. PMID:22905506

  4. Map and data for Quaternary faults and folds in Washington state

    USGS Publications Warehouse

    Lidke, David J.; Johnson, Samuel Y.; McCrory, Patricia A.; Personius, Stephen F.; Nelson, Alan R.; Dart, Richard L.; Bradley, Lee-Ann; Haller, Kathleen M.; Machette, Michael N.

    2004-01-01

    The map shows faults and folds in Washington State that exhibit evidence of Quaternary deformation and includes data on timing of most recent movement, sense of movement, slip rate, and continuity of surface expression.

  5. The late Quaternary limnological history of Lake Kinneret (Sea of Galilee), Israel

    E-print Network

    Marco, Shmuel "Shmulik"

    The late Quaternary limnological history of Lake Kinneret (Sea of Galilee), Israel N. Hazana , M) during the Neogene­Quartenary periods. We reconstructed the limnological history (level and composition

  6. OMVPE Growth of Quaternary (Al,Ga,In)N for UV Optoelectronics (title change from A)

    SciTech Connect

    HAN,JUNG; FIGIEL,JEFFREY J.; PETERSEN,GARY A.; MYERS JR.,SAMUEL M.; CRAWFORD,MARY H.; BANAS,MICHAEL ANTHONY; HEARNE,SEAN JOSEPH

    2000-01-18

    We report the growth and characterization of quaternary AlGaInN. A combination of photoluminescence (PL), high-resolution x-ray diffraction (XRD), and Rutherford backscattering spectrometry (RBS) characterizations enables us to explore the contours of constant PL peak energy and lattice parameter as functions of the quaternary compositions. The observation of room temperature PL emission at 351nm (with 20% Al and 5% In) renders initial evidence that the quaternary could be used to provide confinement for GaInN (and possibly GaN). AlGaInN/GrdnN MQW heterostructures have been grown; both XRD and PL measurements suggest the possibility of incorporating this quaternary into optoelectronic devices.

  7. Induction of contact drematitis in guinea pigs by quaternary ammonium compounds: the mechanisms of antigen formation

    SciTech Connect

    Schallreuter, K.R.; Schulz, K.H.; Wood, J.M.

    1986-12-01

    Eight quaternary ammonium compounds were tested for their ability to induce contact dermatitis in guinea pigs by using a modified Freund's complete adjuvant test together with the guinea pig maximization test. Only two quaternary ammonium salts of eight tested could be designated as strong allergens. These two active substances were shown to be capable of stable association with membrane lipids in forming immunogenic complexes. This surface complexation phenomenon was confirmed by using a spin-labeled quaternary ammonium salt which competed for binding sites to the surface of epidermal cells in vivo. Electron spin resonance was used to demonstrate that stable ion-pairs are formed between binding sites and the two allergenic preservatives. Furthermore, information was obtained on the kinetics of immunogenic complex formation as well as on the position and orientation of the quaternary ammonium ion at the cell surface.

  8. Metalorganic Vapor-Phase Epitaxial Growth and Characterization of Quaternary AlGaInN

    SciTech Connect

    BANAS, MICHAEL ANTHONY; CRAWFORD, MARY H.; FIGIEL, JEFFREY J.; HAN, JUNG; LEE, STEPHEN R.; MYERS JR., SAMUEL M.; PETERSON, GARY D.

    1999-09-27

    In this letter we report the growth (by MOVPE) and characterization of quaternary AlGaInN. A combination of PL, high-resolution XRD, and RBS characterizations enables us to explore and delineate the contours of equil-emission energy and lattice parameters as functions of the quaternary compositions. The observation of room temperature PL emission as short as 351nm (with 20% Al and 5% In) renders initial evidence that the quaternary could be used to provide confinement for GaInN (and possibly GaN). AlGaInN/GdnN MQW heterostructures have also been grown; both x-ray diffraction and PL measurement suggest the possibility of incorporating this quaternary into optoelectronic devices.

