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

    PubMed Central

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

    2013-01-01

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

  4. Natural AChE Inhibitors from Plants and their Contribution to Alzheimer's Disease Therapy.

    PubMed

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

    2013-07-01

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

  5. Electronic structure calculations toward new potentially AChE inhibitors

    NASA Astrophysics Data System (ADS)

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

    2007-10-01

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

  6. Synthesis and comparison of the biological activity of monocyclic phosphonate, difluorophosphonate and phosphate analogs of the natural AChE inhibitor cyclophostin.

    PubMed

    Martin, Benjamin P; Vasilieva, Elena; Dupureur, Cynthia M; Spilling, Christopher D

    2015-12-15

    New monocyclic phosphate, phosphonate and difluorophosphonate analogs of the natural AChE inhibitor cyclophostin were synthesized and their activity toward human AChE examined. Surprisingly, the phosphate, phosphonate, and difluorophosphonate analogs all showed diminished activity when compared with the natural product. PMID:26585276

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

    SciTech Connect

    Zheng, Wei; NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 ; Li, Juan; Qiu, Zhuibai; Xia, Zheng; Li, Wei; Yu, Lining; Chen, Hailin; Chen, Jianxing; Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao; Xie, Qiong; Chen, Hongzhuan

    2012-10-01

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

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

    PubMed

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

    2015-10-01

    Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2)?=?0.552 and r(2)?=?0.983 and an optimal CoMSIA model with q(2)?=?0.581 and r(2)?=?0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green). PMID:26438408

  9. (Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies.

    PubMed

    D'Ascenzio, Melissa; Chimenti, Paola; Gidaro, Maria Concetta; De Monte, Celeste; De Vita, Daniela; Granese, Arianna; Scipione, Luigi; Di Santo, Roberto; Costa, Giosuè; Alcaro, Stefano; Yáñez, Matilde; Carradori, Simone

    2015-12-01

    Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases. PMID:25807300

  10. The interaction of quaternary reversible acetylcholinesterase inhibitors with the nicotinic receptor.

    PubMed

    Sepsova, V; Krusek, J; Zdarova Karasova, J; Zemek, F; Musilek, K; Kuca, K; Soukup, O

    2014-01-01

    Acetylcholinesterase inhibitors (AChEIs) are used in the treatment of myasthenia gravis (MG). We investigated the effects of AChEIs on peripheral nicotinic receptors (nAChR), which play a crucial role in the treatment of MG symptoms. The positive modulation of those receptors by AChE inhibitors could have an added value to the anti-AChE activity and might be useful in the therapy of MG. Furthermore, to estimate the potential drawbacks of the compounds, cytotoxicity has been assessed on various cell lines. The whole-cell mode of the patch-clamp method was employed. The experiments were performed on medulloblastoma/rhabdomyosarcoma cell line TE671 expressing human embryonic muscle-like receptor with subunits alpha2betagammadelta. The effect of the compounds on cell viability was measured by standard MTT assay (Sigma Aldrich) on ACHN (renal cell adenocarcinoma), HeLa (immortal cell line derived from a cervical carcinoma), HEPG2 (hepatocellular carcinoma) and BJ (skin fibroblasts) cell lines. No positive modulation by the tested AChE inhibitors was observed. Moreover, the compounds exhibited antagonistic activity on the peripheral nAChR. Standard drugs used in MG treatment were shown to be less potent inhibitors of muscle-type nAChR than the newly synthesized compounds. The new compounds showed very little effect on cell viability, and toxicities were comparable to standards. Newly synthesized AChEIs inhibited peripheral nAChR. Furthermore, the inhibition was higher than that of standards used for the treatment of MG. They could be used for the study of nAChR function, thanks to their high antagonizing potency and fast recovery of receptor activity after their removal. However, since no positive modulation was observed, the new compounds do not seem to be promising candidates for MG treatment, even though their cytotoxic effect was relatively low. PMID:25157661

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

    PubMed

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

    2016-01-15

    Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders. PMID:26467607

  12. 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

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

    PubMed Central

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

    2014-01-01

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

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

    SciTech Connect

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

    2011-05-01

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

  15. 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

  16. 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

  17. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  19. 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

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

    PubMed Central

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

    2014-01-01

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

  1. Readthrough acetylcholinesterase (AChE-R) and regulated necrosis: pharmacological targets for the regulation of ovarian functions?

    PubMed Central

    Blohberger, J; Kunz, L; Einwang, D; Berg, U; Berg, D; Ojeda, S R; Dissen, G A; Fröhlich, T; Arnold, G J; Soreq, H; Lara, H; Mayerhofer, A

    2015-01-01

    Proliferation, differentiation and death of ovarian cells ensure orderly functioning of the female gonad during the reproductive phase, which ultimately ends with menopause in women. These processes are regulated by several mechanisms, including local signaling via neurotransmitters. Previous studies showed that ovarian non-neuronal endocrine cells produce acetylcholine (ACh), which likely acts as a trophic factor within the ovarian follicle and the corpus luteum via muscarinic ACh receptors. How its actions are restricted was unknown. We identified enzymatically active acetylcholinesterase (AChE) in human ovarian follicular fluid as a product of human granulosa cells. AChE breaks down ACh and thereby attenuates its trophic functions. Blockage of AChE by huperzine A increased the trophic actions as seen in granulosa cells studies. Among ovarian AChE variants, the readthrough isoform AChE-R was identified, which has further, non-enzymatic roles. AChE-R was found in follicular fluid, granulosa and theca cells, as well as luteal cells, implying that such functions occur in vivo. A synthetic AChE-R peptide (ARP) was used to explore such actions and induced in primary, cultured human granulosa cells a caspase-independent form of cell death with a distinct balloon-like morphology and the release of lactate dehydrogenase. The RIPK1 inhibitor necrostatin-1 and the MLKL-blocker necrosulfonamide significantly reduced this form of cell death. Thus a novel non-enzymatic function of AChE-R is to stimulate RIPK1/MLKL-dependent regulated necrosis (necroptosis). The latter complements a cholinergic system in the ovary, which determines life and death of ovarian cells. Necroptosis likely occurs in the primate ovary, as granulosa and luteal cells were immunopositive for phospho-MLKL, and hence necroptosis may contribute to follicular atresia and luteolysis. The results suggest that interference with the enzymatic activities of AChE and/or interference with necroptosis may be novel approaches to influence ovarian functions. PMID:25766324

  2. Discovery of new acetylcholinesterase inhibitors with small core structures through shape-based virtual screening.

    PubMed

    Chen, Yao; Liu, Zong-liang; Fu, Ting-ming; Li, Wei; Xu, Xiao-li; Sun, Hao-peng

    2015-09-01

    Targeting acetylcholinesterase (AChE) using small molecule inhibitors is considered to be the most successful therapeutic strategy in the treatment of Alzheimer's disease (AD). Herein we present a shape-based virtual screening to identify new cores for the designing of AChE inhibitors. Ten active hits are identified and the most active hit, 5169-0032 and T5369186, showed comparable AChE inhibitory activity to tacrine. Prediction of physicochemical properties and ADME/T risk indicates their potential in druggability and safety. The two compounds provide new core and can serve as a promising fragment to design potent AChE inhibitors. PMID:26212777

  3. Inhibitors

    MedlinePLUS

    ... caregivers to learn how to care for the device. CDC Research CDC is interested in learning more about why some people develop inhibitors and how they could be prevented. The Inhibitor Project began in 2005 and was implemented to explore ...

  4. Discovering New Acetylcholinesterase Inhibitors by Mining the Buzhongyiqi Decoction Recipe Data.

    PubMed

    Cui, Lu; Wang, Yu; Liu, Zhihong; Chen, Hongzhuan; Wang, Hao; Zhou, Xinxin; Xu, Jun

    2015-11-23

    Myasthenia gravis (MG) is a neuromuscular disease that is conventionally treated with acetylcholinesterase (AChE) inhibitors, which may not fully remove the symptom for many reasons. When AChE inhibitors do not work, Chinese patients turn to Chinese medicine, such as the Buzhongyiqi decoction (BD), to treat MG. By elucidating the relations between the herbs of the Buzhongyiqi decoction recipe and AChE inhibitors with structure-based and ligand-based drug design methods and chemoinformatics approaches, we have found the key active components of BD. Using these key active components as templates, we have discovered five new AChE inhibitors through virtual screening of a commercial compound library. The new AChE inhibitors have been confirmed with Ellman assays. This study demonstrates that lead identification can be inspired by elucidating Chinese medicine. Since BD is a mixture, further studies against other drug targets are needed. PMID:26509353

  5. 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.

  6. Substance P preferentially inhibits large conductance nicotinic ACh receptor channels in rat intracardiac ganglion neurons.

    PubMed

    Cuevas, J; Adams, D J

    2000-10-01

    The effects of substance P (SP) on nicotinic acetylcholine (ACh)-evoked currents were investigated in parasympathetic neurons dissociated from neonatal rat intracardiac ganglia using standard whole cell, perforated patch, and outside-out recording configurations of the patch-clamp technique. Focal application of SP onto the soma reversibly decreased the peak amplitude of the ACh-evoked current with half-maximal inhibition occurring at 45 microM and complete block at 300 microM SP. Whole cell current-voltage (I-V) relationships obtained in the absence and presence of SP indicate that the block of ACh-evoked currents by SP is voltage independent. The rate of decay of ACh-evoked currents was increased sixfold in the presence of SP (100 microM), suggesting that SP may increase the rate of receptor desensitization. SP-induced inhibition of ACh-evoked currents was observed following cell dialysis and in the presence of either 1 mM 8-Br-cAMP, a membrane-permeant cAMP analogue, 5 microM H-7, a protein kinase C inhibitor, or 2 mM intracellular AMP-PNP, a nonhydrolyzable ATP analogue. These data suggest that a diffusible cytosolic second messenger is unlikely to mediate SP inhibition of neuronal nicotinic ACh receptor (nAChR) channels. Activation of nAChR channels in outside-out membrane patches by either ACh (3 microM) or cytisine (3 microM) indicates the presence of at least three distinct conductances (20, 35, and 47 pS) in rat intracardiac neurons. In the presence of 3 microM SP, the large conductance nAChR channels are preferentially inhibited. The open probabilities of the large conductance classes activated by either ACh or cytisine were reversibly decreased by 10- to 30-fold in the presence of SP. The single-channel conductances were unchanged, and mean apparent channel open times for the large conductance nAChR channels only were slightly decreased by SP. Given that individual parasympathetic neurons of rat intracardiac ganglia express a heterogeneous population of nAChR subunits represented by the different conductance levels, SP appears to preferentially inhibit those combinations of nAChR subunits that form the large conductance nAChR channels. Since ACh is the principal neurotransmitter of extrinsic (vagal) innervation of the mammalian heart, SP may play an important role in modulating autonomic control of the heart. PMID:11024089

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

    PubMed

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

    2015-01-01

    The use of biomarkers as a tool to assess responses of organisms exposed to pollutants in toxicity bioassays, as well as in aquatic environmental risk assessment protocols, requires the understanding of the natural fluctuation of the particular biomarker. The aim of this study was to characterize the intrinsic variations of acetylcholinesterase (AChE) activity in tissues of a native freshwater teleost fish to be used as biomarker in toxicity tests, taking into account both seasonal influence and fish size. Specific AChE activity was measured by the method of Ellman et al. (1961) in homogenates of fish anterior section finding a seasonal variability. The highest activity was observed in summer, decreasing significantly below 40% in winter. The annual AChE activity cycle in the anterior section was fitted to a sinusoidal function with a period of 11.2 months. Moreover, an inverse relationship between enzymatic activity and the animal size was established. The results showed that both the fish length and seasonal variability affect AChE activity. AChE activity in fish posterior section showed a similar trend to that in the anterior section, while seasonal variations of the activity in midsection were observed but differences were not statistically significant. In addition, no relationship between AChE and total tissue protein was established in the anterior and posterior sections suggesting that the circannual rhythms observed are AChE-specific responses. Results highlight the importance of considering both the fish size and season variations to reach valid conclusions when AChE activity is employed as neurotoxicity biomarker. PMID:25450939

  8. 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

  9. Current acetylcholinesterase-inhibitors: a neuroinformatics perspective.

    PubMed

    Shaikh, Sibhghatulla; Verma, Anupriya; Siddiqui, Saimeen; Ahmad, Syed S; Rizvi, Syed M D; Shakil, Shazi; Biswas, Deboshree; Singh, Divya; Siddiqui, Mohmmad H; Shakil, Shahnawaz; Tabrez, Shams; Kamal, Mohammad A

    2014-04-01

    This review presents a concise update on the inhibitors of the neuroenzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE is a serine protease, which hydrolyses the neurotransmitter, acetylcholine into acetate and choline thereby terminating neurotransmission. Molecular interactions (mode of binding to the target enzyme), clinical applications and limitations have been summarized for each of the inhibitors discussed. Traditional inhibitors (e.g. physostigmine, tacrine, donepezil, rivastigmine etc.) as well as novel inhibitors like various physostigmine-derivatives have been covered. This is followed by a short glimpse on inhibitors derived from nature (e.g. Huperzine A and B, Galangin). Also, a discussion on 'hybrid of pre-existing drugs' has been incorporated. Furthermore, current status of therapeutic applications of AChEinhibitors has also been summarized. PMID:24059296

  10. Preventing Tech Aches: Using Smart Phones Wisely

    MedlinePLUS

    ... in the News Media Guidelines for Conferences Preventing Tech Aches: Using Smart Phones Wisely BETHESDA, MD (Dec. ... do not walk or drive while using high-tech gadgets. “Our thumbs were not created for the ...

  11. Vasoactive intestinal polypeptide modulation of nicotinic ACh receptor channels in rat intracardiac neurones.

    PubMed

    Cuevas, J; Adams, D J

    1996-06-01

    1. The effects of vasoactive intestinal polypeptide (VIP) on isolated parasympathetic neurones of rat intracardiac ganglia were examined under voltage clamp using dialysed and perforated patch whole-cell and excised outside-out membrane patch recording configurations. 2. VIP reversibly potentiated nicotinic ACh-evoked whole-cell currents, with half-maximal potentiation (EC50) obtained with 260 pM VIP. However, VIP had no effect on muscarinic ACh-evoked currents, ATP-evoked currents, or depolarization-activated ionic currents in these neurones. 3. VIP-induced potentiation of nicotinic ACh-evoked whole-cell currents was observed following cell dialysis, and was inhibited reversibly by bath application of the VIP receptor-binding inhibitor L-8-K (5 microM) or the neuronal nicotinic receptor antagonist mecamylamine (3 microM). 4. The signal transduction pathway mediating VIP-induced potentiation of nicotinic ACh-evoked currents involves a guanine nucleotide-binding protein (G-protein) but not cyclic AMP. Intracellular application of 100 microM GDP-beta-S, or pre-incubation of neurones with pertussis toxin, inhibited VIP-induced potentiation of ACh-evoked whole-cell currents. 5. In outside-out membrane patches, co-application of ACh (4 microM) and VIP (4 nM) decreased the duration of closings between bursts and clusters of bursts of ACh single-channel activity relative to control (4 microM, ACh alone). VIP, however, did not alter single ACh receptor channel current amplitude, duration of closings and openings within a burst, or mean burst duration. 6. VIP-induced modification of nicotinic ACh receptor channel kinetics results in an increase in the open-channel probability which is sufficient to account for the VIP-mediated potentiation of nicotinic ACh-evoked whole-cell currents. 7. The potentiation of nicotinic ACh-evoked currents by VIP is likely to account for the altered neuronal activity observed in the mammalian intracardiac ganglia in vivo and consequent changes in heart rate and cardiac contractility. PMID:8782112

  12. 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

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

    PubMed

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

    2011-03-01

    The olive fruit fly Bactrocera oleae is the most destructive and intractable pest of olives. The management of B. oleae has been based on the use of organophosphate (OP) insecticides, a practice that induced resistance. OP-resistance in the olive fly was previously shown to be associated with two mutations in the acetylcholinesterase (AChE) enzyme that, apparently, hinder the entrance of the OP into the active site. The search for additional mutations in the ace gene that encodes AChE revealed a short deletion of three glutamines (?3Q) from a stretch of five glutamines, in the C-terminal peptide that is normally cleaved and substituted by a GPI anchor. We verified that AChEs from B. oleae and other Dipterans are actually GPI-anchored, although this is not predicted by the "big-PI" algorithm. The ?3Q mutation shortens the unusually long hydrophilic spacer that follows the predicted GPI attachment site and may thus improve the efficiency of GPI anchor addition. We expressed the wild type B. oleae AChE, the natural mutant ?3Q and a constructed mutant lacking all 5 consecutive glutamines (?5Q) in COS cells and compared their kinetic properties. All constructs presented identical K(m) and k(cat) values, in agreement with the fact that the mutations did not affect the catalytic domain of the enzyme. In contrast, the mutants produced higher AChE activity, suggesting that a higher proportion of the precursor protein becomes GPI-anchored. An increase in the number of GPI-anchored molecules in the synaptic cleft may reduce the sensitivity to insecticides. PMID:21112395

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

    PubMed

    Demirci, Gökhan; Do?aç, Yasemin ?spirli; Teke, Mustafa

    2015-11-01

    In the present study, we immobilized acetylcholinesterase (AChE) enzyme onto acetylcholine removed imprinted polymer and acetylcholine containing polymer. First, the polymers were produced with acetylcholine, substrate of AChE, by dispersion polymerization. Then, the enzyme was immobilized onto the polymers by using two different methods: In the first method (method A), acetylcholine was removed from the polymer, and then AChE was immobilized onto this polymer (acetylcholine removed imprinted polymer). In the second method (method B), AChE was immobilized onto acetylcholine containing polymer by affinity. In method A, enzyme-specific species (binding sites) occurred by removing acetylcholine from the polymer. The immobilized AChE reached 240% relative specific activity comparison with free AChE because the active enzyme molecules bounded onto the polymer. Transmission electron microscopy results were taken before and after immobilization of AChE for the assessment of morphological structure of polymer. Also, the experiments, which include optimum temperature (25-65°C), optimum pH (3-10), thermal stability (4-70°C), kinetic parameters, operational stability and reusability, were performed to determine the characteristic of the immobilized AChE. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25857716

  15. Novel and selective acetylcholinesterase inhibitors for Tetranychus cinnabarinus (Acari: Tetranychidae).

    PubMed

    Bu, Chunya; Peng, Bo; Cao, Yang; Wang, Xiaoqin; Chen, Qing; Li, Jinling; Shi, Guanglu

    2015-11-01

    The carmine spider mite, Tetranychus cinnabarinus (Acari: Tetranychidae), is an economically important and extremely polyphagous herbivorous pest, with the title of "resistance champion" among arthropods. Anticholinesterase insecticides such as organophosphate and carbamate account for more than one-third of global insecticide sales. The non-target toxicity and resistance problem of organophosphate and carbamate have become of growing concern, which may be due to the fact that they target the ubiquitous catalytic serine residue of acetylcholinesterase (AChE) in mammals, birds, and beneficial insects. In this study, the structural differences between T. cinnabarinus AChE and human AChE, at or near the catalytic pocket, were illustrated. From the SPECS chemical lead-compound database, 55 AChE inhibitor candidates were screened for high affinity for T. cinnabarinus AChE, but low affinity for human AChE, using the DOCK 6 and AutoDock Vina software. Three of the fifty-five candidates had inhibitory activity greater than that of the reversible AChE inhibitor eserine, with no observed inhibitory activities against human AChE. Two of the three had toxicity to T. cinnabarinus comparable to that of natural insecticidal pyrethrins. However, their potency is low compared with that of etoxazole, and further work is needed to optimize their potency. The selectivity of the three compounds over human and mite AChE may be due to their interaction with the mite-specific residues, as analyzed by Cyscore. The three compounds are potential lead compounds for development of novel acaricides against T. cinnabarinus with reduced toxicity to non-target species and a low propensity for resistance. PMID:26520174

  16. 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"…

  17. Thiocholine mediated stabilization of in situ produced CdS quantum dots: application for the detection of acetylcholinesterase activity and inhibitors.

    PubMed

    Garai-Ibabe, Gaizka; Saa, Laura; Pavlov, Valeri

    2014-01-01

    The use of acetylcholinesterase (AChE) inhibitors as chemical warfare agents or pesticides represents a strong hazard against human health. The high toxicity of these compounds arises from their ability to inhibit acetylcholinesterase from degrading acetylcholine (ACh), which could affect the physiology of the nervous system with serious or fatal consequences. Here we report a simple and fluorimetric system for a highly sensitive detection of AChE activity and inhibitors. The principle of this approach is based on the hydrolysis of acetylthiocholine (ATCh) by AChE, which yields the thiol-bearing compound thiocholine (TCh) that at trace concentrations stabilized the in situ generated CdS quantum dots (QDs). The system shows a linear relationship between the fluorescence intensity and AChE activity from 1 to 10 mU mL(-1) in buffer solution. The accuracy of the proposed system was further demonstrated through the determination of AChE activity in human serum (HS) by the standard addition method. Furthermore, this novel and highly sensitive sensing system allows the detection of 80 pM of the AChE inhibitor paraoxon and 100 nM of galanthamine. The reported methodology shows potential applications for the development of a simple and inexpensive assay for the routine quantification of AChE activity and inhibitors. PMID:24225492

  18. 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

  19. Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: role of alpha4 and alpha7 receptors in neuroprotection.

    PubMed

    Akaike, Akinori; Takada-Takatori, Yuki; Kume, Toshiaki; Izumi, Yasuhiko

    2010-01-01

    Neurotoxicity induced by glutamate and other excitatory amino acids has been implicated in various neurodegenerative disorders including hypoxic ischemic events, trauma, and Alzheimer's and Parkinson's diseases. We examined the roles of nicotinic acetylcholine receptors (nAChRs) in survival of CNS neurons during excitotoxic events. Nicotine as well as other nicotinic receptor agonists protected cortical neurons against glutamate neurotoxicity via alpha4 and alpha7 nAChRs at least partly by inhibiting the process of apoptosis in near-pure neuronal cultures obtained from the cerebral cortex of fetal rats. Donepezil, galanatamine and tacrine, therapeutic acetylcholinesterase (AChE) inhibitors currently being used for treatment of Alzheimer's disease also protected neuronal cells from glutamate neurotoxicity. Protective effects of nicotine and the AChE inhibitors were antagonized by nAChR antagonists. Moreover, nicotine and those AChE inhibitors induced up-regulation of nAChRs. Inhibitors for a non-receptor-type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galantamine. Furthermore, a phosphatidylinositol 3-kinase (PI3K) inhibitor also suppressed the neuroprotective effect of the AChE inhibitors. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galantamine treatments. These results suggest that nicotine as well as AChE inhibitors, donepezil and galantamine, prevent glutamate neurotoxicity through alpha4 and alpha7 nAChRs and the PI3K-Akt pathway. PMID:19714494

  20. 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

  1. Acetylcholinesterase inhibitors with photoswitchable inhibition of ?-amyloid aggregation.

    PubMed

    Chen, Xinyu; Wehle, Sarah; Kuzmanovic, Natascha; Merget, Benjamin; Holzgrabe, Ulrike; König, Burkhard; Sotriffer, Christoph A; Decker, Michael

    2014-05-21

    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

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

    E-print Network

    Nieh, James

    (Breer and Sattelle, 1987; Tomizawa and Casida, 2003). One ACh receptor, the nicotinic acetylcholine receptor (nAChR), belongs to the superfamily of Cys-loop ligand-gated ion channels and mediates signal) and genetics. Page and Fondrk identified quantitative trait loci that are SUMMARY A nicotinic acetylcholine

  3. Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors.

    PubMed

    Aslam, Sana; Zaib, Sumera; Ahmad, Matloob; Gardiner, John M; Ahmad, Aqeel; Hameed, Abdul; Furtmann, Norbert; Gütschow, Michael; Bajorath, Jürgen; Iqbal, Jamshed

    2014-05-01

    Two series of novel pyrazolobenzothiazine-based hybrid compounds were efficiently synthesized starting from saccharin sodium salt. Pyrazolo[4,3-c][1,2]benzothiazine scaffolds were N-arylated by using p-fluorobenzaldehyde, followed by the incorporation of a benzimidazole or similar ring systems by treatment with arylenediamines. These phenylene-connected hybrid compounds were investigated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compounds 12d and 12k were the most potent AChE inhibitors with IC50 values of 11 and 13 nM, respectively, while 6j (IC50 = 17 nM) proved to be the most active inhibitor against BuChE with remarkable selectivity for BuChE over AChE. Molecular docking studies were also performed on human AChE and BuChE to suggest possible binding modes in which the inhibitor's extended structure is accommodated along the active site gorge of both enzymes. PMID:24681070

  4. 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

  5. QSAR study on maximal inhibition (Imax) of quaternary ammonium antagonists for S-(-)-nicotine-evoked dopamine release from dopaminergic nerve terminals in rat striatum.

    PubMed

    Zheng, Fang; McConnell, Matthew J; Zhan, Chang-Guo; Dwoskin, Linda P; Crooks, Peter A

    2009-07-01

    Maximal inhibition (I(max)) of the agonist effect is an important pharmacological property of inhibitors that interact with multiple receptor subtypes that are activated by the same agonist and which elicit the same functional response. This report represents the first QSAR study on a set of 66 mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating nicotine-evoked dopamine release, conducted using multi-linear regression (MLR) and neural network (NN) analysis with the maximal inhibition (I(max)) values of the antagonists as target values. The statistical results for the generated MLR model were: r(2)=0.89, rmsd=9.01, q(2)=0.83 and loormsd=11.1; the statistical results for the generated NN model were: r(2)=0.89, rmsd=8.98, q(2)=0.83 and loormsd=11.2. The maximal inhibition values of the compounds exhibited a good correlation with the predictions made by the QSAR models developed, which provide a basis for rationalizing selection of compounds for synthesis in the discovery of effective and selective second generation inhibitors of nAChRs mediating nicotine-evoked dopamine release. PMID:19477134

  6. QSAR study on maximal inhibition (Imax) of quaternary ammonium antagonists for S-(?)-nicotine-evoked dopamine release from dopaminergic nerve terminals in rat striatum

    PubMed Central

    Zheng, Fang; McConnell, Matthew J.; Zhan, Chang-Guo; Dwoskin, Linda P.; Crooks, Peter A.

    2013-01-01

    Maximal inhibition (Imax) of the agonist effect is an important pharmacological property of inhibitors that interact with multiple receptor subtypes that are activated by the same agonist and which elicit the same functional response. This report represents the first QSAR study on a set of 66 mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating nicotine-evoked dopamine release, conducted using multi-linear regression (MLR) and neural network (NN) analysis with the maximal inhibition (Imax) values of the antagonists as target values. The statistical results for the generated MLR model were: r2 = 0.89, rmsd = 9.01, q2 = 0.83 and loormsd = 11.1; the statistical results for the generated NN model were: r2 = 0.89, rmsd = 8.98, q2 = 0.83 and loormsd = 11.2. The maximal inhibition values of the compounds exhibited a good correlation with the predictions made by the QSAR models developed, which provide a basis for rationalizing selection of compounds for synthesis in the discovery of effective and selective second generation inhibitors of nAChRs mediating nicotine-evoked dopamine release. PMID:19477134

  7. 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 ...