  9. Induction of contact dermatitis in guinea pigs by quaternary ammonium compounds: the mechanism of antigen formation.

    PubMed Central

    Schallreuter, K U; Schulz, K H; Wood, J M

    1986-01-01

    Eight quaternary ammonium compounds were tested for their ability to induce contact dermatitis in guinea pigs by using a modified Freund's complete adjuvant test together with the guinea pig maximization test. Only two quaternary ammonium salts of the eight tested could be designated as strong allergens. These two active substances were shown to be capable of stable association with membrane lipids in forming immunogenic complexes. This surface complexation phenomenon was confirmed by using a spin-labeled quaternary ammonium salt which competed for binding sites at the surface of epidermal cells in vivo. Electron spin resonance was used to demonstrate that stable "ion-pairs" are formed between binding sites and the two allergenic preservatives. Furthermore, information was obtained on the kinetics of immunogenic complex formation as well as on the position and orientation of the quaternary ammonium ion at the cell surface. PMID:3830108

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

    PubMed

    Willis, Katherine J; Niklas, Karl J

    2004-02-29

    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 those of other periods in Earth's history; and (ii) that the mechanisms of isolation during the Quaternary were sufficient in time and space for genetic diversification to foster speciation. These assumptions are addressed by examining the plant fossil record for the Quaternary (in detail) and for the past 410 Myr, which encompasses previous intervals of icehouse Earth. Our examination of the Quaternary record indicates that floristic responses to climate changes during the past 1.8 Myr were complex and that a distinction has to be made between those plants that were able to withstand the extremes of glacial conditions and those that could not. Generation times are also important as are different growth forms (e.g. herbaceous annuals and arborescent perennials), resulting in different responses in terms of genetic divergence rates during isolation. Because of these variations in the duration of isolation of populations and genomic diversification rates, no canonical statement about the predominant floristic response to climatic changes during the Quaternary (i.e. elevated rates of speciation or extinction, or stasis) is currently possible. This is especially true because of a sampling bias in terms of the fossil record of tree species over that of species with non-arborescent growth forms. Nevertheless, based on the available information, it appears that the dominant response of arborescent species during the Quaternary was extinction rather than speciation or stasis. By contrast, our examination of the fossil record of vascular plants for the past 410 Myr indicates that speciation rates often increased during long intervals of icehouse Earth (spanning up to 50 Myr). Therefore, longer periods of icehouse Earth than those occurring during the Quaternary may have isolated plant populations for sufficiently long periods of time to foster genomic diversification and allopatric speciation. Our results highlight the need for more detailed study of the fossil record in terms of finer temporal and spatial resolution than is currently available to examine the significance of intervals of icehouse Earth. It is equally clear that additional and detailed molecular studies of extant populations of Quaternary species are required in order to determine the extent to which these 'relic' species have genomically diversified across their current populations. PMID:15101573

  11. Algicidal Activity of a Surface-Bonded Organosilicon Quaternary Ammonium Chloride

    PubMed Central

    Walters, P. A.; Abbott, E. A.; Isquith, A. J.

    1973-01-01

    The hydrolysis product of a quaternary amine-containing organosilicon salt, 3-(trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride, was found to exhibit algicidal activity while chemically bonded to a variety of substrates. Six representative species of Chlorophyta, Cyanophyta, and Chrysophyta were used to evaluate the algicidal activity. Substrate-bonded 14C-labeled organosilicon quaternary ammonium salt when attached to nonwoven fibers was durable to repeated washings, and algicidal activity could not be attributed to slow release of the chemical. Images PMID:4632852

  12. SURVEY OF TERNARY AND QUATERNARY METASTABLE GAMMA-PHASE URANIUM ALLOYS

    Microsoft Academic Search

    V. W. Storhok; A. A. Bauer; R. F. Dickerson

    1958-01-01

    A survey of the effects of ternary and quaternary alloying on the ;\\u000a stability and properties of uranium-zirconium, -- niobium, and -- molybdenum-base ;\\u000a gammaphase alloys was conducted. The effects of ternary and quaternary additions ;\\u000a of chromium, molybdenum, niobium, ruthenium, vanndium, and zirconium on ;\\u000a transformation kinetics, transformation temperature, hot hardness, and corrosion ;\\u000a resistance were investigated. Niobium or

  13. The performance of direct-sequence spread spectrum with complex processing and quaternary data modulation

    Microsoft Academic Search

    Thomas G. Macdonald; Michael B. Pursley

    2000-01-01

    The receiver processing that is often employed for direct-sequence spread spectrum with quaternary data modulation operates separately on in-phase and quadrature components of the spread-spectrum signal. Previous results on complex quaternary sequences, which are also referred to as four-phase sequences, provide a strong motivation to employ alternative processing methods that permit the receiver to benefit from the correlation properties of

  14. Studies on the synthesis and antibacterial activities of polymeric quaternary ammonium salts from dimethylaminoethyl methacrylate

    Microsoft Academic Search

    Guiqian Lu; Dingcai Wu; Ruowen Fu

    2007-01-01

    Four quaternary ammonium salt monomers were synthesized from dimethylaminoethyl methacrylate (DMAEMA) by quaternization with benzyl chloride (BC), butyl bromide (BB), dodecyl bromide (DB) or hexadecyl bromide (HB), respectively. And then, the monomers were homopolymerized to obtain four polymeric quaternary ammonium materials with different lengths of alkyl chain, which were referred to as poly(DMAEMA-BC), poly(DMAEMA-BB), poly(DMAEMA-DB) and poly(DMAEMA-HB), respectively. The resultant

  15. Mixed Quaternary Ammonium and Phosphonium Salts Bound to Macromolecular Supports for Removal Bacteria from Water

    Microsoft Academic Search

    A. Popa; G. Ilia; S. Iliescu; G. Dehelean; A. Pascariu; A. Bora; C. M. Davidescu

    2004-01-01

    This paper deals with synthesis and characterization of mixed quaternary ammonium and phosphonium salts grafted on macromolecular supports by polymer-analogous trans-quaternization reactions. The degrees of functionalization with quaternary mixed ammonium and phosphonium groups are relatively high, ranging from 0.09 to 1.285 mmoles of functional groups\\/gram of copolymer, ensuring a sufficient concentration of active centers per unit mass of copolymer and

  16. Synthesis and structure-activity relationship (SAR) of novel perfluoroalkyl-containing quaternary ammonium salts

    Microsoft Academic Search

    Jian-Ying Sun; Jing Li; Xiao-Long Qiu; Feng-Ling Qing

    2005-01-01

    A new series of perfluoroalkyl-containing quaternary ammonium compounds were prepared and examined for their antibacterial activities. The perfluoroalkyl-containing quaternary ammonium salts mainly exhibited excellent antibacterial activity for the Gram-positive strain such as Staphylococcus aureus, the MIC (minimal inhibitory concentration) values was between 2.5 and 10?g\\/mL and the MBC (minimal bactericidal concentration) values were 20?g\\/mL. They all showed weak activity against

  17. Synthesis and in vitro antibacterial activity of quaternary ammonium cephalosporin derivatives bearing oxazolidinone moiety

    Microsoft Academic Search

    In Hwa Chung; Choong Sup Kim; Jae Hong Seo; Bong Young Chung

    1999-01-01

    Several oxazolidinones having amine moiety were prepared to form a quaternary ammonium salt with cephalosporin nucleus, and\\u000a antibacterial activity of the quaternary ammonium cephalosporin derivatives bearing oxazolidinone moiety were examined particularly\\u000a with expectation of dual activity. However, the cephalosporin-oxazolidinone compounds revealed rather weaker antibacterial\\u000a activityin vitro than their parent exazolidinone and cephalosporin without showing any characteristic activity as expected.

  18. Antibacterial activity of quaternary ammonium chitosan containing mono or disaccharide moieties: Preparation and characterization

    Microsoft Academic Search

    Warayuth Sajomsang; Pattarapond Gonil; Supawan Tantayanon

    2009-01-01

    The 9 quaternary ammonium chitosans containing monosaccharides or disaccharides moieties were successfully synthesized by reductive N-alkylation then quaternized by N-(3-chloro-2-hydroxypropyl) trimethylammonium chloride (Quat-188). The chemical structures of quaternary ammonium chitosan derivatives were characterized by ATR-FTIR and 1H NMR spectroscopy. The degree of N-substitution (DS) and the degree of quaternization (DQ) were determined by 1H NMR spectroscopic method. It was found

  19. Efficacy of a quaternary ammonium compound against planktonic and sessile populations of different Legionella pneumophila strains

    Microsoft Academic Search

    Ayten Kimiran-Erdem; Nazmiye Ozlem Sanli-Yurudu; Aysin Cotuk

    2007-01-01

    Efficacy of Gemacide PN-50TM (a quaternary ammonium compound) as a commercial formulation recommended for disinfecting heat exchangers was determined\\u000a for both planktonic and sessile populations of variousLegionella pneumophila strains. The quaternary ammonium compound (QAC) was preferred as an alternative due to the emerging resistance of potentially\\u000a pathogenic bacteria against different biocides. PlanktonicL. pneumophila strains were suspended in tap water while

  20. Antibacterial activity of reactive quaternary ammonium compounds in solution and in nonleachable coatings

    Microsoft Academic Search

    G. Gozzelino; D. E. Romero Tobar; N. Chaitiemwong; W. C. Hazeleger; R. R. Beumer

    2011-01-01

    Antibacterial polymers suitable for coating applications without leaching of the biocidal component have been obtained by UV copolymerization of acrylic resins with acrylic monomers containing quaternary ammonium moieties. Suitable reactive biocides, based on quaternary ammonium monomers (QAMs), endowed with undecylacryloyl group and alkyl chains with 2 (QAM-C2), 8 (QAM-C8), and 16 (QAM-C16) carbon atoms have been synthesized. Aqueous solutions of