  8. 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

  9. Esterase metabolism of cholinesterase inhibitors using rat liver in vitro.

    PubMed

    Moser, V C; Padilla, S

    2011-03-15

    A variety of chemicals, such as organophosphate (OP) and carbamate pesticides, nerve agents, and industrial chemicals, inhibit acetylcholinesterase (AChE) leading to overstimulation of the cholinergic nervous system. The resultant neurotoxicity is similar across mammalian species; however, the relative potencies of the chemicals across and within species depend in part on chemical-specific metabolic and detoxification processes. Carboxylesterases and A-esterases (paraoxonases, PON) are two enzymatic detoxification pathways that have been widely studied. We used an in vitro system to measure esterase-dependent detoxification of 15 AChE inhibitors. The target enzyme AChE served as a bioassay of inhibitor concentration following incubation with detoxifying tissue. Concentration-inhibition curves were determined for the inhibitor in the presence of buffer (no liver), rat liver plus calcium (to stimulate PONs and thereby measure both PON and carboxylesterase), and rat liver plus EGTA (to inhibit calcium-dependent PONs, measuring carboxylesterase activity). Point estimates (concentrations calculated to produce 20, 50, and 80% inhibition) were compared across conditions and served as a measure of esterase-mediated detoxification. Results with well-known inhibitors (chlorpyrifos oxon, paraoxon, methyl paraoxon, malaoxon) were in agreement with the literature, serving to support the use of this assay. Only a few other inhibitors showed slight or a trend towards detoxification via carboxylesterases or PONs (mevinphos, aldicarb, oxamyl). There was no apparent PON- or carboxylesterase-mediated detoxification of the remaining inhibitors (carbofuran, chlorfenvinphos, dicrotophos, fenamiphos, methamidophos, methomyl, monocrotophos, phosphamidon), suggesting that the influence of esterases on these chemicals is minimal. Thus, generalizations regarding these metabolic pathways may not be appropriate. As with other aspects of AChE inhibitors, their metabolic patterns appear to be chemical-specific. PMID:21237238

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

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

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

  11. GW1929 inhibits ?7 nAChR expression through PPAR?-independent activation of p38 MAPK and inactivation of PI3-K/mTOR: The role of Egr-1.

    PubMed

    Hahn, Swei Sunny; Tang, Qing; Zheng, Fang; Zhao, Shunyu; Wu, Jingjing

    2014-04-01

    Studies demonstrated that peroxisome proliferator-activated receptor gamma (PPAR?) ligands reduce nicotine-induced non small cell lung carcinoma (NSCLC) cell growth through inhibition of nicotinic acetylcholine receptor (nAChR) mediated signaling pathways. However, the mechanisms by which PPAR? ligands inhibited nAChR expression remain elucidated. Here, we show that GW1929, a synthetic PPAR? ligand, not only inhibited but also antagonized the stimulatory effect of acetylcholine on NSCLC cell proliferation. Interestingly, GW1929 inhibited ?7 nAChR expression, which was not blocked by GW9662, an antagonist of PPAR?, or by PPAR? siRNA, but was abrogated by the p38 MPAK inhibitor SB239063. GW1929 reduced the promoter activity of ?7 nAChR and induced early growth response-1 (Egr-1) protein expression, which was overcame by SB239063, but enhanced by inhibitors of PI3-K and mTOR. Silencing of Egr-1 blocked, while overexpression of Egr-1 enhanced, the effect of GW1929 on ?7 nAChR expression and promoter activity. Finally, GW1929 induced Egr-1 bound to specific DNA areas in the ?7 nAChR gene promoter. Collectively, these results demonstrate that GW1929 not only inhibits but also antagonizes Ach-induced NSCLC cell growth by inhibition of ?7 nAChR expression through PPAR?-independent signals that are associated with activation of p38 MPAK and inactivation of PI3-K/mTOR, followed by inducing Egr-1 protein and Egr-1 binding activity in the ?7 nAChR gene promoter. By downregulation of the ?7 nAchR, GW1929 blocks cholinergic signaling and inhibits NSCLC cell growth. PMID:24412748

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

    PubMed

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

    2015-10-01

    Imidacloprid is a well-known pesticide and it is timely to evaluate its toxicity to earthworms (Eisenia fetida). In the present study, the effect of imidacloprid on reproduction, growth, acetylcholinesterase (AChE) and DNA damage in earthworms was assessed using an artificial soil medium. The median lethal concentration (LC50) and the median number of hatched cocoons (EC50) of imidacloprid to earthworms was 3.05 and 0.92 mg/kg respectively, the lowest observed effect concentration of imidacloprid about hatchability, growth, AChE activity and DNA damage was 0.02, 0.5, 0.1 and 0.5 mg/kg, respectively. PMID:26293707

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

    PubMed Central

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

    2013-01-01

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

  14. 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

  15. Endogenous ACh suppresses LTD induction and nicotine relieves the suppression via different nicotinic ACh receptor subtypes in the mouse hippocampus

    PubMed Central

    Nakauchi, Sakura; Sumikawa, Katumi

    2014-01-01

    Aims Studying the normal role of nicotinic cholinergic systems in hippocampal synaptic plasticity is critical for understanding how cholinergic loss in Alzheimer’s disease (AD) and tobacco use affect cognitive function. However, it is largely unknown how nicotinic cholinergic systems regulate the induction of long-term depression (LTD). Main methods Extracellular field potential recordings were performed in hippocampal slices prepared from wild-type, ?2, ?7, and ?2 knockout (KO) mice. Effects of nicotine and nicotinic antagonists on LTD induction in wild-type, ?2, ?7, and ?2 KO mice were compared. Key findings Activation of ?7 nicotinic acetylcholine receptors (nAChRs) occurs during LTD-inducing stimulation to suppress LTD induction at CA3-CA1 synapses. Nicotine relieves this suppression, causing larger LTD. This nicotine effect was mediated by the activation of non-?7 nAChR subtypes, which were not activated by ACh released during LTD-inducing stimulation, and requires the presence of endogenous ACh-induced ?7 nAChR activation. Furthermore, the effect of nicotine was prevented in the presence of mecamylamine, but not dihydro-?-erythroidine, and was still observed in both ?2 KO and ?2 KO mice. Significance This is the first report to evaluate the involvement of different nAChR subtypes in LTD induction. Findings indicate the involvement of unique non-?7 nAChR subtypes, which have not been considered in the nicotinic modulation of hippocampal long-term potentiation, in the control of LTD induction. The implication of our results is that the loss of cholinergic projections to the hippocampus, which reduces ACh release as seen in AD patients, and nicotine from tobacco smoking can differentially affect LTD induction. PMID:25046735

  16. Reactivation of organophosphate-inhibited human AChE by combinations of obidoxime and HI 6 in vitro.

    PubMed

    Worek, F; Aurbek, N; Thiermann, H

    2007-01-01

    Highly toxic organophosphorus-type (OP) chemical warfare agents (nerve agents) and OP pesticides may be used by terrorists and during military conflicts emphasizing the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators (oximes) is considered to be ineffective with certain nerve agents due to low oxime efficacy. Despite research over decades none of the oximes has turned out to be a broad spectrum reactivator to cover the whole range of potential threat agents. The prospective oxime HI 6 is a weak reactivator of tabun- and pesticide-inhibited AChE, while the established oxime obidoxime mainly lacks efficacy with cyclosarin-inhibited enzyme. In order to investigate the feasibility of combining obidoxime and HI 6, human AChE inhibited by sarin, cyclosarin, VX, tabun and paraoxon was reactivated by these oximes either alone or in combination. Two major findings of this study were that a combination of HI 6 and obidoxime did not impair reactivation, compared with HI 6 or obidoxime alone, but broadened the spectrum compared with the individual oximes. By using different oxime concentrations a combination of oxime doses may be suggested which could be an alternative to individual obidoxime or HI 6 autoinjectors. PMID:17370251

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

    PubMed

    Warner, John; Andreescu, Silvana

    2016-01-01

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

  18. 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. PMID:26090073

  19. Interactions between xylene-linked carbamoyl bis-pyridinium mono-oximes and organophosphates inhibited-AChE: a kinetic study.

    PubMed

    Sharma, Rahul; Gupta, Bhanushree; Acharya, J; Kaushik, M P; Ghosh, Kallol K

    2014-02-28

    Reactivation of organophosphate (OP) inhibited acetylcholinesterase (AChE) by oximes is inadequate against various OP nerve agents known till date owing to their diverse structural features. As a consequence, in the past decades widespread research programs have been undertaken independently throughout the world to develop and identify more effective oxime reactivators. The efficacy of oxime reactivators is estimated through different in vitro and in vivo models using AChE from various sources against structurally different OPs. In the present study, reactivation kinetics of OP (paraoxon, DFP, sarin and VX) inhibited AChE by xylene linked carbamoyl bis-pyridinum mono-oximes have been described. It was found that the reactivation potency of tested oximes varied with the inhibitors used as 5l (4-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bis-pyridinium dibromide) was found to be the most effective reactivator against paraoxon. In case of DFP, 5k (3-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bis-pyridinium dibromide) showed best reactivation while in case of sarin 5e (3-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,4-phenylenedimethyl)-bis-pyridinium dibromide) exhibited outstanding reactivation ability in comparison to standard oximes (2-PAM, obidoxime and TMB-4) as indicated by its highest value of second order reactivation rate constant (k(r2)) 3.26 mM?¹ min?¹. The enhanced reactivation efficacy of oximes may be attributed to the optimal length of xylene linker which facilitates appropriate positioning of carbamoyl function to the peripheral anionic site (PAS) and extending the oxime moiety to the active site of AChE. PMID:24345352

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

    PubMed

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

    2015-10-01

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

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

    SciTech Connect

    Sheldon, R.J.

    1987-01-01

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

  2. 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

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

    PubMed

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

    2015-12-01

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

  4. Applications of Integrated Data Mining Methods to Exploring Natural Product Space for Acetylcholinesterase Inhibitors

    PubMed Central

    Schuster, Daniela; Kern, Lisa; Hristozov, Dimitar P.; Terfloth, Lothar; Bienfait, Bruno; Laggner, Christian; Kirchmair, Johannes; Grienke, Ulrike; Wolber, Gerhard; Langer, Thierry; Stuppner, Hermann; Gasteiger, Johann; Rollinger, Judith M.

    2013-01-01

    Nature, especially the plant kingdom, is a rich source for novel bioactive compounds that can be used as lead compounds for drug development. In order to exploit this resource, the two neural network-based virtual screening techniques novelty detection with self-organizing maps (SOMs) and counterpropagation neural network were evaluated as tools for efficient lead structure discovery. As application scenario, significant descriptors for acetylcholinesterase (AChE) inhibitors were determined and used for model building, theoretical model validation, and virtual screening. Top-ranked virtual hits from both approaches were docked into the AChE binding site to approve the initial hits. Finally, in vitro testing of selected compounds led to the identification of forsythoside A and (+)-sesamolin as novel AChE inhibitors. PMID:20214575

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Anand, Preet; Singh, Baldev

    2013-08-01

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

  7. In vitro effect of H2O 2, some transition metals and hydroxyl radical produced via fenton and fenton-like reactions, on the catalytic activity of AChE and the hydrolysis of ACh.

    PubMed

    Méndez-Garrido, Armando; Hernández-Rodríguez, Maricarmen; Zamorano-Ulloa, Rafael; Correa-Basurto, José; Mendieta-Wejebe, Jessica Elena; Ramírez-Rosales, Daniel; Rosales-Hernández, Martha Cecilia

    2014-11-01

    It is well known that the principal biomolecules involved in Alzheimer's disease (AD) are acetylcholinesterase (AChE), acetylcholine (ACh) and the amyloid beta peptide of 42 amino acid residues (A?42). ACh plays an important role in human memory and learning, but it is susceptible to hydrolysis by AChE, while the aggregation of A?42 forms oligomers and fibrils, which form senile plaques in the brain. The A?42 oligomers are able to produce hydrogen peroxide (H2O2), which reacts with metals (Fe(2+), Cu(2+), Cr(3+), Zn(2+), and Cd(2+)) present at high concentrations in the brain of AD patients, generating the hydroxyl radical ((·)OH) via Fenton (FR) and Fenton-like (FLR) reactions. This mechanism generates high levels of free radicals and, hence, oxidative stress, which has been correlated with the generation and progression of AD. Therefore, we have studied in vitro how AChE catalytic activity and ACh levels are affected by the presence of metals (Fe(3+), Cu(2+), Cr(3+), Zn(2+), and Cd(2+)), H2O2 (without A?42), and (·) OH radicals produced from FR and FLR. The results showed that the H2O2 and the metals do not modify the AChE catalytic activity, but the (·)OH radical causes a decrease in it. On the other hand, metals, H2O2 and (·)OH radicals, increase the ACh hydrolysis. This finding suggests that when H2O2, the metals and the (·)OH radicals are present, both, the AChE catalytic activity and ACh levels diminish. Furthermore, in the future it may be interesting to study whether these effects are observed when H2O2 is produced directly from A?42. PMID:25096900

  8. Self-assembly of SiO2 nanoparticles for the potentiometric detection of neurotransmitter acetylcholine and its inhibitor.

    PubMed

    Arruda, Izabela G; Guimarães, Francisco E G; Ramos, Romildo J; Vieira, Nirton C S

    2014-09-01

    The detection and quantification of neurotransmitter acetylcholine (ACh) are relevant because modifications in the ACh levels constitute a threat to human health. The biological regulator of this neurotransmitter is acetylcholinesterase (AChE), an enzyme that catalyzes the hydrolysis of ACh to choline and acetic acid. However, its activity is inhibited in the presence of organophosphate and carbamate pesticides, compromising the degradation of the neurotransmitter. There has been a growing interest in faster and more sensitive detection systems that include new methods and materials for the determination of the ACh concentration. This paper proposes a potentiometric biosensor for the detection of neurotransmitter ACh and its inhibitors, specifically organophosphate pesticide methamidophos. The biosensor is based on a self-assembled platform formed by poly(allylamine) hydrochloride (PAH) and silicon dioxide nanoparticles (SiO2-Np) that contains the immobilized enzyme AChE. First, the responses of the biosensor were investigated for different concentrations of ACh in buffer solutions. After quantifying ACh, the inhibition of AChE in the presence of methamidophos was determined, enabling the quantification of methamidophos expressed as the percentage of enzyme inhibition. The potential advantages of this biosensor include simplicity in building the electrode, possible production on an industrial scale, limited need for qualified personnel to operate the device and low processing cost. PMID:25924313

  9. AChR-specific immunosuppressive therapy of myasthenia gravis.

    PubMed

    Luo, Jie; Lindstrom, Jon

    2015-10-15

    Myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by muscle fatigability. In most cases, it is mediated by autoantibodies targeting muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. Experimental autoimmune myasthenia gravis (EAMG) is an animal model for MG, which is usually induced by immunization with AChR purified from fish electric organ. Pathological autoantibodies to AChRs are directed at the extracellular surface, especially the main immunogenic region (MIR). Current treatments for MG can help many but not all patients. Antigen-specific immunosuppressive therapy for MG that specifically suppresses the autoimmune response without affecting the entire immune system and avoids side effects of general immunosuppression is currently unavailable. Early attempts at antigen-specific immunosuppression for EAMG using AChR extracellular domain sequences that form epitopes for pathological autoantibodies risked provoking autoimmunity rather than suppressing it. We discovered a novel approach to specific immunosuppression of EAMG with a therapeutic vaccine consisting of bacterially-expressed human AChR cytoplasmic domains, which has the potential to specifically suppress MG without danger of causing exacerbation. This approach prevents development of chronic EAMG when initiated immediately after the acute phase of EAMG, and rapidly reverses established chronic EAMG when started during the chronic phase of EAMG. Successfully treated rats exhibited long-term resistance to re-induction of EAMG. In this review we also discuss the current understanding of the mechanisms by which the therapy works. Vaccination with AChR cytoplasmic domains in adjuvant is promising as a safe, antigen-specific, potent, effective, rapidly acting, and long lasting approach to therapy of MG. PMID:26215875

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

    PubMed Central

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

    2011-01-01

    Cyclophostin, a structurally unique and potent naturally occurring acetyl cholinesterase (AChE) inhibitor, and its unnatural diastereomer were prepared in 6 steps and 15% overall yield from hydroxymethyl butyrolactone. The unnatural diastereomer of cyclophostin was converted into cyclipostin P, a potent naturally occurring hormone sensitive lipase (HSL) inhibitor, using a one pot dealkylation-alkylation process. The inhibition [IC50] of human AChE by cyclophostin and its diastereomer are reported, as well as constituent binding (KI) and reactivity (k2) constants. PMID:21591624

  11. 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

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

    PubMed Central

    Amat-ur-Rasool, Hafsa; Ahmed, Mehboob

    2015-01-01

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

  13. 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

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

    ERIC Educational Resources Information Center

    Munzel, Mark

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

  15. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

    PubMed Central

    Pohanka, Miroslav

    2014-01-01

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

  16. Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, A? aggregation, and ?-secretase.

    PubMed

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

    2014-09-01

    Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both A? aggregation and ?-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery. PMID:25088549

  17. Acetylcholinesterase complexes with the natural product inhibitors dihydrotanshinone I and territrem B: binding site assignment from inhibitor competition and validation through crystal structure determination.

    PubMed

    Cheung, Jonah; Beri, Veena; Shiomi, Kazuro; Rosenberry, Terrone L

    2014-07-01

    Acetylcholinesterase (AChE) is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and organophosphate (OP) chemical warfare agents that cripple the nervous system and cause death through paralysis. We are exploring a strategy to design compounds that bind tightly at or near a peripheral or P-site near the mouth of the AChE active site gorge and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. Here, we review our recent reports on two uncharged, natural product inhibitors of AChE, dihydrotanshinone I and territrem B, that have relatively high affinities for the enzyme. We describe an inhibitor competition assay and comment on the structures of these inhibitors in complex with recombinant human acetylcholinesterase as determined by X-ray crystallography. Our results reveal that dihydrotanshinone I binding is specific to only the P-site, while territrem B binding spans the P-site and extends into the acylation or A-site at the base of the gorge. PMID:24573600

  18. 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

  19. Dihydroagarofuranoid Sesquiterpenes as Acetylcholinesterase Inhibitors from Celastraceae Plants: Maytenus disticha and Euonymus japonicus.

    PubMed

    Alarcón, Julio; Cespedes, Carlos L; Muñoz, Evelyn; Balbontin, Cristian; Valdes, Francisco; Gutierrez, Margarita; Astudillo, Luis; Seigler, David S

    2015-12-01

    Natural cholinesterase inhibitors have been found in many biological sources. Nine compounds with agarofuran (epoxyeudesmane) skeletons were isolated from seeds and aerial parts of Maytenus disticha and Euonymus japonicus. The identification and structural elucidation of compounds were based on spectroscopic data analyses. All compounds had inhibitory acetylcholinesterase (AChE) activity. These natural compounds, which possessed mixed or uncompetitive mechanisms of inhibitory activity against AChE, may be considered as models for the design and development of new naturally occurring drugs for management strategies for neurodegenerative diseases. This is the first report of these chemical structures for seeds of M. disticha. PMID:26545100

  20. 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

  1. Role of acetylcholinesterase (AChE) secreted by parasitic nematodes on the growth of the cell line from epithelial origin HT29-D4.

    PubMed

    Huby, F; Mallet, S; Hoste, H

    1999-05-01

    The excretory-secretory (E-S) products of the parasitic nematodes Trichostrongylus colubriformis and Nematodirus battus were found to modify the in vitro proliferation of the tumorous colic HT29-D4 cell line of epithelial origin. A characteristic feature of these E-S products is the presence of a high level of acetylcholinesterase (AChE) activity, the biological significance of which remains unclear. To determine a possible role of AChE on cell growth, the enzyme was purified from E-S products using edrophonium chloride. Purity was confirmed by polyacrylamide gel electrophoresis, using silver and Karnovsky stains, before assessing its effects on cell proliferation. The purified AChE was incorporated at different concentrations in a culture medium of HT29-D4 cells. A mitogenic effect was shown for low concentrations (0.1-14 units). By contrast, an inhibitory effect was noted at high concentrations (35-1400 units). Furthermore, polyclonal antibodies were prepared and depletion of AChE in E-S products by immunoprecipitation or affinity chromatography resulted in a partial or total disappearance of the stimulatory effect of cell growth. Thus, the results form this in vitro study suggest a modulatory role for AChE secreted by nematode parasites on the proliferation of epithelial cells of the host. PMID:10363282

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

    PubMed

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

    2015-05-20

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

  3. 77 FR 40148 - Proposed Collection of Information: ACH Vendor/Miscellaneous Payment Enrollment Form

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-06

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF THE TREASURY Fiscal Service Proposed Collection of Information: ACH Vendor/Miscellaneous Payment Enrollment Form... comments concerning the SF 3881 ``ACH Vendor/Miscellaneous Payment Enrollment Form.'' DATES:...

  4. Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations

    PubMed Central

    Pecic, Stevan; McAnuff, Marie A.; Harding, Wayne W.

    2015-01-01

    Nantenine, as well as a number of flexible analogs, were evaluated for acetylcholinesterase (AChE) inhibitory activity in microplate spectrophotometric assays based on Ellman’s method. It was found that the rigid aporphine core of nantenine is an important structural requirement for its anticholinesterase activity. Nantenine showed mixed inhibition kinetics in enzyme assays. Molecular docking experiments suggest that nantenine binds preferentially to the catalytic site of AChE but is also capable of interacting with the peripheral anionic site (PAS) of the enzyme, thus accounting for its mixed inhibition profile. The aporphine core of nantenine may thus be a useful template for the design of novel PAS or dual-site AChE inhibitors. Inhibiting the PAS is desirable for prevention of aggregation of the amyloid peptide A?, a major causative factor in the progression of Alzheimer’s disease (AD). PMID:20583856

  5. Synthesis and biological evaluation of novel tacrine derivatives and tacrine-coumarin hybrids as cholinesterase inhibitors.

    PubMed

    Hamulakova, Slavka; Janovec, Ladislav; Hrabinova, Martina; Spilovska, Katarina; Korabecny, Jan; Kristian, Pavol; Kuca, Kamil; Imrich, Jan

    2014-08-28

    A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were found to be the most potent inhibitors of human AChE (hAChE), demonstrating IC50 values of 0.0154 and 0.0263 ?M. Ligands 6b, 6c, and 7c exhibited the highest levels of inhibitory activity against human BuChE (hBuChE), demonstrating IC50 values that range from 0.228 to 0.328 ?M. Docking studies were performed in order to predict the binding modes of compounds 6b and 7c with hAChE/hBuChE. PMID:25089370

  6. 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

  7. Kinetic inhibitor of hydrate crystallization.

    PubMed

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

    2004-02-11

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

  8. 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

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

    NASA Astrophysics Data System (ADS)

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

    2013-01-01

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

  10. Protein-Drug Interactions with Effective Polarization in Polarizable Water: Oxime Unbinding from AChE Gorge.

    PubMed

    Pathak, Arup K; Bandyopadhyay, Tusar

    2015-11-12

    Despite the fact that polarizability of water is different in the bulk and in protein, simulations of protein-ligand complexes are mostly carried out in nonpolarizable water media. We present oxime (HI-6) unbinding from the active site gorge of AChE, known to be strongly influenced by intermolecular cation-?, hydrogen bridge (HB) and water bridge (WB) interactions and by molecular simulations with effective polarization in polarizable mean-field model of TIP3P water. Enabled by the recent availability of a method of obtaining microkinetics of rare events, we set out to investigate the rate constants of unbinding transitions from one basin to the other through a combination of metadynamics and hyperdynamics simulations. The results underpin the importance of electronic polarization effects on the pathways, potential of mean force, rate constants, and HB and WB dynamics of unbinding transitions of a drug molecule ligated to protein interior. The method is also applicable to unravel the binding mechanisms. PMID:26468911

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  12. Non-neuronal cholinergic system in regulation of immune function with a focus on ?7 nAChRs.

    PubMed

    Kawashima, Koichiro; Fujii, Takeshi; Moriwaki, Yasuhiro; Misawa, Hidemi; Horiguchi, Kazuhide

    2015-11-01

    In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal's body. They identified this ACh in the spleens of horses and oxen, which we now know suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades. Recent studies on the source of ACh in the blood revealed ACh synthesis catalyzed by choline acetyltransferase (ChAT) in CD4(+) T cells. T and B cells, macrophages and dendritic cells (DCs) all express all five muscarinic ACh receptor subtypes (mAChRs) and several subtypes of nicotinic AChRs (nAChRs), including ?7 nAChRs. Stimulation of these mAChRs and nAChRs by their respective agonists causes functional and biochemical changes in the cells. Using AChR knockout mice, we found that M1/M5 mAChR signaling up-regulates IgG1 and pro-inflammatory cytokine production, while ?7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts in an autocrine/paracrine fashion at AChRs on various immune cells to modulate immune function. In addition, an endogenous allosteric and/or orthosteric ?7 nAChR ligand, SLURP-1, facilitates functional development of T cells and increases ACh synthesis via up-regulation of ChAT mRNA expression. SLURP-1 is expressed in CD205(+) DCs residing in the tonsil in close proximity to T cells, macrophages and B cells. Collectively, these findings suggest that ACh released from T cells along with SLURP-1 regulates cytokine production by activating ?7 nAChRs on various immune cells, thereby facilitating T cell development and/or differentiation, leading to immune modulation. PMID:25907239

  13. 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

  14. Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration.