  1. Engineering geologic studies of the Austin Chalk, Taylor Marl, and Quaternary alluvium Ellis County, Texas

    E-print Network

    Westerfield, John Gayden

    1989-01-01

    ENGINEERING GEOLOGIC STUDIES OF THE AUSTIN CHALK, TAYLOR MARL, AND QUATERNARY ALLUVIUM, ELLIS COUNTY, TEXAS A Thesis by JOHN GAYDEN WESTERFIELD Submitted to the Office of Graduate Studies of Texas A&M University in partial fullfillment... and content by: Norma (Chair of ford ommittee) Christ pher C. Mathewson (Member) Richard L. Carlson (Member) John H. 'Spa (H ad of Department) May 1989 ABSTRACT Engineering Geologic Studies of the Austin Chalk, Taylor Marl, and Quaternary Alluvium...

  2. Engineering geologic studies of the Austin Chalk, Taylor Marl, and Quaternary alluvium Ellis County, Texas 

    E-print Network

    Westerfield, John Gayden

    1989-01-01

    ENGINEERING GEOLOGIC STUDIES OF THE AUSTIN CHALK, TAYLOR MARL, AND QUATERNARY ALLUVIUM, ELLIS COUNTY, TEXAS A Thesis by JOHN GAYDEN WESTERFIELD Submitted to the Office of Graduate Studies of Texas A&M University in partial fullfillment... of the requirements for the degree of MASTER OF SCIENCE May 1989 Major Subject: Geology ENGINEERING GEOLOGIC STUDIES OF THE AUSTIN CHALX, TAYLOR MARL, AND QUATERNARY ALLUVIUM, ELLIS COUNTY, TEXAS A Thesis by JOHN GAYDEN WESTERFIELD Approved as to style...

  3. Use of quaternary ammonium salts of nitrogen containing polymers for improved carburetor detergency

    SciTech Connect

    Biasotti, J.B.; Vartanian, P.F.

    1980-01-15

    A quaternary ammonium salt is described of a copolymer, said copolymer being the olefin polymerization product of: (A) a nitrogen amine free ester of a C/sub 1/-C/sub 6/ olefinically unsaturated aliphatic mono-, di-, or polycarboxylic acid having a tertiary nitrogen atom; and (B) an olefinically unsaturated co-monomer containing a basic nitrogen atom in a side chain; a fuel component, especially gasoline, containing such quaternary ammonium salt of such copolymer as a detergent.

  4. Characterization of â??the quaternary amine transporters of Rhizobium leguminosarum bv. viciae 3841

    Microsoft Academic Search

    Marc A. Fox; Ramakrishnan Karunakaran; Mary E. Leonard; Bouchra Mouhsine; Allan Williams; Alison K. East; J. Allan Downie; Philip S. Poole

    2008-01-01

    Rhizobium leguminosarum bv. viciae 3841 contains six putative quaternary ammonium transporters (Qat), of the ABC family. Qat6 was strongly induced by hyperosmosis although the solute transported was not identified. All six systems were induced by the quaternary amines choline and glycine betaine. It was confirmed by microarray analysis of the genome that pRL100079-83 (qat6) is the most strongly upregulated transport

  5. Synthesis of a quaternary amine anion exchange resin and study its adsorption behaviour for chromate oxyanions

    Microsoft Academic Search

    Asem A. Atia

    2006-01-01

    Glycidyl methacrylate\\/N,N?-methylene bis-acrylamide (GMA\\/MBA) was prepared and allowed to react with tetraethylenepentamine (TEP) to give glycidyl methacrylate amine resin (RPA) followed by treatment with glycidyl trimethylammonium chloride (GTA) to give glycidyl methacrylate resin bearing quaternary ammonium chloride moieties (RQA). Zeta potential measurements showed that RQA particles are positively charged over pH 2–10 indicating the strong basic nature of the quaternary

  6. Synthesis and characterization of ruthenium(II) phenanthroline complexes containing quaternary amine substituents

    Microsoft Academic Search

    A. A. Bhuiyan; R. Dossey; T. J. Anderson; F. Millett; B. Durham

    2008-01-01

    A series of mixed-ligand complexes of ruthenium(II) containing 5-methylphenanthroline and trimethylamino-5-methylphenanthroline have been synthesized to investigate the impact of the quaternary amine on the photophysical properties. Thermal stability studies indicate that the quaternary amine is stable with respect to hydrolysis. Mass spectral analysis of the complexes revealed only fragments consistent with homolytic cleavage of the amines and no parent ions

  7. Kinetics of extraction in the cupric-chloro-quaternary amine system

    Microsoft Academic Search

    M. C. Fuerstenau; M. R. Elmore; B. R. Palmer; K. N. Han

    1987-01-01

    The kinetics of extraction of the cupric tetrachloro complex with quaternary amine is presented as a function of cupric, chloride,\\u000a and amine concentrations and temperature. Initial rate exhibits first order dependence with respect to the concentrations\\u000a of the cupric tetrachloro complex and quaternary amine. Binary interaction between interfacial cupric tetrachloro complex\\u000a and amine is rate controlling. The enthalpy of activation

  8. Sampling and Analysis of Quaternary Ammonium Compounds (QACs) Traces in Indoor Atmosphere

    Microsoft Academic Search

    Guillaume Vincent; Marie Christine Kopferschmitt-Kubler; Philippe Mirabel; Gabrielle Pauli; Maurice Millet

    2007-01-01

    Quaternary Ammonium Compounds (QACs) are widely found in disinfectants used in hospitals. Benzalkonium chloride (BAC) and\\u000a didecyldimethylammonium chloride (DDAC) predominate in the disinfecting formulations. These compounds are strong irritants\\u000a and can play a role in the induction of Occupational Asthma among the professionals of health and cleaning. In order to evaluate\\u000a the potential health effect of these quaternary ammonium compounds

  9. Mixed ternary ion associate formation between xanthene dye, cinchona-alkaloid and quaternary ammonium ion and its application to the determination of trace amounts of quaternary ammonium salts in pharmaceuticals

    Microsoft Academic Search

    Tadao Sakai; Akihiko Hirose

    2003-01-01

    Xanthene dyes such as eosin and tetraiodofluorescein form 1:2 ion associates with quaternary ammonium ions at pH 7–9; however, the development of color in the organic solvent is poor. When a quaternary ammonium salt is added in the extractable 1:2 associate formed between a xanthene dye and a cinchona-alkaloid in the neutral media, a mixed ternary ion associate (xanthene dye:cinchona-alkaloid:quaternary

  10. Clinical translation of angiogenesis inhibitors

    Microsoft Academic Search

    Robert Kerbel; Judah Folkman

    2002-01-01

    Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians. What are the most common questions that clinicians ask as they begin to

  11. Aminoalcohol based mixed corrosion inhibitors

    Microsoft Academic Search

    F. Wombacher; U. Maeder; B. Marazzani

    2004-01-01

    The objective of this paper is to present new results and sum up the behaviour of aminoalcohol based mixed corrosion inhibitors. These organic and mixed (organic\\/inorganic) inhibitors can be used as concrete admixtures or in repair products to delay the onset of corrosion or to reduce the rate of corrosion of reinforcing steel in concrete structures. The inhibiting properties are

  12. Biocontrol of blue mold on apple fruits by Aureobasidium pullulans (strain Ach 1-1): in vitro and in situ evidence for the possible involvement of competition for nutrients.

    PubMed

    Bencheqroun, S Krimi; Bajji, M; Massart, S; Bentata, F; Labhilili, M; Achbani, H; El Jaafari, S; Jijakli, M H

    2006-01-01

    Aureobasidium pullulans strain Ach1-1 was recently isolated for its biocontrol effectiveness against Penicillium expansum, the causal agent of blue mold on harvested apples. In the present study, strain Ach1-1 was found to be very effective in controlling P. expansum on apple wounds. For in vitro tests, strain Ach1-1 and P. expansum were cocultured in the presence of apple juice (0 - 5%) using a system preventing direct contact between both agents. The presence of the antagonist greatly reduced germination of conidia at low (0.1, 0.5 and 1%) but not at high (5%) juice concentrations. Germination of previously inhibited conidia at 0.5% apple juice was partially restored in the presence of the antagonist when fresh juice was added at a final concentration of 5%, and completely recovered at both 0.5 and 5% juice concentrations in the absence of the antagonist. These data show that P. expansum conidia are able to germinate when cocultered with strain Ach1-1 in conditions of sufficient rather than limited nutrient availability and that the antagonist does not affect the viability of these conidia, indicating that the inhibitory effect of strain Ach1-1 on conidia germination may be due to a competition for nutrients. Such observation was confirmed in situ since the application of high amounts of exogenous amino acids, vitamins or sugars on apple wounds significantly reduced the protective level of strain Ach1-1 against P. expansum, the most important effect was obtained with amino acids followed by vitamins and then by sugars. The present work provides both in vitro and in situ evidence that the biocontrol activity of strain Ach1-1 against P. expansum essentially relies on competition for apple fruit nutrients, especially amino acids. PMID:17390872

  13. Coal cleaning employing quaternary salts. Annual report, July 1, 1984-June 30, 1985. [Tetrabutyl ammonium hydroxide; tetramethyl ammonium hydroxide

    SciTech Connect

    Hippo, E.J.; Murdie, N.