    PubMed

    del Pino, Javier; Moyano, Paula; Anadon, María José; García, José Manuel; Díaz, María Jesús; García, Jimena; Frejo, María Teresa

    2015-10-01

    Chlorpyrifos (CPF) is one of the most widely used organophosphates insecticides that has been reported to induce cognitive disorders both after acute and repeated administration similar to those induced in Alzheimer's disease (AD). However, the mechanisms through which it induces these effects are unknown. On the other hand, the cholinergic system, mainly basal forebrain cholinergic neurons, is involved in learning and memory regulation, and an alteration of cholinergic transmission or/and cholinergic cell loss could induce these effects. In this regard, it has been reported that CPF can affect cholinergic transmission, and alter AChE variants, which have been shown to be related with basal forebrain cholinergic neuronal loss. According to these data, we hypothesized that CPF could induce basal forebrain cholinergic neuronal loss through cholinergic transmission and AChE variants alteration. To prove this hypothesis, we evaluated in septal SN56 basal forebrain cholinergic neurons, the CPF toxic effects after 24h and 14 days exposure on neuronal viability and the cholinergic mechanisms related to it. This study shows that CPF impaired cholinergic transmission, induced AChE inhibition and, only after long-term exposure, increased CHT expression, which suggests that acetylcholine levels alteration could be mediated by these actions. Moreover, CPF induces, after acute and long-term exposure, cell death in cholinergic neurons in the basal forebrain and this effect is independent of AChE inhibition and acetylcholine alteration, but was mediated partially by AChE variants alteration. Our present results provide a new understanding of the mechanisms contributing to the harmful effects of CPF on neuronal function and viability, and the possible relevance of CPF in the pathogenesis of neurodegenerative diseases. PMID:26210949

  15. 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

  16. Muscarinic and nicotinic ACh receptor activation differentially mobilize Ca2+ in rat intracardiac ganglion neurons.

    PubMed

    Beker, Friederike; Weber, Martin; Fink, Rainer H A; Adams, David J

    2003-09-01

    The origin of intracellular Ca2+ concentration ([Ca2+]i) transients stimulated by nicotinic (nAChR) and muscarinic (mAChR) receptor activation was investigated in fura-2-loaded neonatal rat intracardiac neurons. ACh evoked [Ca2+]i increases that were reduced to approximately 60% of control in the presence of either atropine (1 microM) or mecamylamine (3 microM) and to <20% in the presence of both antagonists. Removal of external Ca2+ reduced ACh-induced responses to 58% of control, which was unchanged in the presence of mecamylamine but reduced to 5% of control by atropine. The nAChR-induced [Ca2+]i response was reduced to 50% by 10 microM ryanodine, whereas the mAChR-induced response was unaffected by ryanodine, suggesting that Ca2+ release from ryanodine-sensitive Ca2+ stores may only contribute to the nAChR-induced [Ca2+]i responses. Perforated-patch whole cell recording at -60 mV shows that the rise in [Ca2+]i is concomitant with slow outward currents on mAChR activation and with rapid inward currents after nAChR activation. In conclusion, different signaling pathways mediate the rise in [Ca2+]i and membrane currents evoked by ACh binding to nicotinic and muscarinic receptors in rat intracardiac neurons. PMID:12761283

  17. 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

    PubMed

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

    2015-11-01

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

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

    PubMed

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

    2015-11-01

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

  19. Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.

    PubMed

    Gazzard, Lewis; Williams, Karen; Chen, Huifen; Axford, Lorraine; Blackwood, Elizabeth; Burton, Brenda; Chapman, Kerry; Crackett, Peter; Drobnick, Joy; Ellwood, Charles; Epler, Jennifer; Flagella, Michael; Gancia, Emanuela; Gill, Matthew; Goodacre, Simon; Halladay, Jason; Hewitt, Joanne; Hunt, Hazel; Kintz, Samuel; Lyssikatos, Joseph; Macleod, Calum; Major, Sarah; Médard, Guillaume; Narukulla, Raman; Ramiscal, Judi; Schmidt, Stephen; Seward, Eileen; Wiesmann, Christian; Wu, Ping; Yee, Sharon; Yen, Ivana; Malek, Shiva

    2015-06-25

    Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model. PMID:25988399

  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. 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

  2. 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.

  3. B6) Quaternary Geology QUATERNARY GEOLOGY AND LANDFORMS BETWEEN

    E-print Network

    Briner, Jason P.

    The Quaternary geology and landforms in western New York State north of the southern Finger Lakes (Valley Heads recession across a scarp-dominated bedrock landscape from Batavia to the southern Lake Ontario shoreline. The complex sequence of proglacial lakes that accompanied glacial recession across the Great Lakes region

  4. Angiogenesis Inhibitors

    MedlinePLUS

    ... inhibitors currently being used to treat cancer in humans? How are angiogenesis inhibitors different from conventional anticancer ... inhibitors currently being used to treat cancer in humans? Yes. The U.S. Food and Drug Administration (FDA) ...

  5. 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

  6. Ethynylphenyl carbonates and carbamates as dual-action acetylcholinesterase inhibitors and anti-inflammatory agents.

    PubMed

    Saxena, Jaya; Meloni, David; Huang, Mou-Tuan; Heck, Diane E; Laskin, Jeffrey D; Heindel, Ned D; Young, Sherri C

    2015-12-01

    Novel ethynylphenyl carbonates and carbamates containing carbon- and silicon-based choline mimics were synthesized from their respective phenol and aniline precursors and screened for anticholinesterase and anti-inflammatory activities. All molecules were micromolar inhibitors of acetylcholinesterase (AChE), with IC50s of 28-86?M; the carbamates were two-fold more potent than the carbonates. Two of the most potent AChE inhibitors suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation by 40%. Furthermore, these molecules have physicochemical properties in the range of other CNS drugs. These molecules have the potential to treat inflammation; they could also dually target Alzheimer's disease through restoration of cholinergic balance and inflammation suppression. PMID:26510670

  7. 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.

  8. Higher susceptibility to halothane modulation in open- than in closed-channel alpha4beta2 nAChR revealed by molecular dynamics simulations.

    PubMed

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

    2010-01-14

    The neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR) is a potential molecular target for general anesthetics. It is unclear, however, whether anesthetic action produces the same effect on the open and closed channels. Computations parallel to our previous open channel study (J. Phys. Chem. B 2009, 113, 12581) were performed on the closed-channel alpha4beta2 nAChR to investigate the conformation-dependent anesthetic effects on channel structures and dynamics. Flexible ligand docking and over 20 ns molecular dynamics simulations revealed similar halothane-binding sites in the closed and open channels. The sites with relatively high binding affinities (approximately -6.0 kcal/mol) were identified at the interface of extracellular (EC) and transmembrane (TM) domains or at the interface between alpha4 and beta2 subunits. Despite similar sites for halothane binding, the closed-channel conformation showed much less sensitivity than the open channel to the structural and dynamical perturbations from halothane. Compared to the systems without anesthetics, the amount of water inside the pore decreased by 22% in the presence of halothane in the open channel but only by 6% in the closed channel. Comparison of the nonbonded interactions at the EC/TM interfaces suggested that the beta2 subunits were more prone than the alpha4 subunits to halothane binding. In addition, our data support the notion that halothane exerts its effect by disturbing the quaternary structure and dynamics of the channel. The study concludes that sensitivity and global dynamics responsiveness of alpha4beta2 nAChR to halothane are conformation dependent. The effect of halothane on the global dynamics of the open-channel conformation might also account for the action of other inhaled general anesthetics. PMID:20014754

  9. Higher susceptibility to halothane modulation in open- than in closed-channel ?4?2 nAChR revealed by MD simulations

    PubMed Central

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

    2009-01-01

    The neuronal ?4?2 nicotinic acetylcholine receptor (nAChR) is a potential molecular target for general anesthetics. It is unclear, however, whether anesthetic action produces the same effect on the open and closed channels. Computations parallel to our previous open channel study (J. Phys. Chem. B, 2009) were performed on the closed-channel ?4?2 nAChR to investigate the conformation-dependent anesthetic effects on channel structures and dynamics. Flexible ligand docking and over 20-ns molecular dynamics simulations revealed similar halothane-binding sites in the closed and open channels. The sites with relatively high binding affinities (~?6.0 kcal/mol) were identified at the interface of extracellular (EC) and transmembrane (TM) domains or at the interface between ?4 and ?2 subunits. Despite similar sites for halothane binding, the closed-channel conformation showed much less sensitivity than the open channel to the structural and dynamical perturbations from halothane. Compared to the systems without anesthetics, the amount of water inside the pore decreased by 22% in the presence of halothane in the open channel, but only by 6% in the closed channel. Comparison of the non-bonded interactions at the EC/TM interfaces suggested that the ?2 subunits were more prone than the ?4 subunits to halothane binding. In addition, our data support the notion that halothane exerts its effect by disturbing the quaternary structure and dynamics of the channel. The study concludes that sensitivity and global dynamics responsiveness of ?4?2 nAChR to halothane are conformation dependent. The effect of halothane on global dynamics of open-channel conformation might also account for the action of other inhaled general anesthetics. PMID:20014754

  10. Impact of acetylcholinesterase inhibitors on the occurrence of acute coronary syndrome in patients with dementia.

    PubMed

    Wu, Ping-Hsun; Lin, Yi-Ting; Hsu, Po-Chao; Yang, Yi-Hsin; Lin, Tsung-Hsien; Huang, Chia-Tsuan

    2015-01-01

    The study aimed to investigate the association of acetylcholinesterase inhibitors (AChEIs) use with the risk of acute coronary syndrome (ACS). We conducted a population-based retrospective cohort study of dementia patients during 1 January 1999 to 31 December 2008 using the National Health Insurance Database in Taiwan. New AChEI users during the study period were matched with AChEI nonusers in age-matched and gender-matched cohorts. The risk of ACS associated with use of AChEIs was analyzed using modified Kaplan-Meier analysis and Cox proportional hazard models after adjustment for competing death risk. Use of AChEIs was associated with a lower incidence of ACS (212.8/10,000 person-years) compared to the matched reference cohort (268.7/10,000 person-years). The adjusted hazard ratio for ACS in patients with dementia treated with AChEIs was 0.836 (95% confidence interval, 0.750-0.933; P?AChEI use and ACS risk was significant for the patients with dementia. In patients with dementia, AChEI treatment was associated with decreased risk of ACS. PMID:26577589

  11. 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

  12. Impact of acetylcholinesterase inhibitors on the occurrence of acute coronary syndrome in patients with dementia

    PubMed Central

    Wu, Ping-Hsun; Lin, Yi-Ting; Hsu, Po-Chao; Yang, Yi-Hsin; Lin, Tsung-Hsien; Huang, Chia-Tsuan

    2015-01-01

    The study aimed to investigate the association of acetylcholinesterase inhibitors (AChEIs) use with the risk of acute coronary syndrome (ACS). We conducted a population-based retrospective cohort study of dementia patients during 1 January 1999 to 31 December 2008 using the National Health Insurance Database in Taiwan. New AChEI users during the study period were matched with AChEI nonusers in age-matched and gender-matched cohorts. The risk of ACS associated with use of AChEIs was analyzed using modified Kaplan-Meier analysis and Cox proportional hazard models after adjustment for competing death risk. Use of AChEIs was associated with a lower incidence of ACS (212.8/10,000 person-years) compared to the matched reference cohort (268.7/10,000 person-years). The adjusted hazard ratio for ACS in patients with dementia treated with AChEIs was 0.836 (95% confidence interval, 0.750–0.933; P?AChEI use and ACS risk was significant for the patients with dementia. In patients with dementia, AChEI treatment was associated with decreased risk of ACS. PMID:26577589

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

    PubMed

    Sun, Jian; Yang, Xiurong

    2015-12-15

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

  14. Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl.

    PubMed

    Petroianu, Georg A; Nurulain, Syed M; Hasan, Mohamed Y; Ku?a, Kamil; Lorke, Dietrich E

    2015-05-01

    Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01) 30 min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR = 1). The most efficacious prophylactic agents were K-27 (RR = 0.15) and physostigmine (RR = 0.21), being significantly more efficacious than ranitidine (RR = 0.62) and pyridostigmine (RR = 0.37). Pre-treatment with tacrine (RR = 0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure. PMID:25186309

  15. Andrei Sher and Quaternary science

    NASA Astrophysics Data System (ADS)

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

    2011-08-01

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

  16. Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.

    PubMed

    Schwarz, Stefan; Lucas, Susana Dias; Sommerwerk, Sven; Csuk, René

    2014-07-01

    The development of remedies against the Alzheimer's disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30?M. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. PMID:24853320

  17. Quaternary ecology: A paleoecological perspective

    SciTech Connect

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

    1991-01-01

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

  18. 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,...

  19. 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. 172.165 Section 172...Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used...

  20. 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. 172.165 Section 172...Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used...

  1. 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. 172.165 Section 172...Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used...

  2. 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. 172.165 Section 172...Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used...

  3. 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. 172.165 Section 172...Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used...

  4. 40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...Ethoxylated alkyl quaternary ammonium compound. 721.655 Section 721.655 ...Ethoxylated alkyl quaternary ammonium compound. (a) Chemical substance and significant...ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject...

  5. Expression and function of neuronal nicotinic ACh receptors in rat microvascular endothelial cells.

    PubMed

    Moccia, F; Frost, C; Berra-Romani, R; Tanzi, F; Adams, D J

    2004-02-01

    The expression and function of nicotinic ACh receptors (nAChRs) in rat coronary microvascular endothelial cells (CMECs) were examined using RT-PCR and whole cell patch-clamp recording methods. RT-PCR revealed expression of mRNA encoding for the subunits alpha(2), alpha(3), alpha(4), alpha(5), alpha(7), beta(2), and beta(4) but not beta(3). Focal application of ACh evoked an inward current in isolated CMECs voltage clamped at negative membrane potentials. The current-voltage relationship of the ACh-induced current exhibited marked inward rectification and a reversal potential (E(rev)) close to 0 mV. The cholinergic agonists nicotine, epibatidine, and cytisine activated membrane currents similar to those evoked by ACh. The nicotine-induced current was abolished by the neuronal nAChR antagonist mecamylamine. The direction and magnitude of the shift in E(rev) of nicotine-induced current as a function of extracellular Na(+) concentration indicate that the nAChR channel is cation selective and follows that predicted by the Goldman-Hodgkin-Katz equation assuming K(+)/Na(+) permeability ratio of 1.11. In fura-2-loaded CMECs, application of ACh, but not of nicotine, elicited a transient increase in intracellular free Ca(2+) concentration. Taken together, these results demonstrate that neuronal nAChR activation by cholinergic agonists evokes an inward current in CMECs carried primarily by Na(+), which may contribute to the plasma nicotine-induced changes in microvascular permeability and reactivity induced by elevations in plasma nicotine. PMID:14512281

  6. Local anaesthetic blockade of neuronal nicotinic ACh receptor-channels in rat parasympathetic ganglion cells.

    PubMed

    Cuevas, J; Adams, D J

    1994-03-01

    1 The effects of the local anaesthetics QX-222 and procaine on nicotinic acetylcholine (ACh)-evoked currents in cultured parasympathetic cardiac neurones of the rat were investigated by use of the whole-cell, perforated-patch, and outside-out recording configurations of the patch clamp method. 2 QX-222 and procaine, applied to the extracellular surface, reversibly inhibited the peak amplitude of the whole-cell nicotinic ACh-evoked current in a concentration-dependent manner, with half-maximal inhibitory concentrations (IC50) of 28 microM and 2.8 microM, respectively, at -80 mV. In these neurones, the sustained inward current mediated by M1 muscarinic receptor activation was unaltered by QX-222, and neither local anaesthetic affected the adenosine 5'-triphosphate (ATP)-evoked current. 3 QX-222 and procaine block of nicotinic ACh-evoked inward current was voltage-dependent and enhanced by hyperpolarization. An e-fold change in their dissociation equilibrium constants (Kd) resulted from a 62 mV and a 122 mV change in membrane potential, respectively. 4 Both local anaesthetics produce a concentration-dependent increase in the half-time of decay of the nicotinic ACh-evoked inward current. 5 Measurements of unitary currents in outside-out patches showed that QX-222 reversibly increased the mean burst duration and closed time and reduced the mean channel open time and open-state probability of the nicotinic ACh receptor-channel (AChR) in a concentration-dependent manner. 6 The Kd and voltage sensitivity of local anaesthetic block of the nicotinic AChR in rat intracardiac neurones suggests that the pore-forming region of this channel differs from that of the AChR in frog and rat skeletal muscle and from the neuronal alpha 4 beta 2 ACh receptor-channel. PMID:7517326

  7. RoACH: An autonomous 2.4g crawling hexapod robot Aaron M. Hoover, Erik Steltz, Ronald S. Fearing

    E-print Network

    Fearing, Ron

    RoACH: An autonomous 2.4g crawling hexapod robot Aaron M. Hoover, Erik Steltz, Ronald S. Fearing and battery, RoACH is the smallest and lightest autonomous legged robot produced to date. I. INTRODUCTION.4g robotic, autonomous, crawling hexapod (RoACH) capable of sustained locomotion. The robot makes use

  8. Myasthenia Gravis and the Tops and Bottoms of AChRs Antigenic Structure of the MIR and Specific Immunosuppression of EAMG Using AChR Cytoplasmic Domains

    PubMed Central

    Lindstrom, Jon; Luo, Jie; Kuryatov, Alexander

    2009-01-01

    The main immunogenic region (MIR), against which half or more of the autoantibodies to acetylcholine receptors (AChRs) in myasthenia gravis (MG) or experimental autoimmune MG (EAMG) are directed, is located at the extracellular end of ?1 subunits. Rat monoclonal antibodies (mAbs) to the MIR efficiently compete with MG patient autoantibodies for binding to human muscle AChRs. Antibodies bound to the MIR do not interfere with cholinergic ligand binding or AChR function, but target complement and trigger antigenic modulation. Rat mAbs to the MIR also bind to human ganglionic AChR ?3 subunits, but MG patient antibodies do not. By making chimeras of ?1 subunits with ?7 subunits or ACh binding protein, the structure of the MIR and its functional effects are being investigated. Many mAbs to the MIR bind only to the native conformation of ?1 subunits because they bind to sequences that are adjacent only in the native structure. The MIR epitopes recognized by these mAbs are not recognized by most patient antibodies whose epitopes must be nearby. The presence of the MIR epitopes in ?1/?7 chimeras greatly promotes AChR expression and sensitivity to activation. EAMG can be suppressed by treatment with denatured, bacterially expressed mixtures of extracellular and cytoplasmic domains of human ?1, ?1, ?, ?, and ? subunits. A mixture of only the cytoplasmic domains not only avoids the potential liability of provoking formation antibodies to pathologically significant epitopes on the extracellular surface, but also potently suppresses the development of EAMG. PMID:18567851

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  10. 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

  11. 77 FR 40148 - Proposed Collection of Information: ACH Vendor/Miscellaneous Payment Enrollment Form

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-06

    ...Financial Management Service solicits comments concerning the SF 3881 ``ACH Vendor/Miscellaneous Payment Enrollment Form...Payment Enrollment Form. OMB Number: 1510-0056. Form Number: SF 3881. Abstract: This form is used to collect payment data...

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

    PubMed Central

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

    2011-01-01

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

  13. Late Quaternary history of the Atacama Desert

    E-print Network

    #12;#12;#12;#12;#12;73 Late Quaternary history of the Atacama Desert Claudio Latorre, Julio L and Kate Rylander Of the major subtropical deserts found in the Southern Hemisphere, the Atacama Desert is the driest. Throughout the Quaternary, the most pervasive climatic influence on the desert has been

  14. 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

  15. Ancient biomolecules in Quaternary palaeoecology

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

    The last few years have seen an enormous proliferation of ancient biomolecules research, especially in the field of ancient DNA. Ancient DNA studies have been transformed by the advent of next generation sequencing, with the first Pleistocene sample being analysed in 2005, and several complete and draft genomes that have been compiled from ancient DNA to date. At the same time, although less conspicuous, research on ancient proteins has also seen advances, with the time limit for research on ancient biomolecules now extending to over 1 million years. Here we review which effects these developments have on research in Quaternary science. We identify several lines of research that have the potential to profit substantially from these recent developments in ancient biomolecules research. First, the identification of taxa can be made using ancient biomolecules, and in the case of ancient DNA, specimens can even be assigned to specific populations within a species. Second, increasingly large DNA data sets from Pleistocene animals allow the elucidation of ever more precise pictures of the population dynamic processes whereby organisms respond to climate and environmental change. With the accompanying better understanding of process in the Quaternary, past ecologies can also more realistically be interpreted from proxy data sets. The dominant message from this research so far is that the Quaternary saw a great deal more dynamism in populations than had been forecast by conventional palaeoecology. This suggests that reconstructions of past environmental conditions need to be done with caution. Third, ancient DNA can also now be obtained directly from sediments to elucidate the presence of both plant and animal species in an area even in the absence of identifiable fossils, be it macro- or micro-fossils. Finally, the analysis of proteins enables the identification of bone remains to genus and sometimes species level far beyond the survival time of DNA, at least in temperate regions, illustrating that precise data is now forthcoming from seemingly unlikely sources. Together, these approaches allow the study of environmental dynamics throughout a substantial part, and perhaps even the entire Quaternary (the last 2.6 million years).

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

    PubMed Central

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

    2013-01-01

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

  17. Synthesis and structure-activity relationship study of benzofuran-based chalconoids bearing benzylpyridinium moiety as potent acetylcholinesterase inhibitors.

    PubMed

    Mostofi, Manizheh; Mohammadi Ziarani, Ghodsi; Mahdavi, Mohammad; Moradi, Alireza; Nadri, Hamid; Emami, Saeed; Alinezhad, Heshmatollah; Foroumadi, Alireza; Shafiee, Abbas

    2015-10-20

    A series of benzofuran-based chalconoids 6a-v were designed and synthesized as new potential AChE inhibitors. The in vitro assay of synthesized compounds 6a-v showed that most compounds had significant anti-AChE activity at micromolar or sub-micromolar levels. Among the tested compounds, 3-pyridinium derivative 6m bearing N-(2-bromobenzyl) moiety and 7-methoxy substituent on the benzofuran ring exhibited superior activity. This compound with IC50 value of 0.027 ?M was as potent as standard drug donepezil. PMID:26363872

  18. 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

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

    PubMed

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

    2006-07-01

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

  20. Phosphorylation-Elicited Quaternary Changes of GA Binding Protein in Transcriptional Activation

    PubMed Central

    Sunesen, Morten; Huchet-Dymanus, Monique; Christensen, Morten O.; Changeux, Jean-Pierre

    2003-01-01

    Enrichment of nicotinic acetylcholine receptors (nAChR) on the tip of the subjunctional folds of the postsynaptic membrane is a central event in the development of the vertebrate neuromuscular junction. This is attained, in part, through a selective transcription in the subsynaptic nuclei, and it has recently been shown that the GA binding protein (GABP) plays an important role in this compartmentalized expression. The neural factor heregulin (HRG) activates nAChR transcription in cultured cells by stimulating a signaling cascade of protein kinases. Hence, it is speculated that GABP becomes activated by phosphorylation, but the mechanism has remained elusive. To fully understand the consequences of GABP phosphorylation, we examined the effect of heregulin-elicited GABP phosphorylation on cellular localization, DNA binding, transcription, and mobility. We demonstrate that HRG-elicited phosphorylation dramatically changes the transcriptional activity and mobility of GABP. While phosphorylation of GABP? seems to be dispensable for these changes, phosphorylation of GABP? is crucial. Using fluorescence resonance energy transfer, we furthermore showed that phosphorylation of threonine 280 in GABP? triggers reorganizations of the quaternary structure of GABP. Taken together, these results support a model in which phosphorylation-elicited structural changes of GABP enable engagement in certain interactions leading to transcriptional activation. PMID:14585962

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

    PubMed Central

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

    2014-01-01

    The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer’s disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13–15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD. PMID:25378907

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

    SciTech Connect

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

    2008-07-28

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

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

    PubMed

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

    2015-10-15

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

  4. 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

  5. Tribendimidine: Mode of Action and nAChR Subtype Selectivity in Ascaris and Oesophagostomum

    PubMed Central

    Robertson, Alan P.; Puttachary, Sreekanth; Buxton, Samuel K.; Martin, Richard J.

    2015-01-01

    The cholinergic class of anthelmintic drugs is used for the control of parasitic nematodes. One of this class of drugs, tribendimidine (a symmetrical diamidine derivative, of amidantel), was developed in China for use in humans in the mid-1980s. It has a broader-spectrum anthelmintic action against soil-transmitted helminthiasis than other cholinergic anthelmintics, and is effective against hookworm, pinworms, roundworms, and Strongyloides and flatworm of humans. Although molecular studies on C. elegans suggest that tribendimidine is a cholinergic agonist that is selective for the same nematode muscle nAChR as levamisole, no direct electrophysiological observations in nematode parasites have been made to test this hypothesis. Also the hypothesis that levamisole and tribendimine act on the same receptor, does not explain why tribendimidine is effective against some nematode parasites when levamisole is not. Here we examine the effects of tribendimidine on the electrophysiology and contraction of Ascaris suum body muscle and show that tribendimidine produces depolarization antagonized by the nicotinic antagonist mecamylamine, and that tribendimidine is an agonist of muscle nAChRs of parasitic nematodes. Further pharmacological characterization of the nAChRs activated by tribendimidine in our Ascaris muscle contraction assay shows that tribendimidine is not selective for the same receptor subtypes as levamisole, and that tribendimidine is more selective for the B-subtype than the L-subtype of nAChR. In addition, larval migration inhibition assays with levamisole-resistant Oesophagostomum dentatum isolates show that tribendimidine is as active on a levamisole-resistant isolate as on a levamisole-sensitive isolate, suggesting that the selectivity for levamisole and tribendimidine is not the same. It is concluded that tribendimidine can activate a different population of nematode parasite nAChRs than levamisole, and is more like bephenium. The different nAChR subtype selectivity of tribendimidine may explain why the spectrum of action of tribendimidine is different to that of other cholinergic anthelmintics like levamisole. PMID:25679515

  6. TEA inhibits ACh-induced EDRF release: endothelial Ca(2+)-dependent K+ channels contribute to vascular tone.

    PubMed

    Demirel, E; Rusko, J; Laskey, R E; Adams, D J; van Breemen, C

    1994-09-01

    The effects of K(+)-channel blockers on the acetylcholine (ACh)-induced relaxation of vascular smooth muscle, intracellular free Ca2+ concentration ([Ca2+]i) elevation, and ACh-evoked outward K+ current of endothelial cells of rabbit aorta were studied using bioassay, spectrofluorimetry, and patch-clamp techniques, respectively. In bioassay experiments, ACh caused relaxation of endothelium-denuded aortic rings in a concentration-dependent manner when perfused through an endothelium-intact donor segment of aorta but not when perfused directly onto the recipient aortic ring. ACh-induced relaxation was inhibited by perfusion of tetraethylammonium ions (TEA; 5 mM) through the donor but not by perfusion directly onto the recipient segment. Glibenclamide had no effect on ACh-induced relaxation of the bioassay ring in either situation. ACh increased [Ca2+]i at the endothelial surface of aortic strips but not at the adventitial surface. TEA inhibited ACh-induced [Ca2+]i elevation, whereas glibenclamide had no effect. In patch-clamp experiments with freshly isolated endothelial cells, ACh evoked a biphasic outward current which was completely abolished by TEA (3 mM). It is concluded that Ca(2+)-dependent K+ channels are important for increasing [Ca2+]i during agonist stimulation and consequently for the synthesis/release of endothelium-derived relaxing factors (EDRFs). Furthermore, endothelial ATP-sensitive K+ channels do not contribute to ACh-induced relaxation or evoke an increase in endothelial [Ca2+]i of rabbit thoracic aorta. PMID:8092278

  7. Factors associated with severity of symptoms in patients with chronic unexplained muscular aching.

    PubMed

    Kolar, E; Hartz, A; Roumm, A; Ryan, L; Jones, R; Kirchdoerfer, E

    1989-04-01

    Subjects with chronic, diffuse, unexplained muscular aching were recruited--21 from a primary care practice, nine from a rheumatology practice, and two from a pain clinic. No additional criteria were used to select subjects. Subjects with mild or moderate symptoms differed from those with severe symptoms with respect to the following characteristics: the presence of fatigue on awakening, the number of tender points, difficulty in sleeping, and the degree of tenderness in typical fibromyalgia areas as measured by a dolorimeter. These findings suggest that muscular aching is likely to be of greater severity if other symptoms or signs of fibromyalgia are also present. PMID:2712612

  8. Quaternary Science Reviews 24 (2005) 19631968 Quaternary coastal morphology and sea-level

    E-print Network

    Laughlin, Robert B.