    1985-09-01

    An investigation into a novel approach to coal desulfurization has been initiated. This approach is in the formative stages, but is envisioned to included a treatment step to swell coal in quaternary salt solution followed by physical separation, chemical reaction to desulfurize the coal, and recovery of the quaternary salt. The present program was aimed at developing fundamental data associated with the first step. This report covers the first six months of the project. The objective of this portion of the program was to define conditions under which complete exchange of quaternary salts with coal hydroxy groups occurs, define the extent of coal swelling and changes in coal properties as a function of amount of exchange, and determine the effect of process variation on swelling rate and coal properties. Results of this research have demonstrated that substantial coal swelling occurs in the presence of quaternary salts. The amount of quaternary exchange is a small portion of the total OH groups present in the coal. Swelling has been found to be dependent on the concentration of quaternary salts, the ratio of solution to coal, time of exchange, and the type of solvent. The data also demonstrate that particle size and size distribution are changed extensively by the quaternary salt treatment. Furthermore, it appears that iron sulfide and/or sulfate are dissolved in the quaternary base. Also, some organic material is dissolved by the quaternary base. Preliminary data indicate that minerals and inertinite can be concentrated after quaternary salt treatment. The results indicate that quaternary recovery should be easier than first expected. Also, the excessive swelling with little exchange indicated that the surface chemistry of the coal is altered after exchange. Thus, oil agglomeration and froth flotation should be improved when coals are treated with the quaternary salt. 11 refs., 11 tabs.

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

    Microsoft Academic Search

    Shin-Hua Lu; Josephine W Wu; Hsuan-Liang Liu; Jian-Hua Zhao; Kung-Tien Liu; Chih-Kuang Chuang; Hsin-Yi Lin; Wei-Bor Tsai; Yih Ho

    2011-01-01

    BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment

  15. New cholinesterase inhibitors from Garcinia atroviridis.

    PubMed

    Tan, Wen-Nee; Khairuddean, Melati; Wong, Keng-Chong; Khaw, Kooi-Yeong; Vikneswaran, Murugaiyah

    2014-09-01

    A triflavanone, Garcineflavanone A (1) and a biflavonol, Garcineflavonol A (2) have been isolated from the stem bark of Garcinia atroviridis (Clusiaceae), collected in Peninsular Malaysia. Their structures were established using one and two-dimensional NMR, UV, IR and mass spectrometry and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activity. Molecular docking studies of the isolated compounds were performed using docking procedure of AutoDock to disclose the binding interaction and orientation of these molecules into the active site gorge. PMID:24924287

  16. Osteocompatibility of Biofilm Inhibitors

    PubMed Central

    Rawson, Monica; Haggard, Warren; Jennings, Jessica A

    2014-01-01

    The demand for infection prevention therapies has led to the discovery of several biofilm inhibitors. These inhibiting signals are released by bacteria, fungi, or marine organisms to signal biofilm dispersal or disruption in Gram-positive, Gram-negative, and fungal microorganisms. The purpose of this study was to test the biocompatibility of five different naturally-produced biofilm chemical dispersal and inhibition signals with osteoblast-like cells: D-amino acids (D-AA), lysostaphin (LS), farnesol, cis-2-decenoic acid (C2DA), and desformyl flustrabromine (dFBr). In this preliminary study, compatibility of these anti-biofilm agents with differentiating osteoblasts was examined over a 21 days period at levels above and below concentrations active against bacterial biofilm. Anti-biofilm compounds listed above were serially diluted in osteogenic media and added to cultures of MC3T3 cells. Cell viability and cytotoxicity, after exposure to each anti-biofilm agent, were measured using a DNA assay. Differentiation characteristics of osteoblasts were determined qualitatively by observing staining of mineral deposits and quantitatively with an alkaline phosphatase assay. D-AA, LS, and C2DA were all biocompatible within the reported biofilm inhibitory concentration ranges and supported osteoblast differentiation. Farnesol and dFBr induced cytotoxic responses within the reported biofilm inhibitory concentration range and low doses of dFBr were found to inhibit osteoblast differentiation. At high concentrations, such as those that may be present after local delivery, many of these biofilm inhibitors can have effects on cellular viability and osteoblast function. Concentrations at which negative effects on osteoblasts occur should serve as upper limits for delivery to orthopaedic trauma sites and guide development of these potential therapeutics for orthopaedics. PMID:25505496

  17. Osteocompatibility of biofilm inhibitors.

    PubMed

    Rawson, Monica; Haggard, Warren; Jennings, Jessica A

    2014-01-01

    The demand for infection prevention therapies has led to the discovery of several biofilm inhibitors. These inhibiting signals are released by bacteria, fungi, or marine organisms to signal biofilm dispersal or disruption in Gram-positive, Gram-negative, and fungal microorganisms. The purpose of this study was to test the biocompatibility of five different naturally-produced biofilm chemical dispersal and inhibition signals with osteoblast-like cells: D-amino acids (D-AA), lysostaphin (LS), farnesol, cis-2-decenoic acid (C2DA), and desformyl flustrabromine (dFBr). In this preliminary study, compatibility of these anti-biofilm agents with differentiating osteoblasts was examined over a 21 days period at levels above and below concentrations active against bacterial biofilm. Anti-biofilm compounds listed above were serially diluted in osteogenic media and added to cultures of MC3T3 cells. Cell viability and cytotoxicity, after exposure to each anti-biofilm agent, were measured using a DNA assay. Differentiation characteristics of osteoblasts were determined qualitatively by observing staining of mineral deposits and quantitatively with an alkaline phosphatase assay. D-AA, LS, and C2DA were all biocompatible within the reported biofilm inhibitory concentration ranges and supported osteoblast differentiation. Farnesol and dFBr induced cytotoxic responses within the reported biofilm inhibitory concentration range and low doses of dFBr were found to inhibit osteoblast differentiation. At high concentrations, such as those that may be present after local delivery, many of these biofilm inhibitors can have effects on cellular viability and osteoblast function. Concentrations at which negative effects on osteoblasts occur should serve as upper limits for delivery to orthopaedic trauma sites and guide development of these potential therapeutics for orthopaedics. PMID:25505496

  18. Late Quaternary carbonate deposition at the bottom of the world

    NASA Astrophysics Data System (ADS)

    Frank, Tracy D.; James, Noel P.; Bone, Yvonne; Malcolm, Isabelle; Bobak, Lindsey E.

    2014-05-01

    Carbonate sediments on polar shelves hold great potential for improving understanding of climate and oceanography in regions of the globe that are particularly sensitive to global change. Such deposits have, however, not received much attention from sedimentologists and thus remain poorly understood. This study investigates the distribution, composition, diagenesis, and stratigraphic context of Late Quaternary calcareous sediments recovered in 15 piston cores from the Ross Sea shelf, Antarctica. Results are used to develop a depositional model for carbonate deposition on glaciated, polar shelves. The utility of the deposits as analogs for the ancient record is explored. In the Ross Sea, carbonate-rich lithofacies, consisting of poorly sorted skeletal sand and gravel, are concentrated in the west and along the outer reaches of the continental shelf and upper slope. Analysis of fossil assemblages shows that deposits were produced by numerous low-diversity benthic communities dominated locally by stylasterine hydrocorals, barnacles, or bryozoans. Radiocarbon dating indicates that carbonate sedimentation was episodic, corresponding to times of reduced siliciclastic deposition. Most accumulation occurred during a time of glacial expansion in the lead-up to the Last Glacial Maximum. A more recent interval of carbonate accumulation postdates the early Holocene sea level rise and the establishment of the modern grounding line for the Ross Ice Shelf. When carbonate factories were inactive, fossil debris was subjected to infestation by bioeroders, dissolution, fragmentation, and physical reworking. This study reveals the episodic nature of carbonate deposition in polar settings and a reciprocal relationship with processes that deliver and redistribute siliciclastic debris. Carbonate production is most active during colder periods of the glacial-interglacial cycle, a potential new sedimentological paradigm for polar carbonate systems. Low accumulation rates and long residence times on the seafloor leave sediments vulnerable to significant post-depositional modification, processes that profoundly affect the appearance of deposits as they enter the rock record. Comparison with other examples of polar carbonates highlights the utility of these Late Quaternary deposits as a well-constrained analog that can aid in the recognition and interpretation of similar deposits from the ancient record.