    2005-01-01

    Quaternary Science Reviews 24 (2005) 1963­1968 Editorial Quaternary coastal morphology and sea-level timescales. The position of sea level (ultimate base level) and changes of sea level over geological geomorphological and environmental change in adjacent landscapes. Sea level determines the lower limit

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

    PubMed

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

    2016-01-20

    Two (2-hydroxypropyl) trimethyl ammonium and/or imidazole-based quaternary ammonium chitosan derivatives (NHT-chitosan and Im-OHT-chitosan) were synthesized by using nucleophilic substitution reaction. These two synthesized chitosan derivatives were characterized by Fourier transform infrared spectroscopy, NMR spectra, and UV-visible spectra. The applications as antioxidant agents and cathepsin D inhibitors were further investigated. Both of quaternary ammonium chitosan derivatives exhibited good antioxidant activity upon scavenging against hydroxyl radical and hydrogen peroxide as well as the lipid peroxidation inhibition in the linoleic acid emulsion system. They also exhibited good inhibition activity of cathepsin D protease. NHT-chitosan and Im-OHT-chitosan are potential the natural, healthy and safe preservatives in food industry. PMID:26572425

  10. The Irish quaternary fauna project

    NASA Astrophysics Data System (ADS)

    Woodman, Peter; Mccarthy, Margaret; Monaghan, Nigel

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

  11. 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

  12. CFTR Inhibitors

    PubMed Central

    Verkman, Alan S.; Synder, David; Tradtrantip, Lukmanee; Thiagarajah, Jay R.; Anderson, Marc O.

    2014-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated Cl? channel whose major function is to facilitate epithelial fluid secretion. Loss-of-function mutations in CFTR cause the genetic disease cystic fibrosis. CFTR is required for transepithelial fluid transport in certain secretory diarrheas, such as cholera, and for cyst expansion in autosomal dominant polycystic kidney disease. High-throughput screening has yielded CFTR inhibitors of the thiazolidinone, glycine hydrazide and quinoxalinedione chemical classes. The glycine hydrazides target the extracellular CFTR pore, whereas the thiazolidinones and quinoxalinediones act at the cytoplasmic surface. These inhibitors have been widely used in cystic fibrosis research to study CFTR function at the cell and organ levels. The most potent CFTR inhibitor has IC50 of approximately 4 nM. Studies in animal models support the development of CFTR inhibitors for antisecretory therapy of enterotoxin-mediated diarrheas and polycystic kidney disease. PMID:23331030

  13. In vitro evaluation and in silico screening of synthetic acetylcholinesterase inhibitors bearing functionalized piperidine pharmacophores.

    PubMed

    Brahmachari, Goutam; Choo, CheeYan; Ambure, Pravin; Roy, Kunal

    2015-08-01

    A series of densely functionalized piperidine (FP) scaffolds was synthesized following a diastereoselective one-pot multicomponent protocol under eco-friendly conditions. The FPs were evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activity, and in silico studies for all the target compounds were carried out using pharmacophore mapping, molecular docking and quantitative structure-activity relationship (QSAR) analysis in order to understand the structural features required for interaction with the AChE enzyme and the key active site residues involved in the intermolecular interactions. Halogenation, nitration or 3,4-methylenedixoxy-substitution at the phenyl ring attached to the 2- and 6-positions of 1,2,5,6-tetrahydropyridine nucleus in compounds 14-17, 19, 20, 24 and 26 greatly enhanced the AChE inhibitory activity. The docking analysis demonstrated that the inhibitors are well-fitted in the active sites. The in silico studies enlighten the future course of studies in modifying the scaffolds for better therapeutic efficacy against the deadly Alzheimer's disease. PMID:26105711

  14. While the functional role of nicotinic acetylcholine (ACh) receptors in the neuromuscular junction has been well

    E-print Network

    Marin-Burgin, Antonia

    While the functional role of nicotinic acetylcholine (ACh) receptors in the neuromuscular junction of nicotinic receptors, which are present in different areas of the central nervous system of different species possible to study the effects of activating neuronal nicotinic receptors in identified neurons (Woodruff et

  15. M4 mAChR-Mediated Modulation of Glutamatergic Transmission at Corticostriatal Synapses

    PubMed Central

    2014-01-01

    The striatum is the main input station of the basal ganglia and is extensively involved in the modulation of motivated behavior. The information conveyed to this subcortical structure through glutamatergic projections from the cerebral cortex and thalamus is processed by the activity of several striatal neuromodulatory systems including the cholinergic system. Acetylcholine potently modulates glutamate signaling in the striatum via activation of muscarinic receptors (mAChRs). It is, however, unclear which mAChR subtype is responsible for this modulatory effect. Here, by using electrophysiological, optogenetic, and immunoelectron microscopic approaches in conjunction with a novel, highly selective M4 positive allosteric modulator VU0152100 (ML108) and M4 knockout mice, we show that M4 is a major mAChR subtype mediating the cholinergic inhibition of corticostriatal glutamatergic input on both striatonigral and striatopallidal medium spiny neurons (MSNs). This effect is due to activation of presynaptic M4 receptors, which, in turn, leads to a decrease in glutamate release from corticostriatal terminals. The findings of the present study raise the interesting possibility that M4 mAChR could be a novel therapeutic target for the treatment of neurological and neuropsychiatric disorders involving hyper-glutamatergic transmission at corticostriatal synapses. PMID:24528004

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

    PubMed

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

    2015-12-01

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

  17. Muscarinic Acetylcholine Receptors (mAChRs) in the Nervous System: Some Functions and Mechanisms

    E-print Network

    Brown, David

    ) to the Gi/Go (Pertussis toxin-sensitive) family of G proteins, though the functional coupling will alsoMuscarinic Acetylcholine Receptors (mAChRs) in the Nervous System: Some Functions and Mechanisms of this Symposium), it is the muscarinic receptor that is the most abundant and functionally predominant. Muscarinic

  18. Deoxyribonuclease inhibitors.

    PubMed

    Kolarevic, Ana; Yancheva, Denitsa; Kocic, Gordana; Smelcerovic, Andrija

    2014-12-17

    Deoxyribonucleases (DNases) are a class of enzymes able to catalyze DNA hydrolysis. DNases play important roles in cell function, while DNase inhibitors control or modify their activities. This review focuses on DNase inhibitors. Some DNase inhibitors have been isolated from various natural sources, such as humans, animals (beef, calf, rabbit and rat), plants (Nicotiana tabacum), and microorganisms (some Streptomyces and Adenovirus species, Micromonospora echinospora and Escherichia coli), while others have been obtained by chemical synthesis. They differ in chemical structure (various proteins, nucleotides, anthracycline and aminoglycoside antibiotics, synthetic organic and inorganic compounds) and mechanism of action (forming complexes with DNases or DNA). Some of the inhibitors are specific toward only one type of DNase, while others are active towards two or more. Physico-chemical properties of DNase inhibitors are calculated using the Molinspiration tool and most of them meet all criteria for good solubility and permeability. DNase inhibitors may be used as pharmaceuticals for preventing, monitoring and treating various diseases. PMID:25042005

  19. DT118A, Revised 05/15 Procedures: Preparing the Revenue Deposit Form (ACH/Wire/Credit Card)

    E-print Network

    DT118A, Revised 05/15 Procedures: Preparing the Revenue Deposit Form (ACH/Wire/Credit Card) Overview: The Revenue Deposit Form (ACH/Wire/Credit Card) is used to make departmental deposits using to deposit cash and checks. Departments which use credit card terminals may submit their batch deposit

  20. DT118A, Revised 03/23 Procedures: Preparing the Revenue Deposit Form (ACH/Wire/Credit Card)

    E-print Network

    DT118A, Revised 03/23 Procedures: Preparing the Revenue Deposit Form (ACH/Wire/Credit Card) Overview: The Revenue Deposit Form (ACH/Wire/Credit Card) is used to make departmental deposits using to deposit cash and checks. Departments which use credit card terminals may submit their batch deposit

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

  2. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Quaternary ammonium chloride combination. 172.165... HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used in food in accordance with...

  3. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Quaternary ammonium chloride combination. 172.165... HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used in food in accordance with...

  4. 40 CFR 721.10569 - Tricyclic quaternary amine salt (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  5. 40 CFR 721.10569 - Tricyclic quaternary amine salt (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  6. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Quaternary ammonium chloride combination. 172.165... § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride... the following compounds: n-dodecyl dimethyl benzyl ammonium chloride (CAS Reg. No. 139-07-1);...

  7. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Quaternary ammonium chloride combination. 172.165... HUMAN CONSUMPTION Food Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be safely used in food in accordance with...

  8. 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.

  9. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocenters

    PubMed Central

    Quasdorf, Kyle W.; Overman, Larry E.

    2015-01-01

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

  10. 7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment.

    PubMed

    Korabecny, Jan; Andrs, Martin; Nepovimova, Eugenie; Dolezal, Rafael; Babkova, Katerina; Horova, Anna; Malinak, David; Mezeiova, Eva; Gorecki, Lukas; Sepsova, Vendula; Hrabinova, Martina; Soukup, Ondrej; Jun, Daniel; Kuca, Kamil

    2015-01-01

    Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies. PMID:26690394

  11. Arctic climates of the Quaternary

    NASA Astrophysics Data System (ADS)

    Spielhagen, R. F.; Bauch, H. A.; Frank, M.; Haley, B. A.

    2009-04-01

    The Atlantic Water (AW) inflow through the Fram Strait and across the Barents Sea and the freshwater runoff and brine rejection from sea ice formation on and close to the surrounding shelves are important processes for the formation of modern water masses in the interior Arctic Ocean. From microfossil and sedimentological data, isotopic data from planktic and benthic foraminifers, and 143Nd/144Nd ratios in leached sediment coatings from several well-dated Arctic sediment cores it is possible to reconstruct the variable influence of both processes on surface and intermediate waters in the Late Quaternary. Interglacials and interstadials were characterized by a broken sea ice cover with some open waters (leads) and a strong subsurface AW advection of Atlantic Water, feeding the deeper water masses. During the last ca. 250 ky such events usually were of a relatively short duration (10 ky or less), at times when the northern Eurasian shelves were ice-free. An exception is the last 50 ky interval, when a continuous inflow is recorded. Low Nd ratios indicate also a strong AW contribution to the intermediate waters since 50 ka and during MIS 5e. This conclusion is corroborated by high benthic carbon isotope values, indicative of well-ventilated waters at ca. 1500 m water depth. The good correlation between microfossil contents and insolation values suggests a dominant solar control of the AW inflow history. The time intervals of extended glaciations in northern Eurasia at ca. 190-130, 80-90, and 50-60 ka were characterized by a weak or lacking AW inflow and a strong input of terrestrial ice-rafted debris (IRD). Deglaciations were marked by strong influxes of freshwater from melting ice sheets and/or discharges from previously ice-dammed lakes. High Nd ratios indicate a significant contribution of brines from northern Siberian shelf/ice sheet margins to intermediate waters on the Lomonosov Ridge. The strongest freshwater events occurred at ca. 130 and 52 ka and resulted in an enhanced stratification of the upper water masses and poorly ventilated halocline and deep waters. While sediment records from the northernmost North Atlantic indicate a trend towards warmer peak interglacials and lesser IRD input during peak glacials in the last 500 ky, Arctic records do not reveal such a development. First strong IRD input occurred only during the Saalian glaciation, while earlier and even more extensive glaciations in northern Asia probably did not reach the Arctic paleo-coastline.

  12. 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 Central

    Dash, Bhagirathi; Li, Ming D.

    2014-01-01

    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

  13. 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

  14. Carboxylesterase inhibitors

    PubMed Central

    Hatfield, M. Jason; Potter, Philip M.

    2011-01-01

    Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

  15. 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

  16. The ?3?4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies

    PubMed Central

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

    2014-01-01

    BACKGROUND AND PURPOSE Recent data have indicated that ?3?4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. EXPERIMENTAL APPROACHES To assess the role of ?3?4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. KEY RESULTS BXD recombinant mouse lines demonstrated an increased expression of ?3, ?4 and ?5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, ?5 and ?4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective ?3?4* nACh receptor antagonists, ?-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the ?3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the ?4?2* nACh receptor subtype is not involved in morphine somatic withdrawal signs. CONCLUSION AND IMPLICATIONS Overall, our findings suggest an important role for the ?3?4* nACh receptor subtype in morphine physical dependence. PMID:24750073

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

    PubMed

    Libertini, G

    2013-09-01

    In the late seventies, a small tribal population of Paraguay, the Ache, living under natural conditions, was studied. Data from this population turn out to be useful for considerations about evolutionary hypotheses on the aging phenomenon. 1) Ache show an age-related increasing mortality, which strongly limits the mean duration of life, as observed in other studies on mammal and bird species. 2) According to current theories on aging, in the wild very few or no individual reach old age and, so, aging cannot be directly influenced by natural selection. However, data from our population show that a significant proportion of the population reaches in the wild 60 and 70 years of age. 3) Data from Ache are also in agreement with the observation about an inverse correlation between extrinsic mortality and deaths due to the age-related increasing mortality. 4) For many gerontologists, the age-related decline of vital functions is a consequence of the gradual decline of cell turnover, genetically determined and regulated by the declining duplication capacities of stem cells. The current interpretation is that these restrictions are a general defense against the proliferation of any tumoral mass. However, among wild Ache cancer is virtually unknown in non-elderly subjects, and only among older individuals are there deaths attributable to oncological diseases. Moreover, fitness decline begins long before oncological diseases have fatal effects in significant numbers. This completely disproves the current hypothesis, because a supposed defense against a deadly disease cannot exterminate a population before the disease begins to kill. These data are consistent with similar data from other species studied under natural conditions, and they bring new arguments against the non-adaptive interpretation of aging and in support of the adaptive interpretation. PMID:24228924

  18. 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

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

    NASA Astrophysics Data System (ADS)

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

    2009-10-01

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

  20. Quaternary Geochronology 1 (2006) 7485 Research paper

    E-print Network

    Briner, Jason P.

    2006-01-01

    of complete shielding by the LIS. The lack of glacial erosion for at least the past 400 kyr suggests Island; Glacial history; Interglaciation; Erosion 1. Introduction The large-scale physiography of BaffinQuaternary Geochronology 1 (2006) 74­85 Research paper Limited ice-sheet erosion and complex

  1. 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.

  2. 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

  3. Muscle aches

    MedlinePLUS

    ... plenty of sleep and try to reduce stress. Yoga and meditation are excellent ways to help you sleep and relax. If home measures aren't working, your health care provider may prescribe medicine or physical therapy, or refer you to a specialized pain ...

  4. Spectral analysis and modelling of ACh and NE effects on shark nervus terminalis activity.

    PubMed

    White, J; Meredith, M

    1993-01-01

    We investigated the effects of acetylcholine (ACh) and norepinephrine (NE) on activity in the nervus terminalis (NT) ganglion of the bonnethead shark (Sphyrna tiburo) using an in vitro preparation and whole nerve recordings. Spectral analysis indicated that ACh (10 and 100 microM) had a variable effect on the total spectral power of whole nerve activity but produced a consistent decrease in half power frequency (HPF; the median frequency of the power spectrum). Norepinephrine (10 microM) reduced baseline activity and total spectral power but produced an increase in HPF in all NT preparations. Computer simulations of extracellular recordings suggested a general explanation for these findings. Acetylcholine may have opposite effects on activity in two NT cell populations with axons in the central nerve trunk, increasing activity in cells whose axons have broad spikes (low spectral frequency) and decreasing activity in cells whose axons have narrow spikes (high spectral frequency). The NE effects are consistent with a decrease in activity of cells whose axons have broad spikes (low spectral frequency) and little or no change in cells whose axons have narrow spikes (high spectral frequency). The physiological data, together with the theoretical analysis, suggest that cholinergic and catecholaminergic neurotransmitter systems are active in the bonnethead NT ganglion, and that ACh and NE have different effects on two populations of ganglion cells. PMID:8490734

  5. Choline acetyltransferase and the nicotinic acetylcholine receptor AChR?7 in experimental myositis.

    PubMed

    Spang, Christoph; Forsgren, Sture

    2015-11-01

    It is not known to what extent a non-neuronal cholinergic system is involved in myositis (muscle inflammation) evoked by marked muscle overuse. Therefore, in the present study, a recently established rabbit myositis model was used and the expression patterns of ChAT and nicotinic acetylcholine receptor AChR?7 (?7nAChR) were evaluated. Immunohistochemistry and in situ hybridization were used. The model leads to myositis including occurrence of muscle fiber necrosis. It was found that the infiltrating white blood cells as well the walls of small blood vessels exhibited immunoreactivity for both ChAT and ?7nAChR. There was also pronounced immunoreactivity for these in the white blood cells that had coalesced within the necrotic muscle fibers. The findings show that there is a presence of a non-neuronal cholinergic system in the situation of muscle inflammation. Cholinergic effects may be highly involved in the inflammation-modifying events that occur in muscle overuse. PMID:26086364

  6. RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions.

    PubMed

    Chandna, Andrew R; Nair, Manoj; Chang, Christine; Pennington, Paul R; Yamamoto, Yasuhiko; Mousseau, Darrell D; Campanucci, Verónica A

    2015-02-01

    Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation-mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co-treatment with either antioxidants or an anti-RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock-out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes. PMID:25431195

  7. 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

  8. ACh- and caffeine-induced Ca2+ mobilization and current activation in rabbit arterial endothelial cells.

    PubMed

    Fransen, P; Katnik, C; Adams, D J

    1998-11-01

    Fura 2 microfluorometry and perforated-patch whole cell recording were carried out simultaneously to investigate the relationship between intracellular free Ca2+ concentration ([Ca2+]i) and membrane current activation in response to ACh and caffeine in freshly dissociated arterial endothelial cells. ACh and caffeine evoked transient increases in [Ca2+]i. The initial increase in [Ca2+]i was accompanied by a transient outward current, which caused membrane hyperpolarization. The amplitudes of the [Ca2+]i transient and outward current were dependent on caffeine concentration (EC50 approximately 1 mM). Cyclopiazonic acid raised resting [Ca2+]i levels by >/=50 nM and failed to completely block caffeine- or ACh-induced [Ca2+]i transients but slowed [Ca2+]i recovery fourfold. The reversal potential of caffeine-induced currents was dependent on external K+ and Cl- concentrations. Caffeine-induced current amplitudes, but not [Ca2+]i responses, were attenuated by external tetraethylammonium, Zn2+, and La3+. A consistent temporal relationship between agonist-activated membrane current and [Ca2+]i increases was not observed, and, in some cases, time differences were greater than expected for simple diffusion of Ca2+ throughout the cell. These results suggest that Ca2+-dependent current activation monitors local [Ca2+]i changes adjacent to the plasmalemma, whereas single-cell photometry provides a measure of global changes in [Ca2+]i. PMID:9815082

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

    PubMed Central

    Schaal, Courtney; Padmanabhan, Jaya; Chellappan, Srikumar

    2015-01-01

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

  10. Converting maslinic acid into an effective inhibitor of acylcholinesterases.

    PubMed

    Schwarz, Stefan; Loesche, Anne; Lucas, Susana Dias; Sommerwerk, Sven; Serbian, Immo; Siewert, Bianka; Pianowski, Elke; Csuk, René

    2015-10-20

    During the last decade, maslinic acid has been evaluated for many biological properties, e.g. as an anti-tumor or an anti-viral agent but also as a nutraceutical. The potential of maslinic acid and related derivatives to act as inhibitors of acetyl- or butyryl-cholinesterase was examined in this communication in more detail. Cholinesterases do still represent an interesting group of target enzymes with respect to the investigation and treatment of the Alzheimer's disease and other dementia illnesses as well. Although other triterpenoic acids have successfully been tested for their ability to act as inhibitors of cholinesterases, up to now maslinic acid has not been part of such studies. For this reason, three series of maslinic acid derivatives possessing modifications at different centers were synthesized and subjected to Ellman's assay to determine their inhibitory strength and type of inhibitory action. While parent compound maslinic acid was no inhibitor in these assays, some of the compounds exhibited an inhibition of acetylcholinesterase in the single-digit micro-molar range. Two compounds were identified as inhibitors of butyrylcholinesterase showing inhibition constants comparable to those of galantamine, a drug often used in the treatment of Alzheimer's disease. Furthermore, additional selectivity as well as cytotoxicity studies were performed underlining the potential of several derivatives and qualifying them for further investigations. Docking studies revealed that the different kinetic behavior within the same compound series may be explained by the ability of the compounds to enter the active site gorge of AChE. PMID:26383128

  11. Acetylcholinesterase inhibitors: structure based design, synthesis, pharmacophore modeling, and virtual screening.

    PubMed

    Valasani, Koteswara Rao; Chaney, Michael O; Day, Victor W; Shidu Yan, Shirley

    2013-08-26

    Acetylcholinesterase (AChE) is a main drug target, and its inhibitors have demonstrated functionality in the symptomatic treatment of Alzheimer's disease (AD). In this study, a series of novel AChE inhibitors were designed and their inhibitory activity was evaluated with 2D quantitative structure-activity relationship (QSAR) studies using a training set of 20 known compounds for which IC?? values had previously been determined. The QSAR model was calculated based on seven unique descriptors. Model validation was determined by predicting IC?? values for a test set of 20 independent compounds with measured IC?? values. A correlation analysis was carried out comparing the statistics of the measured IC?? values with predicted ones. These selectivity-determining descriptors were interpreted graphically in terms of principal component analyses (PCA). A 3D pharmacophore model was also created based on the activity of the training set. In addition, absorption, distribution, metabolism, and excretion (ADME) descriptors were also determined to evaluate their pharmacokinetic properties. Finally, molecular docking of these novel molecules into the AChE binding domain indicated that three molecules (6c, 7c, and 7h) should have significantly higher affinities and solvation energies than the known standard drug donepezil. The docking studies of 2H-thiazolo[3,2-a]pyrimidines (6a-6j) and 5H-thiazolo[3,2-a] pyrimidines (7a-7j) with human AChE have demonstrated that these ligands bind to the dual sites of the enzyme. Simple and ecofriendly syntheses and diastereomeric crystallizations of 2H-thiazolo [3,2-a]pyrimidines and 5H-thiazolo[3,2-a] pyrimidines are described. The solid-state structures for the HBr salts of compounds 6a, 6e, 7a, and 7i have been determined using single-crystal X-ray diffraction techniques, and X-ray powder patterns were measured for the bulk solid remaining after solvent was removed from solutions containing 6a and 7a. These studies provide valuable insight for designing more potent and selective inhibitors for the treatment of AD. PMID:23777291

  12. 7-MEOTA-donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies.

    PubMed

    Korabecny, Jan; Dolezal, Rafael; Cabelova, Pavla; Horova, Anna; Hruba, Eva; Ricny, Jan; Sedlacek, Lukas; Nepovimova, Eugenie; Spilovska, Katarina; Andrs, Martin; Musilek, Kamil; Opletalova, Veronika; Sepsova, Vendula; Ripova, Daniela; Kuca, Kamil

    2014-07-23

    A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment. PMID:24929293

  13. Synthesis of novel N-alkyl carbamates of a-substituted amides of g-hydroxybutyric acid as potential acetylcholinesterase inhibitors.

    PubMed

    Musia?, Anna; Malawska, Barbara

    2004-12-01

    In a search for new acetylcholinesterase (AChE) inhibitors, derivatives of N-alkyl carbamates of a-substituted N-benzylamides of g-hydroxybutyric acid (GHB) 2(a-d); 3(a-d); 4(a-d) were obtained. Starting from 3-bromo-tetrahydrofuran-2-one, and N-phenylpiperazine 3-(4-phenylpiperazin-1-yl) tetrahydrofuran-2-one (1) was obtained. The aminolysis of lactone 1 with 4-substituted derivatives of benzylamine yielded N-substituted benzylamides of a-(4-phenylpiperazin-1-yl)-g-hydroxy-butyric acid (2-4). The target compounds were prepared by refluxing N-substituted benzyl-amides of a-(4-phenylpiperazinyl-1-)-GHB with ethyl-, i-propyl-, n-propyl- or n-butyl-isocyanate in dry acetonitrile. The inhibitory potency of AChE was evaluated by means of Ellman's in vitro test. PMID:15909954

  14. Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers.

    PubMed

    Hamulakova, Slavka; Imrich, Jan; Janovec, Ladislav; Kristian, Pavol; Danihel, Ivan; Holas, Ondrej; Pohanka, Miroslav; Böhm, Stanislav; Kozurkova, Maria; Kuca, Kamil

    2014-09-01

    A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ??Gtheor, and docking studies elucidate these suggestions in more detail. PMID:25036600

  15. Efficacy of acetylcholinesterase inhibitors versus nootropics in Alzheimer's disease: a retrospective, longitudinal study.

    PubMed

    Tsolaki, M; Pantazi, T; Kazis, A

    2001-01-01

    The aim of this study was to investigate the efficacy of nootropics (piracetam, aniracetam, nimodopine and dihydroergicristine) versus acetylcholinesterase inhibitors (AChE-Is) (tacrine and donepezil) in the treatment of Alzheimer's disease. This is a retrospective study of 510 patients with Alzheimer's disease. To determine clinical efficacy of treatment, we used the mean change over time in scores for the following tests: the Mini-Mental State Examination (MMSE); the Cambridge Cognitive Examination for the Elderly; and the Functional Rating Scale for Symptoms of Dementia. In all patients and in patients with severe Alzheimer's disease (baseline MMSE < 11), no significant differences were seen in the neuropsychological test scores between the two treatment groups. In patients with moderate dementia (baseline MMSE between 11 and 20), however, there was a significantly greater deterioration, as shown on the CAMCOG scale, after 12 months' treatment for patients receiving AChE-Is compared with those receiving nootropics (-4.38 for AChE-Is group versus 1.48 for nootropics group). For patients with mild dementia (baseline MMSE score between 21 and 26), there was a significantly greater deterioration on the MMSE scale for each time-point in the nootropics group compared with the AChE-Is group. In conclusion, we did not find any strong evidence that a difference in efficacy exists between AChE-Is and nootropics in the treatment of Alzheimer's disease. PMID:11277345

  16. Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors.

    PubMed

    Qian, Shuai; He, Lisi; Mak, Marvin; Han, Yifan; Ho, Chun-Yu; Zuo, Zhong

    2014-12-30

    Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7)-tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation. PMID:25445524

  17. nAChR-induced octopamine release mediates the effect of nicotine on a startle response in Drosophila melanogaster.