  19. Quaternary ammonium derivatives as spasmolytics for irritable bowel syndrome.

    PubMed

    Evangelista, S

    2004-01-01

    Quaternary ammonium derivatives such as cimetropium, n-butyl scopolammonium, otilonium and pinaverium bromide have been discovered and developed as potent spasmolytics of the gastrointestinal tract. Their pharmacological activity has been proven in both "in vivo" and "in vitro" studies of hypermotility. "In vitro" experiments showed that they possess antimuscarinic activity at nM level but only pinaverium and otilonium are endowed with calcium channel blocker properties. These latter compounds relaxed the gastrointestinal smooth muscle mainly through a specific inhibition of calcium ion influx through L-type voltage operated calcium channels. Molecular pharmacology trials have indicated that pinaverium and otilonium can bind specific subunits of the calcium channel in the external surface of the plasma membrane and in this way they block the machinery of the contraction. Recent evidence showed that otilonium is able to bind tachykinin NK(2) receptors and not only inhibits one of the major contractile agents but can reduce the activation of afferent nerves devoted to the passage of sensory signals from the periphery to the central nervous system. Thanks to their typical physico-chemical characteristics, they are poorly absorbed by the systemic circulation and generally remain in the gastrointestinal tract where they exert the muscle relaxant activity by a local activity. Some differences exists in the absorption among these compounds: both n-butyl scopolammonium and cimetropium are partially taken up in the bloodstream, pinaverium has a low absorption (8-10 %) but is endowed with an excellent hepato-biliary excretion and otilonium, which has the lowest absorption (3 %), is almost totally excreted by faeces. Quaternary ammonium derivatives are widely used for the treatment of irritable bowel syndrome and recent meta-analyses have supported their efficacy in this disease. Due to its therapeutic index, the use of n-butyl scopolammonium is more indicated to treat acute colics than a chronic disease such as irritable bowel syndrome. Taking into consideration the published trials carried out with validated methodology in irritable bowel syndrome, cimetropium and otilonium are the best demonstrated drugs for the improvement in global assessment, pain and abdominal distension. PMID:15579053

  20. A model of the Quaternary geological deposits of Bucharest City

    NASA Astrophysics Data System (ADS)

    Serpescu, Irina; Radu, Emil; Radu Gogu, Constantin; Amine Boukhemacha, Mohamed; Gaitanaru, Dragos; Bica, Ioan

    2013-04-01

    Bucharest city is located in the central part of the Moesic Platform, in the Romanian Plain with micro-relief resulting from erosion and sedimentary processes which extended along the valleys of the Dambovita River to the south and the Colentina River to the north. The city is located in the axial area of a syncline where the thickness of the sedimentary deposits is up to 1000 m. The area lies on a rigid base is made of metamorphites, and various igneous intrusions (granodiorite, granite). The sedimentary deposits covering this rigid base are made by different phases of erosion and sedimentary processes of marine, lacustrian or continental sediments ending with Quaternary sediments. As a result, different alluvial deposits (such as piedmont, deltaic, alluvial cones, terrace, waterside and lacustrine deposits) can be met. Furthermore one also can find loess deposits which in turn cover totally the older deposits where rivers dug the present relief. To highlight the spatial extent of these geological structures, a geological model of Bucharest city is developed. A set of information coming from different sources as geological and geotechnical boreholes showing a detailed geological and lithological description, geological and topographical maps, geological and hydrogeological reports have been used to develop the 3D geological model of this region. 33 geological cross sections were defined and interpreted by using lithological and sedimentological criteria. Using these geological cross sections and prior geological knowledge, the Quaternary deposits have been described and classified into 6 structural units given from top to down as follows: (1) Superficial deposits represented by loess and anthropogenic materials. The geological model indicates that these deposits show a sporadic development becoming more concentrated in the central west part of the city. (2) Colentina Formations composed by of poorly sorted, cross-stratified sand and gravel with clayey lens indicating a high energy deposition environment. The geological model indicates more accentuate vertical lithological heterogeneity than a horizontal one as well as a decrease of the Colentina Formation thickness. (3) Intermediary deposits represented by silty-clay with fine sand intercalation indicating a mixed regime with limited lakes and dry lands. (4) Mostistea Formation made of sediments with a variety of grain size, from fine sand to coarse sand with small intercalations of gravels and scrap of woods. It was found that areas where the Intermediary deposits are less developed making the Colentina Formation in direct connection to Mostistea Formation. (5) Marly Complex composed by a succession of marls and clays with lenticular sandy intercalations indicating a fluvial-lacustrine environment. (6) Fratesti Strata made of sand and gravel which includes A, B and C Fratesti levels.