    PubMed

    Fuenzalida-Uribe, Nicolás; Meza, Rodrigo C; Hoffmann, Hernán A; Varas, Rodrigo; Campusano, Jorge M

    2013-04-01

    Biogenic amines (BAs) play a central role in the generation of complex behaviors in vertebrates and invertebrates, including the fly Drosophila melanogaster. The comparative advantages of Drosophila as a genetic model to study the contribution of BAs to behaviors stumble upon the difficulty to access the fly brain to ask relevant physiological questions. For instance, it is not known whether the activation of nicotinic acetylcholine receptors (nAChRs) induces the release of BAs in fly brain, a phenomenon associated to several behaviors in vertebrates. Here, we describe a new preparation to study the efflux of BAs in the adult fly brain by in vitro chronoamperometry. Using this preparation we show that nAChR agonists including nicotine induce a fast, transient, dose-dependent efflux of endogenous BAs, an effect mediated by ?-bungarotoxin-sensitive nAChRs. By using different genetic tools we demonstrate that the BA whose efflux is induced by nAChR activation is octopamine (Oct). Furthermore, we show that the impairment of a mechanically induced startle response after nicotine exposure is not observed in flies deficient in Oct transmission. Thus, our data show that the efflux of BAs in Drosophila brain is increased by nAChR activation as in vertebrates, and that then AChR-induced Oct release could have implications in a nicotine-induced behavioral response. PMID:23331098

  18. Roles for N-terminal Extracellular Domains of Nicotinic Acetylcholine Receptor (nAChR) ?3 Subunits in Enhanced Functional Expression of Mouse ?6?2?3- and ?6?4?3-nAChRs*

    PubMed Central

    Dash, Bhagirathi; Li, Ming D.; Lukas, Ronald J.

    2014-01-01

    Functional heterologous expression of naturally expressed mouse ?6*-nicotinic acetylcholine receptors (m?6*-nAChRs; where “*” indicates the presence of additional subunits) has been difficult. Here we expressed and characterized wild-type (WT), gain-of-function, chimeric, or gain-of-function chimeric nAChR subunits, sometimes as hybrid nAChRs containing both human (h) and mouse (m) subunits, in Xenopus oocytes. Hybrid m?6m?4h?3- (?5–8-fold) or WT m?6m?4m?3-nAChRs (?2-fold) yielded higher function than m?6m?4-nAChRs. Function was not detected when m?6 and m?2 subunits were expressed together or in the additional presence of h?3 or m?3 subunits. However, function emerged upon expression of m?6m?2m?3V9?S-nAChRs containing ?3 subunits having gain-of-function V9?S (valine to serine at the 9?-position) mutations in transmembrane domain II and was further elevated 9-fold when h?3V9?S subunits were substituted for m?3V9?S subunits. Studies involving WT or gain-of-function chimeric mouse/human ?3 subunits narrowed the search for domains that influence functional expression of m?6*-nAChRs. Using h?3 subunits as templates for site-directed mutagenesis studies, substitution with m?3 subunit residues in extracellular N-terminal domain loops “C” (Glu221 and Phe223), “E” (Ser144 and Ser148), and “?2-?3” (Gln94 and Glu101) increased function of m?6m?2*- (?2–3-fold) or m?6m?4* (?2–4-fold)-nAChRs. EC50 values for nicotine acting at m?6m?4*-nAChR were unaffected by ?3 subunit residue substitutions in loop C or E. Thus, amino acid residues located in primary (loop C) or complementary (loops ?2-?3 and E) interfaces of ?3 subunits are some of the molecular impediments for functional expression of m?6m?2?3- or m?6m?4?3-nAChRs. PMID:25028511

  19. Quaternary glaciations in the Northern Hemisphere

    SciTech Connect

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

    1987-01-01

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

  20. 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

  1. DNA Barcoding through Quaternary LDPC Codes

    PubMed Central

    Tapia, Elizabeth; Spetale, Flavio; Krsticevic, Flavia; Angelone, Laura; Bulacio, Pilar

    2015-01-01

    For many parallel applications of Next-Generation Sequencing (NGS) technologies short barcodes able to accurately multiplex a large number of samples are demanded. To address these competitive requirements, the use of error-correcting codes is advised. Current barcoding systems are mostly built from short random error-correcting codes, a feature that strongly limits their multiplexing accuracy and experimental scalability. To overcome these problems on sequencing systems impaired by mismatch errors, the alternative use of binary BCH and pseudo-quaternary Hamming codes has been proposed. However, these codes either fail to provide a fine-scale with regard to size of barcodes (BCH) or have intrinsic poor error correcting abilities (Hamming). Here, the design of barcodes from shortened binary BCH codes and quaternary Low Density Parity Check (LDPC) codes is introduced. Simulation results show that although accurate barcoding systems of high multiplexing capacity can be obtained with any of these codes, using quaternary LDPC codes may be particularly advantageous due to the lower rates of read losses and undetected sample misidentification errors. Even at mismatch error rates of 10?2 per base, 24-nt LDPC barcodes can be used to multiplex roughly 2000 samples with a sample misidentification error rate in the order of 10?9 at the expense of a rate of read losses just in the order of 10?6. PMID:26492348

  2. [Stomach ache and fever after consumption of watercress in Turkey: fascioliasis].

    PubMed

    van Daele, P L; Madretsma, G S; van Agtmael, M A

    2001-09-29

    A 52-year-old woman presented several months after returning from a visit to Turkey with stomach-ache and fever. Laboratory results showed leucocytosis with marked eosinophilia. Furthermore, serum liver enzyme activities were slightly elevated. A CT scan of the abdomen showed several spots which, on a later scan, had migrated. Serologic tests confirmed the clinical diagnosis of fascioliasis. The patient was successfully treated with triclabendazole. Infection presumably occurred after eating watercress which the patient had bought on a market in Turkey. PMID:11605314

  3. Resistance to Inhibitors of Cholinesterase 3 (Ric-3) Expression Promotes Selective Protein Associations with the Human ?7-Nicotinic Acetylcholine Receptor Interactome

    PubMed Central

    Mulcahy, Matthew J.; Blattman, Sydney B.; Barrantes, Francisco J.; Lukas, Ronald J.; Hawrot, Edward

    2015-01-01

    The ?7-nicotinic acetylcholine receptor (?7-nAChR) is a ligand-gated ion channel widely expressed in vertebrates and is associated with numerous physiological functions. As transmembrane ion channels, ?7-nAChRs need to be expressed on the surface of the plasma membrane to function. The receptor has been reported to associate with proteins involved with receptor biogenesis, modulation of receptor properties, as well as intracellular signaling cascades and some of these associated proteins may affect surface expression of ?7-nAChRs. The putative chaperone resistance to inhibitors of cholinesterase 3 (Ric-3) has been reported to interact with, and enhance the surface expression of, ?7-nAChRs. In this study, we identified proteins that associate with ?7-nAChRs when Ric-3 is expressed. Using ?-bungarotoxin (?-bgtx), we isolated and compared ?7-nAChR-associated proteins from two stably transfected, human tumor-derived cell lines: SH-EP1-h?7 expressing human ?7-nAChRs and the same cell line further transfected to express Ric-3, SH-EP1-h?7-Ric-3. Mass spectrometric analysis of peptides identified thirty-nine proteins that are associated with ?7-nAChRs only when Ric-3 was expressed. Significantly, and consistent with reports of Ric-3 function in the literature, several of the identified proteins are involved in biological processes that may affect nAChR surface expression such as post-translational processing of proteins, protein trafficking, and protein transport. Additionally, proteins affecting the cell cycle, the cytoskeleton, stress responses, as well as cyclic AMP- and inositol triphosphate-dependent signaling cascades were identified. These results illuminate how ?-bgtx may be used to isolate and identify ?7-nAChRs as well as how the expression of chaperones such as Ric-3 can influence proteins associating with ?7-nAChRs. These associating proteins may alter activities of ?7-nAChRs to expand their functionally-relevant repertoire as well as to affect biogenesis and membrane trafficking of ?7-nAChRs. PMID:26258666

  4. 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...

  5. 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...

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

    USGS Publications Warehouse

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

    2005-01-01

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

  7. Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists.

    PubMed

    Tomassoli, Isabelle; Ismaili, Lhassane; Pudlo, Marc; de Los Ríos, Cristóbal; Soriano, Elena; Colmena, Inés; Gandía, Luis; Rivas, Luis; Samadi, Abdelouahid; Marco-Contelles, José; Refouvelet, Bernard

    2011-01-01

    The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c]quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases'; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K(+)-induced calcium signals in bovine chromaffin cells. PMID:21111515

  8. 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

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

    PubMed

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

    2015-10-15

    Methadone is a long-acting opioid agonist that is frequently prescribed as a treatment for opioid addiction. Almost all methadone maintenance patients are smokers, and there is a correlation between smoking habit and use of methadone. Methadone administration increases tobacco smoking, and heavy smokers use higher doses of methadone. Nevertheless, methadone maintenance patients are willing to quit smoking although their quit rates are low. Studies on nicotine-methadone interactions provide an example of the bedside-to-bench approach, i.e., observations in clinical settings have been studied experimentally in vivo and in vitro. In vivo studies have revealed the interplay between nicotine and the endogenous opioid system. At the receptor level, methadone has been shown to be an agonist of human ?7 nAChRs and a non-competitive antagonist of human ?4?2 and ?3* nAChRs. These drugs do not have significant interactions at the level of drug metabolism, and thus the interaction is most likely pharmacodynamic. The net effect of the interaction may depend on individual characteristics because pharmacogenetic factors influence the disposition of both methadone and nicotine. PMID:26231941

  10. Amyloid-? peptide increases cell surface localization of ?7 ACh receptor to protect neurons from amyloid ?-induced damage.

    PubMed

    Jin, Yu; Tsuchiya, Ayako; Kanno, Takeshi; Nishizaki, Tomoyuki

    2015-12-01

    Amyloid-? peptide 1-42 (A?1-42) reduced PC-12 cell viability in a concentration (1-10 ?M)- and treatment time (48-72 h)-dependent manner. Nicotine prevented A?1-42-induced PC-12 cell death, but conversely, the ?7 ACh receptor antagonist ?-bungarotoxin enhanced A?1-42-induced cell toxicity. Extracellularly applied A?1-42 significantly increased cell surface localization of ?7 ACh receptor in PC-12 cells as compared with that for non-treated control cells. Cell surface localization of ?7 ACh receptor in the brain of 5xFAD mouse, an animal model of Alzheimer's disease (AD), apparently increased in an age (1-12 months)-dependent manner in association with increased accumulation of A?1-42 in the plasma membrane component. Taken together, these results indicate that A?1-42 promotes translocation of ?7 ACh receptor towards the cell surface and that ?7 ACh receptor rescues neuronal cells from A?1-42-induced damage. PMID:26522221

  11. H2 formation via the UV photo-processing of a-C:H nano-particles

    NASA Astrophysics Data System (ADS)

    Jones, A. P.; Habart, E.

    2015-09-01

    Context. The photolysis of hydrogenated amorphous carbon, a-C(:H), dust by UV photon-irradiation in the laboratory leads to the release of H2 as well as other molecules and radicals. This same process is also likely to be important in the interstellar medium. Aims: We investigate molecule formation arising from the photo-dissociatively-driven, regenerative processing of a-C(:H) dust. Methods: We explore the mechanism of a-C(:H) grain photolysis leading to the formation of H2 and other molecules/radicals. Results: The rate constant for the photon-driven formation of H2 from a-C(:H) grains is estimated to be 2 × 10-17 cm3 s-1. In intense radiation fields photon-driven grain decomposition will lead to fragmentation into daughter species rather than H2 formation. Conclusions: The cyclic re-structuring of arophatic a-C(:H) nano-particles appears to be a viable route to formation of H2 for low to moderate radiation field intensities (1 ? G0 ? 102), even when the dust is warm (T ~ 50-100 K).

  12. Memantine Inhibits ?3?2-nAChRs-Mediated Nitrergic Neurogenic Vasodilation in Porcine Basilar Arteries

    PubMed Central

    Wu, Celeste Yin-Chieh; Chen, Po-Yi; Chen, Mei-Fang; Kuo, Jon-Son; Lee, Tony Jer-Fu

    2012-01-01

    Memantine, an NMDA receptor antagonist used for treatment of Alzheimer’s disease (AD), is known to block the nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). In the present study, we examined by wire myography if memantine inhibited ?3?2-nAChRs located on cerebral perivascular sympathetic nerve terminals originating in the superior cervical ganglion (SCG), thus, leading to inhibition of nicotine-induced nitrergic neurogenic dilation of isolated porcine basilar arteries. Memantine concentration-dependently blocked nicotine-induced neurogenic dilation of endothelium-denuded basilar arteries without affecting that induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, memantine significantly inhibited nicotine-elicited inward currents in Xenopous oocytes expressing ?3?2-, ?7- or ?4?2-nAChR, and nicotine-induced calcium influx in cultured rat SCG neurons. These results suggest that memantine is a non-specific antagonist for nAChR. By directly inhibiting ?3?2-nAChRs located on the sympathetic nerve terminals, memantine blocks nicotine-induced neurogenic vasodilation of the porcine basilar arteries. This effect of memantine is expected to reduce the blood supply to the brain stem and possibly other brain regions, thus, decreasing its clinical efficacy in the treatment of Alzheimer’s disease. PMID:22792283

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

    PubMed Central

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

    2015-01-01

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

  14. New Quaternary Low Correlation Zone Sequences Sang-Hyo Kim

    E-print Network

    No, Jong-Seon

    New Quaternary Low Correlation Zone Sequences Sang-Hyo Kim Wireless Device Solution Team Telecomm. R&D Center Samsung Electronics Suwon, Korea sanghyo7.kim@samsung.com Ji-Woong Jang, Kyoung-Young n, we propose a method of constructing quaternary low correlation zone(LCZ) sequences of period 2n

  15. 40 CFR 721.10511 - Quaternary ammonium salts (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  17. 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. 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.

  19. Upregulation of Lhx8 increase VAChT expression and ACh release in neuronal cell line SHSY5Y.

    PubMed

    Li, Haoming; Jin, Guohua; Zhu, Peipei; Zou, Linqing; Shi, Jinhong; Yi, Xin; Zhang, Xinhua; Tian, Meiling; Qin, Jianbing

    2014-01-24

    Lhx8 is a transcription factor for cholinergic differentiation. Our previous experiments found upregulation of Lhx8 promoted cholinergic neuronal differentiation of hippocampal neural stem/progenitor cells or hippocampal newborn neurons in vitro. However, the role of Lhx8 in VAChT expression and ACh release is still less understood. In this report, we transfected Lhx8 cDNA into neuronal cell line SHSY5Y by lentiviral vectors to acquire the cells which stably expressed high level of Lhx8. Using this cell model, we provided experimental evidence that increasing Lhx8 upregulated the expression of ChAT and VAChT, and also increased the ACh release in culture medium. We suggested that Lhx8 overexpression is a useful strategy to increase the release of ACh and maybe of therapeutic value to neurodegenerative diseases. PMID:24316404

  20. Unravelling the mechanism of action of NS9283, a positive allosteric modulator of (?4)3(?2)2 nicotinic ACh receptors

    PubMed Central

    Grupe, M; Jensen, AA; Ahring, PK; Christensen, JK; Grunnet, M

    2013-01-01

    Background and Purpose Strong implications in major neurological diseases make the neuronal ?4?2 nicotinic ACh receptor (nAChR) a highly interesting drug target. In this study, we present a detailed electrophysiological characterization of NS9283, a potent positive allosteric modulator acting selectively at 3?:2? stoichiometry of ?2* and ?4* nAChRs. Experimental Approach The whole-cell patch-clamp technique equipped with an ultra-fast drug application system was used to perform electrophysiological characterization of NS9283 modulatory actions on human ?4?2 nAChRs stably expressed in HEK293 cells (HEK293-h?4?2). Key Results NS9283 was demonstrated to increase the potency of ACh-evoked currents in HEK293-h?4?2 cells by left-shifting the concentration–response curve ?60-fold. Interestingly, this modulation did not significantly alter maximal efficacy levels of ACh. Further, NS9283 did not affect the rate of desensitization of ACh-evoked currents, was incapable of reactivating desensitized receptors and only moderately slowed recovery from desensitization. However, NS9283 strongly decreased the rate of deactivation kinetics and also modestly decreased the rate of activation. This resulted in a left-shift of the ACh window current of (?4)3(?2)2 nAChRs in the presence of NS9283. Conclusions and Implications This study demonstrates that NS9283 increases responsiveness of human (?4)3(?2)2 nAChR to ACh with no change in maximum efficacy. We propose that this potentiation is due to a significant slowing of deactivation kinetics. In summary, the mechanism of action of NS9283 bears high resemblance to that of benzodiazepines at the GABAA receptor and to our knowledge, NS9283 constitutes the first nAChR compound of this class. PMID:23278456

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

    PubMed Central

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

    2010-01-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as targets for general anesthetics, but the functional responses to anesthetic modulation vary considerably among different subtypes of nAChRs. Inhaled general anesthetics, such as halothane, could effectively inhibit the channel activity of the ?4?2 nAChR, but not the homologous ?7 nAChR. To understand why ?7 is insensitive to inhaled general anesthetics, we performed multiple sets of 20-ns molecular dynamics (MD) simulations on the closed- and open-channel ?7 in the absence and presence of halothane, and critically compared the results with those from our studies on the ?4?2 nAChR (Liu et al., J. Phys. Chem. B 2009, 113, 12581; J. Phys. Chem. B 2010, 114, 626) Several halothane binding sites with fairly high binding affinities were identified in both closed- and open-channel ?7, suggesting that lack of sensitive functional responses of the ?7 nAChR to halothane in the previous experiments was unlikely due to lack of halothane interaction with ?7. The binding affinities of halothane in ?7 seemed to be protein conformation dependent. Overall halothane affinity was higher in the closed-channel ?7. Halothane binding to ?7 did not induce profound changes in ?7 structure and dynamics that could be related to the channel function. In contrast, correlated motion of the open-channel ?4?2 was reduced substantially in the presence of halothane, primarily due to the more susceptible nature of ?2 to anesthetic modulation. The amphiphilic EC/TM interface of the ?2 subunit is attractive to halothane and is susceptible to halothane perturbation, which may be why ?4?2 is functionally more sensitive to halothane than ?7. PMID:20465243

  2. Unresponsive correlated motion in alpha7 nAChR to halothane binding explains its functional insensitivity to volatile anesthetics.

    PubMed

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

    2010-06-10

    Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as targets for general anesthetics, but the functional responses to anesthetic modulation vary considerably among different subtypes of nAChRs. Inhaled general anesthetics, such as halothane, could effectively inhibit the channel activity of the alpha4beta2 nAChR but not the homologous alpha7 nAChR. To understand why alpha7 is insensitive to inhaled general anesthetics, we performed multiple sets of 20 ns molecular dynamics (MD) simulations on the closed- and open-channel alpha7 in the absence and presence of halothane and critically compared the results with those from our studies on the alpha4beta2 nAChR (Liu et al. J. Phys. Chem. B 2009, 113, 12581 and Liu et al. J. Phys. Chem. B 2010, 114, 626). Several halothane binding sites with fairly high binding affinities were identified in both closed- and open-channel alpha7, suggesting that a lack of sensitive functional responses of the alpha7 nAChR to halothane in the previous experiments was unlikely due to a lack of halothane interaction with alpha7. The binding affinities of halothane in alpha7 seemed to be protein conformation-dependent. Overall, halothane affinity was higher in the closed-channel alpha7. Halothane binding to alpha7 did not induce profound changes in alpha7 structure and dynamics that could be related to the channel function. In contrast, correlated motion of the open-channel alpha4beta2 was reduced substantially in the presence of halothane, primarily due to the more susceptible nature of beta2 to anesthetic modulation. The amphiphilic extracellular and transmembrane domain interface of the beta2 subunit is attractive to halothane and is susceptible to halothane perturbation, which may be why alpha4beta2 is functionally more sensitive to halothane than alpha7. PMID:20465243

  3. 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

  4. Prophylactic administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using terbufos sulfone.

    PubMed

    Lorke, Dietrich E; Nurulain, Syed M; Hasan, Mohamed Y; Ku?a, Kamil; Petroianu, Georg A

    2014-10-01

    Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)-approved substance for such pre-treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad-spectrum alternatives, we have assessed in vivo the mortality-reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K-27), when given in equitoxic dosage (25% of LD01 ) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR?=?1 for animals given only terbufos sulfone, but no pre-treatment. All tested AChE inhibitors reduced terbufos sulfone-induced mortality significantly (p???0.05) as compared with the non-treatment group (RR?=?1: terbufos sulfone only). Best in vivo protection from terbufos sulfone-induced mortality was achieved, when K-27 was given before terbufos sulfone exposure (RR?=?0.06), which was significantly (P???0.05) superior to the pre-treatment with all other tested compounds, for example tacrine (RR?=?0.21), pyridostigmine (RR?=?0.28), physostigmine (RR?=?0.29) and ranitidine (RR?=?0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K-27) in case of imminent OPC exposure may be a viable option. PMID:24136594

  5. Calcium signalling mediated through ?7 and non-?7 nAChR stimulation is differentially regulated in bovine chromaffin cells to induce catecholamine release

    PubMed Central

    del Barrio, Laura; Egea, Javier; León, Rafael; Romero, Alejandro; Ruiz, Ana; Montero, Mayte; Álvarez, Javier; López, Manuela G

    2011-01-01

    BACKGROUND AND PURPOSE Ca2+ signalling and exocytosis mediated by nicotinic receptor (nAChR) subtypes, especially the ?7 nAChR, in bovine chromaffin cells are still matters of debate. EXPERIMENTAL APPROACH We have used chromaffin cell cultures loaded with Fluo-4 or transfected with aequorins directed to the cytosol or mitochondria, several nAChR agonists (nicotine, 5-iodo-A-85380, PNU282987 and choline), and the ?7 nAChR allosteric modulator PNU120596. KEY RESULTS Minimal [Ca2+]c transients, induced by low concentrations of selective ?7 nAChR agonists and nicotine, were markedly increased by the ?7 nAChR allosteric modulator PNU120596. These potentiated responses were completely blocked by the ?7 nAChR antagonist ?-bungarotoxin (?7-modulated-response). Conversely, high concentrations of the ?7 nAChR agonists, nicotine or 5-iodo-A-85380 induced larger [Ca2+]c transients, that were blocked by mecamylamine but were unaffected by ?-bungarotoxin (non-?7 response). [Ca2+]c increases mediated by ?7 nAChR were related to Ca2+ entry through non-L-type Ca2+ channels, whereas non-?7 nAChR-mediated signals were related to L-type Ca2+ channels; Ca2+-induced Ca2+-release contributed to both responses. Mitochondrial involvement in the control of [Ca2+]c transients, mediated by either receptor, was minimal. Catecholamine release coupled to ?7 nAChRs was more efficient in terms of catecholamine released/[Ca2+]c. CONCLUSIONS AND IMPLICATIONS [Ca2+]c and catecholamine release mediated by ?7 nAChRs required an allosteric modulator and low doses of the agonist. At higher agonist concentrations, the ?7 nAChR response was lost and the non-?7 nAChRs were activated. Catecholamine release might therefore be regulated by different nAChR subtypes, depending on agonist concentrations and the presence of allosteric modulators of ?7 nAChRs. PMID:20840468

  6. Differential Cytokine Changes in Patients with Myasthenia Gravis with Antibodies against AChR and MuSK

    PubMed Central

    Yilmaz, Vuslat; Oflazer, Piraye; Aysal, Fikret; Durmus, Hacer; Poulas, Kostas; Yentur, Sibel P.; Gulsen-Parman, Yesim; Tzartos, Socrates; Marx, Alexander; Tuzun, Erdem; Deymeer, Feza; Saruhan-Direskeneli, Güher

    2015-01-01

    Neuromuscular transmission failure in myasthenia gravis (MG) is most commonly elicited by autoantibodies (ab) to the acetylcholine receptor or the muscle-specific kinase, constituting AChR-MG and MuSK-MG. It is controversial whether these MG subtypes arise through different T helper (Th) 1, Th2 or Th17 polarized immune reactions and how these reactions are blunted by immunosuppression. To address these questions, plasma levels of cytokines related to various Th subtypes were determined in patients with AChR-MG, MuSK-MG and healthy controls (CON). Peripheral blood mononuclear cells (PBMC) were activated in vitro by anti-CD3, and cytokines were quantified in supernatants. In purified blood CD4+ T cells, RNA of various cytokines, Th subtype specific transcription factors and the co-stimulatory molecule, CD40L, were quantified by qRT-PCR. Plasma levels of Th1, Th2 and Th17 related cytokines were overall not significantly different between MG subtypes and CON. By contrast, in vitro stimulated PBMC from MuSK-MG but not AChR-MG patients showed significantly increased secretion of the Th1, Th17 and T follicular helper cell related cytokines, IFN-?, IL-17A and IL-21. Stimulated expression of IL-4, IL-6, IL-10 and IL-13 was not significantly different. At the RNA level, expression of CD40L by CD4+ T cells was reduced in both AChR-MG and MuSK-MG patients while expression of Th subset related cytokines and transcription factors were normal. Immunosuppression treatment had two effects: First, it reduced levels of IL12p40 in the plasma of AChR-MG and MuSK-MG patients, leaving other cytokine levels unchanged; second, it reduced spontaneous secretion of IFN-? and increased secretion of IL-6 and IL-10 by cultured PBMC from AChR-MG, but not MuSK-MG patients. We conclude that Th1 and Th17 immune reactions play a role in MuSK-MG. Immunosuppression attenuates the Th1 response in AChR-MG and MuSK-MG, but otherwise modulates immune responses in AChR-MG and MuSK-MG patients differentially. PMID:25893403

  7. Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases.

    PubMed

    Farina, Roberta; Pisani, Leonardo; Catto, Marco; Nicolotti, Orazio; Gadaleta, Domenico; Denora, Nunzio; Soto-Otero, Ramon; Mendez-Alvarez, Estefania; Passos, Carolina S; Muncipinto, Giovanni; Altomare, Cosimo D; Nurisso, Alessandra; Carrupt, Pierre-Alain; Carotti, Angelo

    2015-07-23

    The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity. PMID:26107513

  8. Semisynthetic Analogues of Toxiferine I and Their Pharmacological Properties at ?7 nAChRs, Muscle-Type nAChRs, and the Allosteric Binding Site of Muscarinic M2 Receptors

    PubMed Central

    2015-01-01

    A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at ?7 and muscle-type nAChRs and the allosteric site of muscarinic M2 receptors. The new ligands differ from toxiferine I by the absence of one (2a–c) or two (3a–c) hydroxy groups, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (Ki = 75 nM) and 3c (Ki = 82 nM) displaying the highest affinity. At ?7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (Ki = 82 nM) over ?7 (IC50 = 21 ?M). As for the allosteric site of M2 receptors, binding was found to be dependent on N-substitution rather than on the nature of the side chains. The most potent ligands were the N-allyl analogues 2b and 3b (EC0.5,diss = 12 and 36 nM) and the N-nitrobenzyl derivatives 2c and 3c (EC0.5,diss = 32 and 49 nM). The present findings should help delineate the structural requirements for activity at different types of AChRs and for the design of novel selective ligands. PMID:25192059

  9. Semisynthetic analogues of toxiferine I and their pharmacological properties at ?7 nAChRs, muscle-type nAChRs, and the allosteric binding site of muscarinic M2 receptors.

    PubMed

    Zlotos, Darius P; Tränkle, Christian; Holzgrabe, Ulrike; Gündisch, Daniela; Jensen, Anders A

    2014-09-26

    A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at ?7 and muscle-type nAChRs and the allosteric site of muscarinic M2 receptors. The new ligands differ from toxiferine I by the absence of one (2a-c) or two (3a-c) hydroxy groups, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (Ki = 75 nM) and 3c (Ki = 82 nM) displaying the highest affinity. At ?7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (Ki = 82 nM) over ?7 (IC50 = 21 ?M). As for the allosteric site of M2 receptors, binding was found to be dependent on N-substitution rather than on the nature of the side chains. The most potent ligands were the N-allyl analogues 2b and 3b (EC0.5,diss = 12 and 36 nM) and the N-nitrobenzyl derivatives 2c and 3c (EC0.5,diss = 32 and 49 nM). The present findings should help delineate the structural requirements for activity at different types of AChRs and for the design of novel selective ligands. PMID:25192059

  10. Beyond the 5-HT3 receptors: A role for ?7nACh receptors in neuroprotective aspects of tropisetron.

    PubMed

    Khalifeh, S; Fakhfouri, G; Mehr, S E; Mousavizadeh, K; Dehpour, A R; Khodagholi, F; Kazmi, S; Rahimian, R

    2015-09-01

    Accumulation of reactive oxygen species, such as hydrogen peroxide (H2O2), generated by inflammatory cells or other pathological conditions, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders such as Alzheimer's disease. Recent investigations have described effective properties of tropisetron, such as antiphlogistic action or protection against ?-amyloid induced-neuroinflammation in rats. Our data revealed that H2O2-induced cell death in rat pheochromocytoma cell line (PC12) can be inhibited by tropisetron, as defined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay, caspase 3 and caspase 12 levels. We further showed that tropisetron exerts its protective effects by upregulation of heme oxygenase-1, glutathione, catalase activity, and nuclear factor-erythroid 2 p45-related factor 2 level. Moreover, tropisetron was recently found to be a partial agonist of ?7 nicotinic acetylcholine receptor (?7nAChR). The activation of ?7nAChR could inhibit inflammatory and apoptotic signaling pathways in the oxidative stress conditions. In this study, selective ?7nAChR antagonists (methyllycaconitine) reversed the effects of tropisetron on caspase 3 level. Our findings indicated that tropisetron can protect PC12 cells against H2O2-induced neurotoxicity through ?7nAChR in vitro. PMID:26286524

  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. R86Q, a mutation in BmAChE3 yielding a Rhipicephalus microplus organophosphate-insensitive acetylcholinesterase

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations were identified in the sequence encoding the acetylcholinesterase, BmAChE3, in strains of Rhipicephalus (Boophilus) microplus (Canestrini) resistant or susceptible to orgaonphosphorus acaricide. The mutation which appeared most frequently in the organophosphorus-resistant San Román strain...

  13. 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

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

    SciTech Connect

    Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K.; Cho, C.H.; Sung, J.J.Y.

    2008-12-01

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

  15. Quaternary geology of Avery Island, Louisiana

    SciTech Connect

    Autin, W.J.; McCulloh, R.P.; Davison, A.T.

    1986-09-01

    Avery Island, one of the Five Islands salt domes of south-central Louisiana, is a piercement-type dome that has been uplifted from several kilometers' depth. It is nearly circular in plan with a maximum elevation approximately 50 m above the surrounding coastal marsh. Dissection has produced a terrain of gullies and steep slopes. The features identified indicate a complex geologic history for Avery Island. Deposition of late Pleistocene sediments in a low-relief alluvial plain and subsequent soil development predate domal uplift. The stratigraphy of loess and colluvial silts indicates the island was emergent during loess depositions. The degree of dissection, distribution of colluvium, and shearing of Quaternary sediments reflects continual uplift after loess deposition.

  16. 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

  17. Fourfold nanosystems for quaternary storage devices

    NASA Astrophysics Data System (ADS)

    Blachowicz, T.; Ehrmann, A.

    2011-10-01

    In nano-magnetic coupled systems of wires, pronounced magnetization steps in the hysteresis loops have been found by micromagnetic simulations. The steps can be attributed to stable intermediate states, similar to flux-closed vortex states in ferromagnetic nano-rings. Due to the fourfold anisotropy of the system of four crossed nanowires, these states can be distinguished even by measuring the magnetization of the whole system, giving rise to four separated states without application of external magnetic field. Opposite to actual trials with nano-rings or layered structures, no additional method of symmetry breaking is necessary. Such an easily created system can be utilized, e.g., in quaternary (four states, i.e., two bits per magnetic nano-object) magnetic storage applications.

  18. 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.

  19. 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.

  20. 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.

  1. Continuing Education in the Era of Quantum Change. 2003 ACHE Proceedings. (65th Annual Meeting, Charlottesville, VA, November 8-12, 2003)

    ERIC Educational Resources Information Center

    Barrineau, Irene T., Ed.

    2003-01-01

    This document presents the proceedings of the 2003 annual meeting of the Association for Continuing Higher Education (ACHE). These proceedings record the 65th Annual Meeting of ACHE held in Charlottesville, Virginia. President Allen Varner's theme for this annual meeting was, "Continuing Education in the Era of Quantum Change." The theme was…

  2. Assessment of the functionality and stability of detergent purified nAChR from Torpedo using lipidic matrixes and macroscopic electrophysiology

    E-print Network

    Lasalde Dominicc, Jose A. - Department of Biology, Universidad de Puerto Rico

    Assessment of the functionality and stability of detergent purified nAChR from Torpedo using Available online 8 October 2015 Keywords: Lipidic Cubic Phase Detergents NAChR Two-electrode voltage clamp detergents. In the present study we enhanced the functional characterization of nAChR- DCs by recording

  3. 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

  4. 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

  5. Late Quaternary history of North Eurasian Norway spruce (Picea abies)

    E-print Network

    Tinner, Willy

    Journal of Biogeography (J. Biogeogr.) (2015) 42, 1431­1442 #12;INTRODUCTION The boreal forest or taiga, the taiga experienced repeated range contractions and expansions driven by the Quaternary climate

  6. Conotoxin Interactions with ?9?10-nAChRs: Is the ?9?10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management?

    PubMed Central

    Mohammadi, Sarasa A.; Christie, MacDonald J.

    2015-01-01

    The ?9?10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the ?9?10-nAChR in pain is conflicted. This receptor was first implicated in pain with the characterisation of conotoxin Vc1.1, which is highly selective for ?9?10-nAChRs and is an efficacious analgesic in chronic pain models with restorative capacities and no reported side effects. Numerous other analgesic conotoxin and non-conotoxin molecules have been subsequently characterised that also inhibit ?9?10-nAChRs. However, there is evidence that ?9?10-nAChR inhibition is neither necessary nor sufficient for analgesia. ?9?10-nAChR-inhibiting analogues of Vc1.1 have no analgesic effects. Genetically-modified ?9-nAChR knockout mice have a phenotype that is markedly different from the analgesic profile of Vc1.1 and similar conotoxins, suggesting that the conotoxin effects are largely independent of ?9?10-nAChRs. Furthermore, an alternative mechanism of analgesia by Vc1.1 and other similar conotoxins involving non-canonical coupling of GABAB receptors to voltage-gated calcium channels is known. Additional incongruities regarding ?9?10-nAChRs in analgesia are discussed. A more comprehensive characterisation of the role of ?9?10-nAChRs in pain is crucial for understanding the analgesic action of conotoxins and for improved drug design. PMID:26426047

  7. Modeling growth and senescence in physical performance among the ache of eastern Paraguay.

    PubMed

    Walker, Robert; Hill, Kim

    2003-01-01

    This article seeks to partially fill a paucity of available data on physical performance in hunter-gatherer societies. Quantitative data are presented on various physical performance measures conducted on the Ache of eastern Paraguay, hunter-gatherers up to the 1970s and now part-time foragers and horticulturists. The performance battery was conducted on most individuals over 10 years of age, allowing for cross-sectional examination of growth and senescence patterns across the lifespan for both sexes. These measures tend to display steep ascents and peak in the early 20s with slight declines thereafter with age for males, whereas females demonstrate peaks in performance earlier in life, with lower or no senescence rates thereafter. The result is a convergence in physical performance between men and women at later ages. We suggest that the female physiology faces reproductive constraints to performance early in life but shifts allocation to increased work output later in life during the long human postmenopausal stage. In contrast, the male physiology maximizes work output in early adult life. These schedules of physical performance are contrasted with schedules of food production ability, which tend to occur later in life, and therefore imply that skill rather than strength alone is an important component of the human foraging niche. PMID:12621608

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

    SciTech Connect

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

    2007-04-01

    Hydrogenated diamond-like-carbon (a-C:H) and hydrogen-free amorphous carbon (a-C) coatings are known to be biocompatible and have good chemical inertness. For this reason, both of these materials are strong candidates to be used as a matrix that embeds metallic elements with antimicrobial effect. In this comparative study, we have incorporated silver into diamond-like carbon (DLC) coatings by plasma based ion implantation and deposition (PBII&D) using methane (CH4) plasma and simultaneously depositing Ag from a pulsed cathodic arc source. In addition, we have grown amorphous carbon - silver composite coatings using a dual-cathode pulsed filtered cathodic-arc (FCA) source. The silver atomic content of the deposited samples was analyzed using glow discharge optical spectroscopy (GDOES). In both cases, the arc pulse frequency of the silver cathode was adjusted in order to obtain samples with approximately 5 at.% of Ag. Surface hardness of the deposited films was analyzed using the nanoindentation technique. Cell viability for both a-C:H/Ag and a-C:/Ag samples deposited on 24-well tissue culture plates has been evaluated.

  9. Identification and Characterization of ML352: A Novel, Noncompetitive Inhibitor of the Presynaptic Choline Transporter

    PubMed Central

    2015-01-01

    The high-affinity choline transporter (CHT) is the rate-limiting determinant of acetylcholine (ACh) synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. To expand CHT pharmacology, we pursued a high-throughput screen for novel CHT-targeted small molecules based on the electrogenic properties of transporter-mediated choline transport. In this effort, we identified five novel, structural classes of CHT-specific inhibitors. Chemical diversification and functional analysis of one of these classes identified ML352 as a high-affinity (Ki = 92 nM) and selective CHT inhibitor. At concentrations that fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase (AChE) or cholineacetyltransferase (ChAT) and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and synaptosomes and reduced the apparent density of hemicholinium-3 (HC-3) binding sites in membrane assays, suggesting allosteric transporter interactions. Pharmacokinetic studies revealed limited in vitro metabolism and significant CNS penetration, with features predicting rapid clearance. ML352 represents a novel, potent, and specific tool for the manipulation of CHT, providing a possible platform for the development of cholinergic imaging and therapeutic agents. PMID:25560927

  10. Identification and characterization of ML352: a novel, noncompetitive inhibitor of the presynaptic choline transporter.

    PubMed

    Ennis, Elizabeth A; Wright, Jane; Retzlaff, Cassandra L; McManus, Owen B; Lin, Zhinong; Huang, Xiaofang; Wu, Meng; Li, Min; Daniels, J Scott; Lindsley, Craig W; Hopkins, Corey R; Blakely, Randy D

    2015-03-18

    The high-affinity choline transporter (CHT) is the rate-limiting determinant of acetylcholine (ACh) synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. To expand CHT pharmacology, we pursued a high-throughput screen for novel CHT-targeted small molecules based on the electrogenic properties of transporter-mediated choline transport. In this effort, we identified five novel, structural classes of CHT-specific inhibitors. Chemical diversification and functional analysis of one of these classes identified ML352 as a high-affinity (Ki = 92 nM) and selective CHT inhibitor. At concentrations that fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase (AChE) or cholineacetyltransferase (ChAT) and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and synaptosomes and reduced the apparent density of hemicholinium-3 (HC-3) binding sites in membrane assays, suggesting allosteric transporter interactions. Pharmacokinetic studies revealed limited in vitro metabolism and significant CNS penetration, with features predicting rapid clearance. ML352 represents a novel, potent, and specific tool for the manipulation of CHT, providing a possible platform for the development of cholinergic imaging and therapeutic agents. PMID:25560927

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

    E-print Network

    Taber, Douglass

    inhibitor1 isolated from the Mesembryanthemaceae family (Sceletium tortuosum), has become an interesting of the inexpensive 1-chloro-2-methylpropene.9 With the alkylating agent 4 in hand, we effected alkylation of the acetoacetate dianion10 to give the ketoester 5 in good yield. Reduction then gave the secondary alcohol 6. We

  12. Proton pump inhibitors

    MedlinePLUS

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  13. Microstructure of a-C:H films prepared on a microtrench and analysis of ions and radicals behavior

    NASA Astrophysics Data System (ADS)

    Hirata, Yuki; Choi, Junho

    2015-08-01

    Amorphous carbon films (a-C:H) were prepared on a microtrench (4-?m pitch and 4-?m depth), and the uniformity of film thickness and microstructure of the films on the top, sidewall, and bottom surfaces of the microtrench were evaluated by scanning electron microscopy and Raman spectroscopy. The a-C:H films were prepared by bipolar-type plasma based ion implantation and deposition (bipolar PBII&D), and the negative pulse voltage, which is the main parameter dominating the film structure, was changed from -1.0 to -15 kV. Moreover, the behavior of ions and radicals was analyzed simultaneously by combining the calculation methods of Particle-In-Cell/Monte Carlo Collision (PIC-MCC) and Direct Simulation Monte Carlo (DSMC) to investigate the coating mechanism for the microtrench. The results reveal that the thickness uniformity of a-C:H films improves with decreasing negative pulse voltage due to the decreasing inertia of incoming ions from the trench mouth, although the film thickness on the sidewall tends to be much smaller than that on the top and bottom surfaces of the trench. The normalized flux and the film thickness show similar behavior, i.e., the normalized flux or thickness at the bottom surface increases at low negative pulse voltages and then saturates at a certain value, whereas at the sidewall it monotonically decreases with increasing negative voltage. The microstructure of a-C:H films on the sidewall surface is very different from that on the top and bottom surfaces. The film structure at a low negative pulse voltage shifts to more of a polymer-like carbon (PLC) structure due to the lower incident energy of ions. Although the radical flux on the sidewall increases slightly, the overall film structure is not significantly changed because this film formation at a low negative voltage is originally dominated by radicals. On the other hand, the flux of radicals is dominant on the sidewall in the case of high negative pulse voltage, resulting in a deviation from the Raman behavior of a-C:H films deposited by bipolar PBII&D. This tendency intensifies as the negative voltage becomes greater. Also, the energy of incident ions on the sidewall of the trench increases with increasing negative voltage, which causes a shift in the Raman data of the sidewall to the bottom right corner on the figure depicting the relationship of the FWHM(G) and the G-peak position, indicating increased graphitization of a-C:H film.

  14. Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of ?3?4 nicotinic acetylcholine receptor.

    PubMed

    Jozwiak, Krzysztof; Targowska-Duda, Katarzyna M; Kaczor, Agnieszka A; Kozak, Joanna; Ligeza, Agnieszka; Szacon, Elzbieta; Wrobel, Tomasz M; Budzynska, Barbara; Biala, Grazyna; Fornal, Emilia; Poso, Antti; Wainer, Irving W; Matosiuk, Dariusz

    2014-12-15

    9 N-alkylated derivatives of dextromethorphan are synthesized and studied as non-competitive inhibitors of ?3?4 nicotinic acetylcholine receptors (nAChRs). In vitro activity towards ?3?4 nicotinic acetylcholine receptor is determined using a patch-clamp technique and is in the micromolar range. Homology modeling, molecular docking and molecular dynamics of ligand-receptor complexes in POPC membrane are used to find the mode of interactions of N-alkylated dextromethorphan derivatives with ?3?4 nAChR. The compounds, similarly as dextromethorphan, interact with the middle portion of ?3?4 nAChR ion channel. Finally, behavioral tests confirmed potential application of the studied compounds for the treatment of addiction. PMID:25464883

  15. Quaternary cave levels in peninsular Florida

    NASA Astrophysics Data System (ADS)

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

    2007-05-01

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

  16. 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.

  17. Automated Docking with Protein Flexibility in the Design of Femtomolar “Click Chemistry” Inhibitors of Acetylcholinesterase

    PubMed Central

    Morris, Garrett M.; Green, Luke G.; Radi?, Zoran; Taylor, Palmer; Sharpless, K. Barry; Olson, Arthur J.; Grynszpan, Flavio

    2013-01-01

    The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands.1 Here we describe the application of the program AutoDock2 to the design of a focused library that was used in the “click chemistry in-situ” generation of the most potent non-covalent inhibitor of the enzyme acetylcholinesterase (AChE) yet developed (Kd = ~100 fM).3 AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid sidechains of the target protein. PMID:23451944

  18. Activation of Functional ?7-Containing nAChRs in Hippocampal CA1 Pyramidal Neurons by Physiological Levels of Choline in the Presence of PNU-120596

    PubMed Central

    Kalappa, Bopanna I.; Gusev, Alexander G.; Uteshev, Victor V.

    2010-01-01

    Background The level of expression of functional ?7-containing nicotinic acetylcholine receptors (nAChRs) in hippocampal CA1 pyramidal neurons is believed to be very low compared to hippocampal CA1 interneurons, and for many years this expression was largely overlooked. However, high densities of expression of functional ?7-containing nAChRs in CA1 pyramidal neurons may not be necessary for triggering important cellular and network functions, especially if activation of ?7-containing nAChRs occurs in the presence of positive allosteric modulators such as PNU-120596. Methodology/Principal Findings An approach previously developed for ?7-containing nAChRs expressed in tuberomammillary neurons was applied to investigate functional CA1 pyramidal ?7-containing nAChRs using rat coronal hippocampal slices and patch-clamp electrophysiology. The majority (?71%) of tested CA1 pyramidal neurons expressed low densities of functional ?7-containing nAChRs as evidenced by small whole-cell responses to choline, a selective endogenous agonist of ?7 nAChRs. These responses were potentiated by PNU-120596, a novel positive allosteric modulator of ?7 nAChRs. The density of functional ?7-containing nAChRs expressed in CA1 pyramidal neurons (and thus, the normalized net effect of activation, i.e., response net charge per unit of membrane capacitance per unit of time) was estimated to be ?5% of the density observed in CA1 interneurons. The results of this study demonstrate that despite low levels of expression of functional pyramidal ?7-containing nAChRs, physiological levels of choline (?10 µM) are sufficient to activate these receptors and transiently depolarize and even excite CA1 pyramidal neurons in the presence of PNU-120596. The observed effects are possible because in the presence of 10 µM choline and 1–5 µM PNU-120596, a single opening of an individual pyramidal ?7-containing nAChR ion channel appears to transiently depolarize (?4 mV) the entire pyramidal neuron and occasionally trigger action potentials. Conclusions 1) The majority of hippocampal CA1 pyramidal neurons express functional ?7-containing nAChRs. In the absence of PNU-120596, a positive allosteric modulator of ?7 nAChRs, a lack of responsiveness of some hippocampal CA1 pyramidal neurons to focal application of 0.5–1 mM choline does not imply a lack of expression of functional ?7-containing nAChRs in these neurons. Rather, it may indicate a lack of detection of ?7-containing nAChR-mediated currents by patch-clamp electrophysiology. 2) PNU-120596 can serve as a powerful tool for detection and enhancement of responsiveness of low densities of functional ?7-containing nAChRs such as those present in hippocampal CA1 pyramidal neurons. 3) In the presence of PNU-120596, physiological concentrations of choline activate functional CA1 pyramidal ?7-containing nAChRs and produce step-like currents that cause repetitive step-like depolarizations, occasionally triggering bursts of action potentials in CA1 pyramidal neurons. Therefore, the results of this study suggest that in the presence of PNU-120596 and possibly other positive allosteric modulators, endogenous choline may persistently activate CA1 pyramidal ?7-containing nAChRs, enhance the excitability of CA1 pyramidal neurons and thus act as a potent therapeutic agent with potential neuroprotective and cognition-enhancing properties. PMID:21103043

  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 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

  20. Haemocompatibility of hydrogenated amorphous carbon (a-C:H) films synthesized by plasma immersion ion implantation-deposition

    NASA Astrophysics Data System (ADS)

    Yang, P.; Kwok, S. C. H.; Chu, P. K.; Leng, Y. X.; Chen, J. Y.; Wang, J.; Huang, N.

    2003-05-01

    Diamond-like-carbon has attracted much attention recently as a potential biomaterial in blood contacting biomedical devices. However, previous reports in this area have not adequately addressed the biocompatibility and acceptability of the materials in blood contacting applications. In this study, hydrogenated amorphous carbon (a-C:H) films were fabricated on silicon wafers (1 0 0) using plasma immersion ion implantation-deposition. A series of a-C:H films with different structures and chemical bonds were fabricated under different substrate voltages. The results indicate that film graphitization is promoted at higher substrate bias. The film deposited at a lower substrate bias of -75 V possesses better blood compatibility than the films at higher bias and stainless steel. Our results suggest two possible paths to improve the blood compatibility, suppression of the endogenic clotting system and reduction of platelet activation.

  1. Endogenously released ACh and exogenous nicotine differentially facilitate long-term potentiation induction in the hippocampal CA1 region of mice.

    PubMed

    Nakauchi, Sakura; Sumikawa, Katumi

    2012-05-01

    We examined the role of ?7- and ?2-containing nicotinic acetylcholine receptors (nAChRs) in the induction of long-term potentiation (LTP). Theta-burst stimulation (TBS), mimicking the brain's naturally occurring theta rhythm, induced robust LTP in hippocampal slices from ?7 and ?2 knockout mice. This suggests TBS is capable of inducing LTP without activation of ?7- or ?2-containing nAChRs. However, when weak TBS was applied, the modulatory effects of nicotinic receptors on LTP induction became visible. We showed that during weak TBS, activation of ?7 nAChRs occurs by the release of ACh, contributing to LTP induction. Additionally, bath-application of nicotine activated ?2-containing nAChRs to promote LTP induction. Despite predicted nicotine-induced desensitization, synaptically mediated activation of ?7 nAChRs still occurs in the presence of nicotine and contributed to LTP induction. Optical recording of single-stimulation-evoked excitatory activity with a voltage-sensitive dye revealed enhanced excitatory activity in the presence of nicotine. This effect of nicotine was robust during high-frequency stimulation, and was accompanied by enhanced burst excitatory postsynaptic potentials. Nicotine-induced enhancement of excitatory activity was observed in slices from ?7 knockout mice, but was absent in ?2 knockout mice. These results suggest that the nicotine-induced enhancement of excitatory activity is mediated by ?2-containing nAChRs, and is related to the nicotine-induced facilitation of LTP induction. Thus, our study demonstrates that the activation of ?7- and ?2-containing nAChRs differentially facilitates LTP induction via endogenously released ACh and exogenous nicotine, respectively, in the hippocampal CA1 region of mice. PMID:22462479

  2. 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

  3. 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

  4. 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

  5. West Cameroon Quaternary lacustrine deposits: preliminary results

    NASA Astrophysics Data System (ADS)

    Maley, J.; Livingstone, D. A.; Giresse, P.; Brenac, P.; Kling, G.; Stager, C.; Thouveny, N.; Kelts, K.; Haag, M.; Fournier, M.; Bandet, Y.; Williamson, D.; Zogning, A.

    We present preliminary results from the study of a 23.50 m core (BM-6) representing the last 25 000 years. The core was collected in Barombi Mbo, an explosion crater lake formed probably during the Quaternary. The finely laminated sediment are composed mostly of dark brown to green clay rich organic matter (5-10% organic carbon). Each couplet is commonly composed of a lower unit rich in quartz, plant debris, muscovite and sponge spicules, and of a more clayey upper unit often with siderite (FeCO 3) crystals. The average periodicity for one couplet is between 6 and 20 radiocarbon years. The pollen results, which are compared with those of another forested site in Ghana, demonstrate the presence of a forest refuge in West Cameroon during the last major arid period, about 18 000 years BP. At the same time that equatorial forest was broken up, elements of montain vegetation descended to the lowlands. To provide an explanation for these phenomena marked by a drying and cooling of the climate, modern examples of extensions of montain biotopes to low altitude are described. These localized extensions are due to the persistence of cloud cover, often of stratiform type, generated over the relatively cold water of ocean upwellings. Such lowering of sea-surface temperature might be the primary regional cause of the changes of climate and vegetation that occurred in humid tropical Africa. The upwelling, presently synchronous throughout the Guinea Gulf, amplify the trade winds, which could account for the observed changes inland.

  6. Late Quaternary mammalian zoogeography of eastern Washington

    NASA Astrophysics Data System (ADS)

    Lyman, R. Lee; Livingston, Stephanie D.

    1983-11-01

    The late Quaternary mammalian zoogeographic history of eastern Washington as revealed by archaeological and paleontological research conforms to a set of past environmental conditions inferred from botanical data. During the relatively cool and moist late Pleistocene and early Holocene, Cervus cf. elaphus, Ovis canadensis, Vulpes vulpes, Martes americana, Alopex lagopus, and perhaps Rangifer sp., taxa with ecological preferences for mesic steppe habitats, were present in the now xeric Columbia Basin. As the climate became progressively warmer and drier during the late Pleistocene and early Holocene, Antilocapra americana, Onychomys leucogaster, Spermophilus townsendii, and Neotoma cinerea, taxa with ecological preferences for xeric steppe habitats, appear in the Columbia Basin. Bison sp. and Taxidea taxus may have been present in eastern Washington for the last 20,000 yr. Middle and late Holocene records for Oreamnos americanus, Spermophilus columbianus, S. townsendii, Lagurus curtatus, and Urocyon cinereoargenteus in central eastern Washington suggest fluctuations in the ranges of these taxa that conform to a middle Holocene period of less effective precipitation and a ca. 3500-yr-old period of more effective precipitation before essentially modern environmental conditions prevailed.

  7. A Quaternary Fault Database for Central Asia

    NASA Astrophysics Data System (ADS)

    Mohadjer, S.; Ehlers, T. A.; Bendick, R.; Stübner, K.; Strube, T.

    2015-09-01

    Earthquakes represent the highest risk in terms of potential loss of lives and economic damage for Central Asian countries. Knowledge of fault location and behavior is essential in calculating and mapping seismic hazard. Previous efforts in compiling fault information for Central Asia have generated a large amount of data that are published in limited-access journals with no digital maps publicly available, or are limited in their description of important fault parameters such as slip rates. This study builds on previous work by improving access to fault information through a web-based interactive map and an online database with search capabilities that allow users to organize data by different fields. The data presented in this compilation include fault location, its geographic, seismic and structural characteristics, short descriptions, narrative comments and references to peer-reviewed publications. The interactive map displays 1196 fault segments and 34 000 earthquake locations on a shaded-relief map. The online database contains attributes for 122 faults mentioned in the literature, with Quaternary and geodetic slip rates reported for 38 and 26 faults respectively, and earthquake history reported for 39 faults. This work has implications for seismic hazard studies in Central Asia as it summarizes important fault parameters, and can reduce earthquake risk by enhancing public access to information. It also allows scientists and hazard assessment teams to identify structures and regions where data gaps exist and future investigations are needed.

  8. 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

  9. General Anesthetic Binding to ?4?2 nAChR and Its Effects on Global Dynamics

    PubMed Central

    Liu, Lu Tian; Willenbring, Dan; Xu, Yan; Tang, Pei

    2009-01-01

    The neuronal ?4?2 nicotinic acetylcholine receptor (nAChR) is a target for general anesthetics. Currently available experimental structural information is inadequate to understand where anesthetics bind and how they modulate the receptor motions essential to function. Using our published open-channel structure model of ?4?2 nAChR, we identified and evaluated six amphiphilic interaction sites for the volatile anesthetic halothane via flexible ligand docking and subsequent 20-ns molecular dynamics simulations. Halothane binding energies ranged from ?6.8 to ?2.4 kcal/mol. The primary binding sites were located at the interface of extracellular and transmembrane domains, where halothane perturbed conformations of, and widened the gap among, the Cys-loop, the ?1-?2 loop, and the TM2-TM3 linker. The halothane with the highest binding affinity at the interface between the ?4 and ?2 subunits altered interactions between the protein and nearby lipids by competing for hydrogen bonds. Gaussian network model analyses of the ?4?2 nAChR structures at the end of 20-ns simulations in the absence or presence of halothanes revealed profound changes in protein residue mobility. The concerted motions critical to protein function were also perturbed considerably. Halothane's effect on protein dynamics was not confined to the residues adjacent to the binding sites, indicating an action on a more global scale. PMID:19697903

  10. Topographic Characterization of Cu-Ni NPs @ a-C:H Films by AFM and Multifractal Analysis.

    PubMed

    ??lu, ?tefan; Stach, Sebastian; Ghodselahi, Tayebeh; Ghaderi, Atefeh; Solaymani, Shahram; Boochani, Arash; Garczyk, ?aneta

    2015-04-30

    In the present work three-dimensional (3-D) surface topography of Cu-Ni nanoparticles in hydrogenated amorphous carbon (Cu-Ni NPs @ a-C:H) with constant thickness of Cu and three thicknesses of Ni prepared by RF-Plasma Enhanced Chemical Vapor Deposition (RF-PECVD) system were investigated. The thin films of Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni deposited by radio frequency (RF)-sputtering and RF-PECVD systems, were characterized. To determine the mass thickness and atomic structure of the films, the Rutherford backscattering spectroscopy (RBS) spectra was applied. The absorption spectra were applied to study localized surface plasmon resonance (LSPR) peaks of Cu-Ni NPs (observed around 608 nm in visible spectra), which is widened and shifted to lower wavelengths as the thickness of Ni over layer increases, and their changes are also evaluated by the 3-D surface topography. These nanostructures were investigated over square areas of 1 ?m × 1 ?m using atomic force microscopy (AFM) and multifractal analysis. Topographic characterization of surface samples (in amplitude, spatial distribution, and pattern of surface characteristics) highlighted 3-D surfaces with multifractal features which can be quantitatively estimated by the multifractal measures. The 3-D surface topography Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni prepared by RF-PECVD system can be characterized using the multifractal geometry in correlation with the surface statistical parameters. PMID:25839675

  11. Effects of a7nAChR agonist on the tissue estrogen receptor expression of castrated rats

    PubMed Central

    Ma, Feng; Gong, Fan; Lv, Jinhan; Gao, Jun; Ma, Jingzu

    2015-01-01

    Osteoporosis is one common disease in postmenopausal women due to depressed estrogen level. It has been known that inflammatory factors are involved in osteoporosis pathogenesis. One regulator of inflammatory cascade reaction, a7-nicotinic acetylcholine receptor (a7nAChR), therefore, may exert certain role in osteoporosis. This study thus investigated this question on an osteoporosis rat model after castration. Rats were firstly castrated to induce osteoporosis, and then received a7nAChR agonist (PNU-282987), diethylstilbestrol or saline via intraperitoneal injection. After 6 or 12 weeks, bone samples were collected for counting osteoblast number, bone density and estrogen receptor (ER? and ER?) expression, in addition to the serum laboratory of inflammatory factors. Bone density, osteoclast number, ER? and ER? expression level were significantly depressed in model group, and were remarkable potentiated in the drug treatment group (P<0.05). The levels of BGP and PTH in drug treatment group were decreased compared to diethylstilbestrol group, while E2 and IGF-1 showed up-regulation. Agonist of a7nAChR can up-regulate estrogen receptor expression and may prevent the occurrence and development of osteoporosis. PMID:26722551

  12. Carbohydrate Binding, Quaternary Structure and a Novel Hydrophobic Binding Site in Two Legume

    E-print Network

    Hamelryck, Thomas

    Carbohydrate Binding, Quaternary Structure and a Novel Hydrophobic Binding Site in Two Legume to four. # 1999 Academic Press Keywords: protein-carbohydrate interactions; quaternary structure; legume carbohydrates in a reversible fashion, without showing enzymatic activity towards these carbohydrates. Lectins

  13. 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.

  14. The effect of in vitro formation of acetylcholine receptor (AChR) clusters in engineered muscle fibers on subsequent innervation of constructs in vivo.

    PubMed

    Ko, In Kap; Lee, Bu-Kyu; Lee, Sang Jin; Andersson, Karl-Erik; Atala, Anthony; Yoo, James J

    2013-04-01

    Timely innervation of muscle tissue is critical in the recovery of function, and this time-sensitive process relies heavily on the host tissue microenvironment after implantation. However, restoration of muscle tissue mass and function has been a challenge. We investigated whether pre-forming acetylcholine receptor (AChR) clusters on engineered muscle fibers using an AChR cluster-inducing factor (agrin) prior to implantation would facilitate established contacts between implanted muscle tissues and nerves and result in rapid innervation of engineered muscle in vivo. We showed that agrin treatment significantly increased the formation of AChR clusters on culture differentiated myotubes (C2C12), enhanced contacts with nerves in vitro and in vivo, and increased angiogenesis. Pre-fabrication of AChR clusters on engineered skeletal muscle using a released neurotrophic factor can accelerate innervations following implantation in vivo. This technique has considerable potential for enhancing muscle tissue function. PMID:23391495

  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. Assessment of the functionality and stability of detergent purified nAChR from Torpedo using lipidic matrixes and macroscopic electrophysiology.

    PubMed

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

    2016-01-01

    In our previous study we examined the functionality and stability of nicotinic acetylcholine receptor (nAChR)-detergent complexes (nAChR-DCs) from affinity-purified Torpedo californica (Tc) using fluorescence recovery after photobleaching (FRAP) in Lipidic Cubic Phase (LCP) and planar lipid bilayer (PLB) recordings for phospholipid and cholesterol like detergents. In the present study we enhanced the functional characterization of nAChR-DCs by recording macroscopic ion channel currents in Xenopus oocytes using the two electrode voltage clamp (TEVC). The use of TEVC allows for the recording of macroscopic currents elicited by agonist activation of nAChR-DCs that assemble in the oocyte plasma membrane. Furthermore, we examined the stability of nAChR-DCs, which is obligatory for the nAChR crystallization, using a 30day FRAP assay in LCP for each detergent. The present results indicate a marked difference in the fractional fluorescence recovery (?FFR) within the same detergent family during the 30day period assayed. Within the cholesterol analog family, sodium cholate and CHAPSO displayed a minimum ?FFR and a mobile fraction (MF) over 80%. In contrast, CHAPS and BigCHAP showed a marked decay in both the mobile fraction and diffusion coefficient. nAChR-DCs containing phospholipid analog detergents with an alkylphosphocholine (FC) and lysofoscholine (LFC) of 16 carbon chains (FC-16, LFC-16) were more effective in maintaining a mobile fraction of over 80% compared to their counterparts with shorter acyl chain (C12, C14). The significant differences in macroscopic current amplitudes, activation and desensitization rates among the different nAChR-DCs evaluated in the present study allow to dissect which detergent preserves both, agonist activation and ion channel function. Functionality assays using TEVC demonstrated that LFC16, LFC14, and cholate were the most effective detergents in preserving macroscopic ion channel function, however, the nAChR-cholate complex display a significant delay in the ACh-induce channel activation. In summary, these results suggest that the physical properties of the lipid analog detergents (headgroup and acyl chain length) are the most effective in maintaining both the stability and functionality of the nAChR in the detergent solubilized complex. PMID:26454038

  17. Ternary and quaternary antimonide devices for thermophotovoltaic applications

    NASA Astrophysics Data System (ADS)

    Hitchcock, C. W.; Gutmann, R. J.; Ehsani, H.; Bhat, I. B.; Wang, C. A.; Freeman, M. J.; Charache, G. W.

    1998-12-01

    Thermophotovoltaic (TPV) devices have been fabricated using epitaxial ternary and quaternary layers grown on GaSb substrates. GaInSb ternary devices were grown by metalorganic vapor-phase epitaxy (MOVPE) with buffer layers to accommodate the lattice mismatch, and GaInAsSb lattice-matched quaternaries were grown by MOVPE and by liquid-phase epitaxy (LPE). Improved devices are obtained when optical absorption occurs in the p-layer due to the longer minority carrier diffusion length. Thick emitter p/n devices are limited by surface recombination, with highest quantum efficiency and lowest dark current being achieved with epitaxially grown surface passivation layers on lattice-matched MOVPE quaternaries. Thin emitter/thick base n/p devices are very promising, but require improved shallow high-quality n-type ohmic contacts.

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

    SciTech Connect

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

    1984-04-01

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

  19. Ternary and quaternary antimonide devices for thermophotovoltaic applications

    SciTech Connect

    Hitchcock, C.W.; Gutmann, R.J.; Ehsani, H.; Bhat, I.B.; Wang, C.A.; Freeman, M.J.; Charache, G.W.

    1998-06-01

    Thermophotovoltaic (TPV) devices have been fabricated using epitaxial ternary and quaternary layers grown on GaSb substrates. GaInSb ternary devices were grown by metalorganic vapor phase epitaxy (MOVPE) with buffer layers to accommodate the lattice mismatch, and GaInAsSb lattice-matched quaternaries were grown by MOVPE and by liquid phase epitaxy (LPE). Improved devices are obtained when optical absorption occurs in the p-layer due to the longer minority carrier diffusion length. Thick emitter p/n devices are limited by surface recombination, with highest quantum efficiency and lowest dark current being achieved with epitaxially grown surface passivation layers on lattice-matched MOVPE quaternaries. Thin emitter/thick base n/p devices are very promising, but require improved shallow high-quality n-type ohmic contacts.

  20. Conjugates of ?-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease.

    PubMed

    Makhaeva, Galina F; Lushchekina, Sofya V; Boltneva, Natalia P; Sokolov, Vladimir B; Grigoriev, Vladimir V; Serebryakova, Olga G; Vikhareva, Ekaterina A; Aksinenko, Alexey Yu; Barreto, George E; Aliev, Gjumrakch; Bachurin, Sergey O

    2015-01-01

    Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule ?-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is ?-? stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions. PMID:26281952

  1. Conjugates of ?-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease

    PubMed Central

    Makhaeva, Galina F.; Lushchekina, Sofya V.; Boltneva, Natalia P.; Sokolov, Vladimir B.; Grigoriev, Vladimir V.; Serebryakova, Olga G.; Vikhareva, Ekaterina A.; Aksinenko, Alexey Yu.; Barreto, George E.; Aliev, Gjumrakch; Bachurin, Sergey O.

    2015-01-01

    Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule ?-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is ?-? stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions. PMID:26281952

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

    PubMed Central

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

    2015-01-01

    Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

  3. 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

  4. The use of ?-conotoxin ImI to actualize the targeted delivery of paclitaxel micelles to ?7 nAChR-overexpressing breast cancer.

    PubMed

    Mei, Dong; Lin, Zhiqiang; Fu, Jijun; He, Bing; Gao, Wei; Ma, Ling; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Lu, Wanliang; Zhou, Demin; Zhang, Qiang

    2015-02-01

    Alpha7 nicotinic acetylcholine receptor (?7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the ?7 nAChR-overexpressing tumors, herein, ?-conotoxin ImI, a disulfide-rich toxin with highly affinity for ?7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of ?7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the ?7 nAChR-targeted nanomedicines could deliver more specifically and faster into ?7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca(2+) transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro, paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, ?7 nAChR is also a promising target for anti-tumor drug delivery and in this case, ?-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting ?7 nAChR-overexpressing tumors. PMID:25542793

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  6. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  7. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  8. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  9. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Quaternary ammonium salt of... New Uses for Specific Chemical Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl... identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  10. 40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...2011-07-01 2011-07-01 false Modified polymer of vinyl acetate and quaternary ammonium...Chemical Substances § 721.8658 Modified polymer of vinyl acetate and quaternary ammonium...substance identified generically as modified polymer of vinyl acetate and quaternary...

  11. 40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...2010-07-01 2010-07-01 false Modified polymer of vinyl acetate and quaternary ammonium...Chemical Substances § 721.8658 Modified polymer of vinyl acetate and quaternary ammonium...substance identified generically as modified polymer of vinyl acetate and quaternary...

  12. 40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  13. Effects of deposition rate and ion bombardment on properties of a-C:H films deposited by H-assisted plasma CVD method

    NASA Astrophysics Data System (ADS)

    Dong, Xiao; Koga, Kazunori; Yamashita, Daisuke; Seo, Hyunwoong; Itagaki, Naho; Shiratani, Masaharu; Setsuhara, Yuichi; Sekine, Makoto; Hori, Masaru

    2016-01-01

    In our previous study, we realized conformal, subconformal, and anisotropic deposition profiles of hydrogenated amorphous carbon (a-C:H) films formed on trench substrates by plasma CVD using toluene. To obtain information on the film structures, we investigated the effects of deposition rate and ion bombardment on hydrogen bonding configurations and hydrogen content in the a-C:H films deposited by plasma CVD using toluene. The structure of a-C:H films transforms from polymer-like a-C:H (PLCH) for the ion energy <75 eV to diamond-like a-C:H (DLCH) for the ion energy ?75 eV. The hydrogen bonding configurations in a-C:H films are closely related to the ion energy, whereas they are less dependent on ion flux and deposition rate. The mass density increases gradually with decreasing hydrogen content in the PLCH region, and it increases sharply with decreasing hydrogen content in the DLCH region. This difference is due to the different C–C sp3 concentration in PLCH and DLCH films.

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

    SciTech Connect

    Keshavarzian, A.; Gordon, J.H.; Urban, G.; Fields, J.Z. VA Hospital, Hines, IL )

    1991-03-11

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

  15. 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.

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

    SciTech Connect

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

    1995-12-31

    This report presents the results of geologic studies that help define the Quaternary history of selected faults in the region around Yucca Mountain, Nevada. These results are relevant to the seismic-design basis of a potential nuclear waste repository at Yucca Mountain. The relevancy is based, in part, on a need for additional geologic data that became apparent in ongoing studies by S. Pezzopane (written commun., 1995) that resulted in the identification of 51 relevant and potentially relevant (see appendix A for definitions) individual and compound faults and fault zones in the 100-km-radius region around the Yucca Mountain site. These structures were divided into local and regional categories by Pezzopane (1995); this report deals with selected regional structures. In this introduction, the authors outline the scope and strategy of the studies and the tectonic environment of the studied structures.

  17. The Effect of Two Amine-Based Corrosion Inhibitors in Improving the Corrosion Resistance of Carbon Steel in Sea Water

    NASA Astrophysics Data System (ADS)

    Rihan, Rihan; Shawabkeh, Reyad; Al-Bakr, Nawaf

    2014-03-01

    This study investigates the effect of two amine-based corrosion inhibitors in reducing the corrosion rate (CR) of 1018 carbon steel in formulated sea water. For discussion purposes, the two inhibitors are named Inhibitor A (belongs to the alkyl pyridine benzyl chloride quaternary family of inhibitors) and Inhibitor B (belongs to the alkyl amines family of inhibitors). The two inhibitors are routinely considered for applications by Saudi Aramco, the world's largest oil producing and processing company, for reducing its corrosion problems in carbon steel pipelines carrying oil and gas. The experimental apparatus was a circulating flow loop system inside an autoclave. The experimental work was performed at pH 8.2, 55 °C, and 1000 rpm. The inhibitors were evaluated at three different concentrations of 5, 10, and 15 ppm. The CR was determined using the weight loss method and electrochemical methods such potentiodynamic sweep and linear polarization resistance. The experimental results indicate that Inhibitor B reduced the CR more than that of Inhibitor A.

  18. The role of structured water in mediating general anesthetic action on alpha4beta2 nAChR.

    PubMed

    Willenbring, Dan; Xu, Yan; Tang, Pei

    2010-09-21

    Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming water clathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within alpha4beta2 nAChR, a putative protein target hypersensitive to volatile anesthetics. Experimental structure-derived closed- and open-channel nAChR systems in a fully hydrated lipid bilayer were examined using all-atom molecular dynamics simulations. At the majority of binding sites in alpha4beta2 nAChR, halothane replaced the slow-exchanging water molecules and caused a regional water population decrease. Only two binding sites had an increased quantity of water in the presence of halothane, where water arrangements resemble clathrate-like structures. The small number of such clathrate-like water clusters suggests that the formation of water clathrates is unlikely to be a primary cause for anesthesia. Despite the decrease in water population at most of the halothane binding sites, the number of sites that can be occupied transiently by water is actually increased in the presence of halothane. Many of these water sites were located between two subunits or in regions containing agonist binding sites or critical structural elements for transducing agonist binding to channel gating. Changes in water sites in the presence of halothane affected water-mediated protein-protein interactions and the protein dynamics, which can have direct impact on protein function. Collectively, water contributes to the action of anesthetics in proteins by mediating interactions between protein subunits and altering protein dynamics, instead of forming water clathrates around anesthetics. PMID:20661501

  19. The Role of Structured Water in Mediating General Anesthetic Action on ?4?2 nAChR

    PubMed Central

    Willenbring, Dan; Xu, Yan; Tang, Pei

    2010-01-01

    Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming water clathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within ?4?2 nAChR, a putative protein target hypersensitive to volatile anesthetics. Experimental structure-derived closed- and open-channel nAChR systems in a fully hydrated lipid bilayer were examined using all-atom molecular dynamics simulations. At the majority of binding sites in ?4?2 nAChR, halothane replaced the slow-exchanging water molecules and caused a regional water population decrease. Only two binding sites had an increased quantity of water in the presence of halothane, where water arrangements resemble clathrate-like structures. The small number of such clathrate-like water clusters suggests that the formation of water clathrates is unlikely to be a primary cause for anesthesia. Despite the decrease in water population at most of the halothane binding sites, the number of sites that can be occupied transiently by water is actually increased in the presence of halothane. Many of these water sites were located between two subunits or in regions containing agonist binding sites or critical structural elements for transducing agonist binding to channel gating. Changes in water sites in the presence of halothane affected water-mediated protein-protein interactions and the protein dynamics, which can have direct impact on protein function. Collectively, water contributes to the action of anesthetics in proteins by mediating interactions between protein subunits and altering protein dynamics, instead of forming water clathrates around anesthetics. PMID:20661501

  20. 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.

  1. VIP and PACAP potentiation of nicotinic ACh-evoked currents in rat parasympathetic neurons is mediated by G-protein activation.

    PubMed

    Liu, D M; Cuevas, J; Adams, D J

    2000-07-01

    The effects of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP27 and PACAP38) on isolated parasympathetic neurons of rat intracardiac and submandibular ganglia were examined under voltage clamp using whole-cell patch-clamp recording techniques. VIP and PACAP (AChRs) for their agonists resulting in a potentiation of acetylcholine (ACh)-evoked whole-cell currents at low agonist concentrations. VIP-induced potentiation was observed with either ACh or nicotine as the cholinergic agonist. The VIP- but not the PACAP-induced potentiation of ACh-evoked currents was inhibited by [Ac-Tyr1, D-Phe2]-GRF 1-29, amide (100 nM), a selective antagonist of VPAC1 and VPAC2 receptors; whereas the PACAP38- but not the VIP-induced potentiation was inhibited by 100 nM PACAP6-38, a PAC1 and VPAC2 receptor antagonist. The signal transduction pathway mediating VIP- and PACAP-induced potentiation of nicotinic ACh-evoked currents involves a pertussis toxin (PTX)-sensitive G-protein. Intracellular application of 200 microM GTPgammaS or GDPbetaS inhibited VIP-induced potentiation of ACh-evoked whole-cell currents. GTPgammaS alone potentiated ACh- and nicotine-evoked currents and the magnitude of these currents was not further increased by VIP or PACAP. The G-protein subtype modulating the neuronal nAChRs was examined by intracellular dialysis with antibodies directed against alphao, alphai-1,2, alphai-3 or beta G-protein subunits. Only the anti-Galphao and anti-Gbeta antibodies significantly inhibited the effect of VIP and PACAP on ACh-evoked currents. The potentiation of ACh-evoked currents by VIP and PACAP may be mediated by a membrane-delimited signal transduction cascade involving the PTX-sensitive Go protein. PMID:10947803

  2. Novel corrosion inhibitor technology

    SciTech Connect

    Van de Ven, P.; Fritz, P.; Pellet, R.

    1999-11-01

    A novel, patented corrosion inhibitor technology has been identified for use in heat transfer applications such as automotive and heavy-duty coolant. The new technology is based on a low-toxic, virtually depletion-free carboxylic acid corrosion inhibitor package that performs equally well in mono ethylene glycol and in less toxic propylene glycol coolants. An aqueous inhibitor concentrate is available to provide corrosion protection where freezing protection is not an issue. In the present paper, this inhibitor package is evaluated in the different base fluids: mono ethylene glycol, mono propylene glycol and water. Results are obtained in both standardized and specific corrosion tests as well as in selected field trials. These results indicate that the inhibitor package remains effective and retains the benefits previously identified in automotive engine coolant applications: excellent corrosion protection under localized conditions, general corrosion conditions as well as at high temperature.

  3. Acute toxicity of a commercial glyphosate formulation on European sea bass juveniles (Dicentrarchus labrax L.): gene expressions of heme oxygenase-1 (ho-1), acetylcholinesterase (AChE) and aromatases (cyp19a and cyp19b).

    PubMed

    Prevot-D'Alvise, N; Richard, S; Coupé, S; Bunet, R; Grillasca, J P

    2013-01-01

    Acute toxicity of Roundup, a commercial glyphosate--based herbicide, was evaluated in a teleost marine fish, the European sea bass, after 96 h of exposure. The LC50 96-h value of Roundup was 529 mg/L. Juveniles (Dicentrarchus labrax L.) were exposed to a sublethal concentration (35% of the LC50, i.e. 193 mg/L) of Roundup for 96-h. The study of heme oxygenase-1 (ho-1) gene expression was performed in four tissues (liver, gills, brain and gonads) and highlighted the disruption of antioxidant defence system. Results showed that ho-1 mRNA levels in liver and gills significantly decreased (p<0.001 and p<0.01 respectively) in fish exposed to 193 mg/L of Roundup, whereas in brain and gonads, ho-1 mRNA level was not altered. The analysis of acetylcholinesterase expression was used to evaluate the overall neurotoxicity of the herbicide and aromatase genes to assess the alteration of the endocrine system. Results showed that AChE and cyp19b gene transcriptions significantly increased (p<0.01) in brain of sea bass, whereas aromatase gene expression (cyp19a) in gonads was not significantly altered. Our results showed complex tissue-specific transcriptional responses after 96 h of exposure to a sublethal concentration. All these disruptions confirmed the deleterious effects of this glyphosate-based herbicide in a marine species. PMID:24461331

  4. Quaternary International 90 (2002) 4156 Incipient tunnel channels

    E-print Network

    Fisher, Timothy G.

    2002-01-01

    Quaternary International 90 (2002) 41­56 Incipient tunnel channels Darren B. Sjogrena, *, Timothy G are often interpreted as tunnel channels or subaerial channels, partly filled with sediment from erosion. We conclude that the erosion of these linked pothole channels (incipient tunnel channels

  5. 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…

  6. 21 CFR 172.165 - Quaternary ammonium chloride combination.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Quaternary ammonium chloride combination. 172.165 Section 172.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Food Preservatives §...

  7. QUATERNARY RESEARCH 45, 282288 (1996) ARTICLE NO. 0029

    E-print Network

    Amundson, Ronald

    1996-01-01

    process. The apparent ages deduced from Radiocarbon ages of soil organic matter are evaluatedQUATERNARY RESEARCH 45, 282­288 (1996) ARTICLE NO. 0029 Radiocarbon Dating of Soil Organic Matter Hall, University of California, Berkeley, California 94720 AND SUSAN TRUMBORE Department of Earth

  8. Synthesis of Adjacent Quaternary Stereocenters by Catalytic Asymmetric Allylboration.

    PubMed

    Alam, Rauful; Vollgraff, Tobias; Eriksson, Lars; Szabó, Kálmán J

    2015-09-01

    Allylboration of ketones with ?-disubstituted allylboronic acids is performed in the presence of chiral BINOL derivatives. The reaction is suitable for single-step creation of adjacent quaternary stereocenters with high selectivity. We show that, with an appropriate choice of the chiral catalyst and the stereoisomeric prenyl substrate, full control of the stereo- and enantioselectivity is possible in the reaction. PMID:26316158

  9. Enantioselective Construction of ?-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation**

    PubMed Central

    Reeves, Corey M.; Eidamshaus, Christian; Kim, Jimin; Stoltz, Brian M.

    2013-01-01

    No Strain, No Gain! The first transition metal-catalyzed enantioselective ?-alkylation of cyclobutanones is reported. This method employs palladium catalysis and an electron deficient PHOX type ligand to afford all–carbon ?-quaternary cyclobutanones in good to excellent yields and enantioselectivities. PMID:23686812

  10. 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

  11. Minimal erosion of Arctic alpine topography during late Quaternary glaciation

    NASA Astrophysics Data System (ADS)

    Gjermundsen, Endre F.; Briner, Jason P.; Akçar, Naki; Foros, Jørn; Kubik, Peter W.; Salvigsen, Otto; Hormes, Anne

    2015-10-01

    The alpine topography observed in many mountainous regions is thought to have formed during repeated glaciations of the Quaternary period. Before this time, landscapes had much less relief. However, the spatial patterns and rates of Quaternary exhumation at high latitudes--where cold-based glaciers may protect rather than erode landscapes--are not fully quantified. Here we determine the exposure and burial histories of rock samples from eight summits of steep alpine peaks in northwestern Svalbard (79.5° N) using analyses of 10Be and 26Al concentrations. We find that the summits have been preserved for at least the past one million years. The antiquity of Svalbard’s alpine landscape is supported by the preservation of sediments older than one million years along a fjord valley, which suggests that both mountain summits and low-elevation landscapes experienced very low erosion rates over the past million years. Our findings support the establishment of northwestern Svalbard’s alpine topography during the early Quaternary. We suggest that, as the Quaternary ice age progressed, glacial erosion in the Arctic became inefficient and confined to ice streams, and high-relief alpine landscapes were preserved by minimally erosive glacier armour.

  12. Reduced airway hyperresponsiveness by phosphodiesterase 3 and 4 inhibitors in guinea-pigs.

    PubMed Central

    Germain, N; Boichot, E; Planquois, J M; Lagente, V

    1999-01-01

    The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48h after OA, a significant reduction (P<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (P<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma. PMID:10704053

  13. Population variation and differences in serum leptin independent of adiposity: a comparison of Ache Amerindian men of Paraguay and lean American male distance runners

    PubMed Central

    Bribiescas, Richard G; Hickey, Matthew S

    2006-01-01

    Background Serum leptin variation is commonly associated with fat percentage (%), body mass index (BMI), and activity. In this investigation, we report population differences in mean leptin levels in healthy men as well as associations with fat % and BMI that are independent of these factors and reflect likely variation resulting from chronic environmental conditions. Methods Serum leptin levels, fat %, and BMI were compared between lean American distance runners and healthy Ache Native Americans of Paraguay. Mean levels were compared as were the regressions between fat %, BMI, and leptin. Comparisons were performed between male American distance runners (n = 13, mean age 32.2 ± 9.2 SD) and highly active male New World indigenous population (Ache of Paraguay, n = 20, mean age 32.8 ± 9.2) in order to determine whether significant population variation in leptin is evident in physically active populations living under different ecological circumstances independent of adiposity and BMI. Results While the Ache were hypothesized to exhibit higher leptin due to significantly greater adiposity (fat %, Ache 17.9 ± 1.8 SD; runners 9.7 ± 3.2, p < 0.0001), leptin levels were nonetheless significantly higher in American runners (Ache 1.13 ng/ml ± 0.38 SD; runners 2.19 ± 1.15; p < 0.007). Significant differences in the association between leptin and fat % was also evident between Ache and runner men. Although fat % was significantly related with leptin in runners (r = 0.90, p < 0.0001) fat % was negatively related in Ache men (r = -0.50, p < 0.03). Conclusion These results illustrate that chronic ecological conditions in addition to activity are likely factors that contribute to population variation in leptin levels and physiology. Population variation independent of adiposity should be considered to be an important source of variation, especially in light of ethnic and population differences in the incidence and etiology of obesity, diabetes, and other metabolic conditions. PMID:16942616

  14. 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

  15. Diamond-like a-C:H coatings deposited in a non-self-sustained discharge with plasma cathode

    NASA Astrophysics Data System (ADS)

    Gavrilov, N. V.; Mamaev, A. S.; Ka?igorodov, A. S.

    2009-01-01

    Hydrogenated amorphous carbon (a-C:H) coatings have been obtained by means of acetylene decomposition in a non-self-sustained periodic pulse discharge (2A, 50 kHz, 10 ?s) with hollow cathode. The discharge operation was maintained by plasma cathode emission with grid stabilization based on dc glow discharge. Using the proposed method, it is possible to control the deposition conditions (total pressure of the Ar + C2H2 mixture, partial pressure of C2H2, ion current density, carbon ion energy) within broad limits, to apply a-C:H coatings onto large-area articles, and to perform deposition in one technological cycle with ion etching and ion implantation treatments aimed at improving the adhesion of coatings to substrates (Ti, Al, stainless steel, VK8 hard alloy) at temperatures below 150°C. Results of determining the deposition rate (1-8 ?m), the nanohardness of coatings (up to 70 GPa), and the fraction of sp 3 bonds (25-70%) in the diamond-like coating material are presented.

  16. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

    SciTech Connect

    Sharma, Bhupesh Sharma, P.M.

    2013-11-15

    Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in As induced VaD.

  17. Further proof of the existence of a non-neuronal cholinergic system in the human Achilles tendon: Presence of the AChR?7 receptor in tendon cells and cells in the peritendinous tissue.

    PubMed

    Forsgren, Sture; Alfredson, Håkan; Andersson, Gustav

    2015-11-01

    Human tendon cells have the capacity for acetylcholine (ACh) production. It is not known if the tendon cells also have the potential for ACh breakdown, nor if they show expression of the nicotinic acetylcholine receptor AChR?7 (?7nAChR). Therefore, tendon tissue specimens from patients with midportion Achilles tendinopathy/tendinosis and from normal midportion Achilles tendons were examined. Reaction for the degradative enzyme acetylcholinesterase (AChE) was found in some tenocytes in only a few tendinopathy tendons, and was never found in those of control tendons. Tenocytes displayed more regularly ?7nAChR immunoreactivity. However, there was a marked heterogeneity in the degree of this reaction within and between the specimens. ?7nAChR immunoreactivity was especially pronounced for tenocytes showing an oval/widened appearance. There was a tendency that the magnitude of ?7nAChR immunoreactivity was higher in tendinopathy tendons as compared to control tendons. A stronger ?7nAChR immunoreactivity than seen for tenocytes was observed for the cells in the peritendinous tissue. It is likely that the ?7nAChR may be an important part of an auto-and paracrine loop of non-neuronal ACh that is released from the tendon cells. The effects may be related to proliferative and blood vessel regulatory functions as well as features related to collagen deposition. ACh can furthermore be of importance in leading to anti-inflammatory effects in the peritendinous tissue, a tissue nowadays considered to be of great relevance for the tendinopathy process. Overall, the findings show that tendon tissue, a tissue known to be devoid of cholinergic innervation, is a tissue in which there is a marked non-neuronal cholinergic system. PMID:25981114

  18. Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

    PubMed Central

    Lecoutey, Cédric; Hedou, Damien; Freret, Thomas; Giannoni, Patrizia; Gaven, Florence; Since, Marc; Bouet, Valentine; Ballandonne, Céline; Corvaisier, Sophie; Malzert Fréon, Aurélie; Mignani, Serge; Cresteil, Thierry; Boulouard, Michel; Claeysen, Sylvie; Rochais, Christophe; Dallemagne, Patrick

    2014-01-01

    RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-? peptide leads to the secretion of the neurotrophic protein sAPP?. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer’s disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPP? release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment. PMID:25157130

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

    SciTech Connect

    Grandi?, Marjana; Aráoz, Romulo; Molgó, Jordi; Turk, Tom; Sep?i?, Kristina; Benoit, Evelyne; Frangež, Robert

    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.

  20. Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal ?7 from Muscle ?1(2)??? 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

  1. Characterization of Quaternary and suspected Quaternary faults, regional studies, Nevada and California

    SciTech Connect

    Anderson, R.E.; Bucknam, R.C.; Crone, A.J.; Haller, K.M.; Machette, M.N.; Personius, S.F.; Barnhard, T.P.; Cecil, M.J.; Dart, R.L.

    1995-12-31

    This report presents the results of geologic studies that help define the Quaternary history of selected faults in the region around Yucca Mountain, Nevada. These results are relevant to the seismic-design basis of a potential nuclear waste repository at Yucca Mountain. The relevancy is based, in part, on a need for additional geologic data that became apparent in ongoing studies that resulted in the identification of 51 relevant and potentially relevant individual and compound faults and fault zones in the 100-km-radius region around the Yucca Mountain site. Geologic data used to characterize the regional faults and fault zones as relevant or potentially relevant seismic sources includes age and displacement information, maximum fault lengths, and minimum distances between the fault and the Yucca Mountain site. For many of the regional faults, no paleoseismic field studies have previously been conducted, and age and displacement data are sparse to nonexistent. In November 1994, the Branch of Earthquake and Landslide Hazards entered into two Memoranda of Agreement with the Yucca Mountain Project Branch to conduct field reconnaissance, analysis, and interpretation of six relevant and six potentially relevant regional faults. This report describes the results of study of those faults exclusive of those in the Pahrump-Stewart Valley-Ash Meadows-Amargosa Valley areas. We also include results of a cursory study of faults on the west flank of the Specter Range and in the northern part of the Last Chance Range. A four-phase strategy was implemented for the field study.

  2. Comparing effectiveness of rhamnolipid biosurfactant with a quaternary ammonium salt surfactant for hydrate anti-agglomeration.

    PubMed

    York, J Dalton; Firoozabadi, Abbas

    2008-01-24

    Natural gas is projected to be the premium fuel of the 21st century because of availability, as well as economical and environmental considerations. Natural gas is coproduced with water from the subsurface forming gas hydrates. Hydrate formation may result in shutdown of onshore and offshore operations. Industry practice has been usage of alcohols--which have undesirable environmental impacts--to affect bulk-phase properties and inhibit hydrate formation. An alternative to alcohols is changing the surface properties through usage of polymers and surfactants, effective at 0.5-3 wt % of coproduced water. One group of low-dosage hydrate inhibitors (LDHI) are kinetic inhibitors, which affect nucleation rate and growth. A second group of LDHI are anti-agglomerants, which prevent agglomeration of small hydrate crystallites. Despite great potential, reported work on hydrate anti-agglomeration is very limited. In this paper, our focus is on the use of two vastly different surfactants as anti-agglomerants. We use a model oil, water, and tetrahydrofuran as a hydrate-forming species. We examine the effectiveness of a quaternary ammonium salt (i.e., quat). Visual observation measurements show that a small concentration of the quat (0.01%) can prevent agglomeration. However, a quat is not a green chemical and therefore may be undesirable. We show that a rhamnolipid biosurfactant can be effective to a concentration of 0.05 wt %. One difference between the two surfactants is the stability of the water-in-oil emulsions created. The biosurfactant forms a less stable emulsion, which makes it very desirable for hydrate application. PMID:18171051

  3. Esterase metabolism of cholinesterase inhibitors using rat liver in vitro

    EPA Science Inventory

    A variety of chemicals, such as organophosphate (OP) and carbamate pesticides, nerve agents, and industrial chemicals, inhibit acetylcholinesterase (AChE) leading to overstimulation of the cholinergic nervous system. The resultant neurotoxicity is similar across mammalian species...

  4. Quaternary ammonium polyethylenimine nanoparticles for treating bacterial contaminated water.

    PubMed

    Farah, Shady; Aviv, Oren; Laout, Natalia; Ratner, Stanislav; Beyth, Nurit; Domb, Abraham J

    2015-04-01

    This study highlights the potential application of antimicrobial quaternary ammonium nanomaterials for water disinfection. Quaternary ammonium polyethylenimine (QA-PEI) nanoparticles (NPs) were synthesized by polyethylenimine crosslinking and alkylation with octyl iodide followed by methyl iodide quaternization. Particles modified with octyldodecyl alkyl chains were also prepared and evaluated. The antimicrobial activity of QA-PEI NPs was studied after anchoring in non-leaching polymeric coatings and also in aqueous suspension. Particles at different loadings (w/w) were embedded in polyethylene vinyl acetate and polyethylene methacrylic acid coatings and tested for antimicrobial activity against four representative strains of bacteria in static and dynamic modes. Coatings embedded with fluorescent labelled particles tracked by Axioscope fluorescence microscope during the antimicrobial test indicates no particles leaching out. Coatings loaded with 5% w/w QA-PEI exhibited strong antibacterial activity. Aqueous suspension was tested and found effective for bacterial decontamination at 0.1 ppm and maintains its activity for several weeks. PMID:25800358

  5. 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

  6. 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

  7. Synthesis and Antibacterial Activity of Novel Quaternary Ammonium Pyridoxine Derivatives.

    PubMed

    Shtyrlin, Nikita V; Sapozhnikov, Sergey V; Koshkin, Sergey A; Iksanova, Alfiya G; Sabirov, Arthur H; Kayumov, Airat R; Nureeva, Aliya A; Zeldi, Marina I; Shtyrlin, Yurii G

    2015-01-01

    A series of 26 quaternary ammonium pyridoxine derivatives were synthesized and their cytotoxicity and antibacterial activities against clinically relevant bacterial strains were tested in vitro. The antibacterial activity of mono-ammonium salts increased with the rise of the lipophilicity and compound 3,3,5-trimethyl-8,8-dioctyl-1,7,8,9-tetrahydro-[1,3]dioxino[5,4-d]pyrrolo[3,4-b]pyridin-8- ium chloride (2d) reaches a maximum among them. Bis-ammonium salt of pyridoxine 4 with two dimethyloctylamine groups also demonstrated high antibacterial activity despite lower lipophilicity. The results of MTT assay indicated that HEK 293 cells were more sensitive than HSF to quaternary ammonium pyridoxine derivatives. Compounds 2d and 4 did not induce the damage of the DNA and might be of interest in the development of new antimicrobials. PMID:25938426

  8. Bifunctional compounds targeting both D2 and non-?7 nACh receptors: design, synthesis and pharmacological characterization.

    PubMed

    Matera, Carlo; Pucci, Luca; Fiorentini, Chiara; Fucile, Sergio; Missale, Cristina; Grazioso, Giovanni; Clementi, Francesco; Zoli, Michele; De Amici, Marco; Gotti, Cecilia; Dallanoce, Clelia

    2015-08-28

    We designed, prepared and tested a set of structural analogs 1-4 as new hybrid compounds by incorporating, through a common alkyl chain of variable length, the pharmacophoric elements of N-n-alkyl nicotinium salts (non-?7 nicotinic acetylcholine receptors antagonists) and of 7-hydroxy-2-(aminomethyl)chromanes (dopaminergic D2 receptor agonists). The target compounds, which were assayed in binding experiments and electrophysiological, functional and Erk1/2 activation tests, essentially combined the pharmacological profiles of their individual receptor ligands. Among the studied derivatives, hybrid 2, one of the shortest homologs, in addition to the antagonist nicotinic profile similar to the other three congeners, behaved as a high affinity ligand at the investigated heteromeric nAChRs and as a low efficacy agonist at D2Rs. These bifunctional derivatives represent novel pharmacological tools in the study of nicotine addiction. PMID:26164842

  9. Analysis of Human Dopamine D3 Receptor Quaternary Structure.

    PubMed

    Marsango, Sara; Caltabiano, Gianluigi; Pou, Chantevy; Varela Liste, María José; Milligan, Graeme

    2015-06-12

    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

  10. The impact of Quaternary Ice Ages on mammalian evolution.

    PubMed Central

    Lister, Adrian M

    2004-01-01

    The Quaternary was a time of extensive evolution among mammals. Most living species arose at this time, and many of them show adaptations to peculiarly Quaternary environments. The latter include continental northern steppe and tundra, and the formation of lakes and offshore islands. Although some species evolved fixed adaptations to specialist habitats, others developed flexible adaptations enabling them to inhabit broad niches and to survive major environmental changes. Adaptation to short-term (migratory and seasonal) habitat change probably played a part in pre-adapting mammal species to the longer-term cyclical changes of the Quaternary. Fossil evidence indicates that environmental changes of the order of thousands of years have been sufficient to produce subspeciation, but speciation has typically required one hundred thousand to a few hundred thousand years, although there are both shorter and longer exceptions. The persistence of taxa in environments imposing strong selective regimes may have been important in forcing major adaptive change. Individual Milankovitch cycles are not necessarily implicated in this process, but nor did they generally inhibit evolutionary change among mammals: many evolutionary divergences built over multiple climatic cycles. Deduction of speciation timing requires input from fossils and modern phenotypic and breeding data, to complement and constrain mitochondrial DNA coalescence dates which appear commonly to overestimate taxic divergence dates and durations of speciation. Migrational and evolutionary responses to climate change are not mutually exclusive but, on the contrary, may be synergistic. Finally, preliminary analysis suggests that faunal turnover, including an important element of speciation, was elevated in the Quaternary compared with the Neogene, at least in some biomes. Macroevolutionary species selection or sorting has apparently resulted in a modern mammalian fauna enriched with fast-reproducing and/or adaptively generalist species. PMID:15101579

  11. Quaternary diversification in a sexual Holarctic zooplankter, Daphnia galeata.

    PubMed

    Ishida, Seiji; Taylor, Derek J

    2007-02-01

    The effects of Quaternary glacial range partitioning on the diversification of Holarctic biota remain unclear. Glacial refugial lineages may form vicariant species, hybrid products, or merge after secondary contact. Here, we assess the effects of Quaternary glaciation on a Holarctic sexual zooplankter, Daphnia galeata, with apparently marked dispersal capacity and a widespread hybrid lineage in the New World. We collected samples of this species from 148 Holarctic lakes, analysed the nuclear and mitochondrial gene sequences, and tested predictions for hypotheses that account for the origin and spread of the New World D. galeata. We detected five nuclear phylogroups and four mitochondrial phylogroups, most of which were restricted to either the New World or the Old World. The oldest mitochondrial phylogroup was restricted to Japan. One major mitochondrial clade was distributed throughout the Holarctic, but only four haplotypes were shared among continents, and analysis of molecular variance indicated significant structure at the continental level. Haplotype sharing among continents could largely be attributed to anthropogenic introductions. Mismatch distributions, haplotype networks, phylogenetic trees, longitudinal haplotype diversity erosion and coalescence analyses are consistent with colonization from an Old World and a New World refugium. Our nuclear and mitochondrial DNA sequence evidence supports the hypothesis that the New World D. galeata underwent introgression with Daphnia dentifera, with dispersal being enhanced by glaciation. We conclude that Quaternary glaciation had a pronounced effect on the diversification of a Holarctic sexual zooplankter. PMID:17257114

  12. Multiple sources of alkanes in Quaternary oceanic sediment of Antarctica

    USGS Publications Warehouse

    Kvenvolden, K.A.; Rapp, J.B.; Golan-Bac, M.; Hostettler, F.D.

    1987-01-01

    Normal alkanes (n-C13n-C36), isoprenoid hydrocarbons (i-C15, i-C16, i-C18, i-C19, and i-C20) triterpanes (C27C32), and (C27C29) are present in low concentrations offshore Antarctica in near-surface, Quaternary sediment of the Wilkes Land continental margin and of the western Ross Sea. The distributions of these hydrocarbons are interpreted relative to possible sources and processes. The hydrocarbons appear to be mixtures of primary and recycled material from marine and terrigenous sources. The n-alkanes are most abundant and are characterized by two distinct populations, one of probable marine origin and the other likely from terrigenous, vascular plant sources. Because the continent of Antarctica today is devoid of higher plants, the plant-derived hydrocarbons in these offshore sediments probably came from wind-blown material and recycled Antarctic sediment that contains land-plant remains from an earlier period of time. Isoprenoid hydrocarbons are partially recycled and mainly of marine origin; the dominance of pristane over phytane suggests oxic paleoenvironmental conditions. Both modern and ancient triterpanes and steranes are present, and the distribution of these indicates a mixture of primary and recycled bacterial, algal, and possible higher-plant materials. Although the sampled sediments were deposited during the Quaternary, they apparently contain a significant component of hydrocarbons of pre-Quaternary age. ?? 1987.

  13. 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.

  14. SEDIMENTOLOGY AND GEOMORPHOLOGY OF QUATERNARY ALLUVIAL FANS WITH IMPLICATIONS TO GROWTH STRATA, LOST RIVER RANGE,

    E-print Network

    Dyer, Bill

    SEDIMENTOLOGY AND GEOMORPHOLOGY OF QUATERNARY ALLUVIAL FANS WITH IMPLICATIONS TO GROWTH STRATA......................................................................................14 5. UPPER CEDAR CREEK ALLUVIAL FAN.............................................. 19 Surface 6. JONES CREEK ALLUVIAL FAN......................................................... 67 Surface

  15. The Quaternary adakite distribution of Kyushu Island, Ryukyu Arc, Japan

    NASA Astrophysics Data System (ADS)

    Shibata, T.; Yoshikawa, M.; Takemura, K.

    2011-12-01

    The Quaternary volcanoes are widely distributed in Kyusu Island, Japan. Philippine Sea plate is subducting beneath Kyushu. Clear distribution of deep seismic foci is observed below the Quaternary volcanoes in southern area, but not in northern area. Notsu et al. (1990, JVGR) examined the contribution of subduction to the magma source, and emphasized that no slab derived material is observed in northern area from Sr isotopic compositions. Volcanic activity similar to the within-plate type volcanism has been also emphasized for the magma genesis of this area (e.g. Kita et al, 2001, JVGR). However, we found adakitic rocks, which show high Sr/Y ratios and low Y concentrations (e.g. Defant and Drummond, 1990, Nature) from some Quaternary volcanoes in north Kyushu on the basis of published data (Otha et al, 1990, GANKO; Itoh, 1990, GANKO). Therefore, the magma genesis is still controversial. We studied lateral variations of Sr, Nd and Pb isotopic and trace element compositions for Quaternary volcanics from Kyushu to investigate the magma genesis. From the results, a clear variation of Sr/Y ratio, decreasing from north to south, is observed along the volcanic front. Some of the Sr/Y ratio of the most northern part of Kyusu shows the value >100. The all analyzed Pb isotope compositions show a single liner trend in 208Pb/204Pb v.s. 206Pb/204Pb diagram. The liner trend of Pb isotope ratios can be explained by the binary mixing of the Shikoku Basin basalt and tereginious sediment which might be a constituent of the subducting slab. The similar binary mixing relationships are found in Sr and Nd isotopic systematics. The isotopic characteristics of the Quaternary magma in Kyushu can be explained by the magma generation process of island arc, in spite of the lack of deep seismic foci in northern area. It is considered that high and low Sr/Y ratios suggest the contributions of partial melt in the north and aqueous fluid derived from subducting slab in the south, respectively. If these suggestions are correct, the difference of magma genesis in north and south might be related with the ages of subducting Philippine Sea plate which are < 25Ma at northern and >50 Ma at southern area.

  16. [DNA methyltransferase inhibitors * histone deacetylase inhibitors].

    PubMed

    Kikuchi, Jiro; Furukawa, Yusuke

    2014-06-01

    Epigenetics is a cell intrinsic mechanism to maintain genomic integrity by modifying chromatin architecture independently of changes in heritable DNA sequences namely genetic code. Chromatin is composed of nucleosome cores, in which DNA(147bp) is wrapped around a core histone octamer(two each of histones H2A, H2B, H3 and H4), arranged in a "beads-on-a-string array" with linker histones and non-histone nuclear proteins. The chromatin structure could be altered by chemical modifications of DNA and histones, including methylation and acetylation, without affecting genetic codes. In mammals, DNA methylation is mediated via DNA methyltransferases (Dnmt) at CpG dinucleotides. Histones are modified by numerous enzymes, such as histone acetyltransferases (HATs), deacetylases (HDACs), methyltransferases and demethylases, in spatio-temporarily distinct manners. These modifications could alter chromatin structures to regulate a wide variety of biological processes such as gene expression, cell cycle progression and DNA repair. Given the biological importance of epigenetic modifications, it is easy to speculate that the abnormalities of chromatin modifying enzymes and reader proteins underlie several human diseases such as cancer, inflammation and metabolic disorders. Because epigenetic states are reversible and could be modified in response to extrinsic signals, including small molecular compounds, an increased understanding of their molecular framework would allow us to treat pathological conditions caused by epigenetic alterations. Indeed, Dnmt inhibitors and HDAC inhibitors have already applied to the treatment of hematological malignancies with considerable success. PMID:25016817

  17. Digital release of the Alaska Quaternary fault and fold database

    NASA Astrophysics Data System (ADS)

    Koehler, R. D.; Farrell, R.; Burns, P.; Combellick, R. A.; Weakland, J. R.

    2011-12-01

    The Alaska Division of Geological & Geophysical Surveys (DGGS) has designed a Quaternary fault and fold database for Alaska in conformance with standards defined by the U.S. Geological Survey for the National Quaternary fault and fold database. Alaska is the most seismically active region of the United States, however little information exists on the location, style of deformation, and slip rates of Quaternary faults. Thus, to provide an accurate, user-friendly, reference-based fault inventory to the public, we are producing a digital GIS shapefile of Quaternary fault traces and compiling summary information on each fault. Here, we present relevant information pertaining to the digital GIS shape file and online access and availability of the Alaska database. This database will be useful for engineering geologic studies, geologic, geodetic, and seismic research, and policy planning. The data will also contribute to the fault source database being constructed by the Global Earthquake Model (GEM), Faulted Earth project, which is developing tools to better assess earthquake risk. We derived the initial list of Quaternary active structures from The Neotectonic Map of Alaska (Plafker et al., 1994) and supplemented it with more recent data where available. Due to the limited level of knowledge on Quaternary faults in Alaska, pre-Quaternary fault traces from the Plafker map are shown as a layer in our digital database so users may view a more accurate distribution of mapped faults and to suggest the possibility that some older traces may be active yet un-studied. The database will be updated as new information is developed. We selected each fault by reviewing the literature and georegistered the faults from 1:250,000-scale paper maps contained in 1970's vintage and earlier bedrock maps. However, paper map scales range from 1:20,000 to 1:500,000. Fault parameters in our GIS fault attribute tables include fault name, age, slip rate, slip sense, dip direction, fault line type (i.e., well constrained, moderately constrained, or inferred), and mapped scale. Each fault is assigned a three-integer CODE, based upon age, slip rate, and how well the fault is located. This CODE dictates the line-type for the GIS files. To host the database, we are developing an interactive web-map application with ArcGIS for Server and the ArcGIS API for JavaScript from Environmental Systems Research Institute, Inc. (Esri). The web-map application will present the database through a visible scale range with each fault displayed at the resolution of the original map. Application functionality includes: search by name or location, identification of fault by manual selection, and choice of base map. Base map options include topographic, satellite imagery, and digital elevation maps available from ArcGIS on-line. We anticipate that the database will be publically accessible from a portal embedded on the DGGS website by the end of 2011.

  18. Comparative experimental analysis of the a-C:H deposition processes using CH4 and C2H2 as precursors

    NASA Astrophysics Data System (ADS)

    Peter, S.; Graupner, K.; Grambole, D.; Richter, F.

    2007-09-01

    The plasma enhanced chemical vapor deposition of a-C:H films using methane and acetylene as precursors was studied. Noninvasive in situ techniques were used to analyze the plasma processes with respect to the self-bias voltage, the displacement currents to the grounded electrode, the neutral gas composition, the optical sheath thickness as well as current and energy of the ions hitting the powered electrode. The a-C:H films were characterized for their deposition rate, surface roughness, hardness, mass density, and hydrogen content. Ion mean free paths, suitable for low-pressure rf sheaths, have been quantified for both precursors. The film with the highest hardness of 25GPa was formed in the C2H2 discharge when the mean energy per deposited carbon atom was approximately 50eV. The hardness obtained with the CH4 discharge was lower at 17GPa and less sensitive to changes in the process parameters. It was found that the creation of hard (hardness >15GPa) a-C:H films from both precursors is possible if the mean energy per deposited carbon atom exceeds only ˜15eV. Further film characteristics such as surface roughness and hydrogen content show the interplay of ion flux and deposition from radicals to form the a-C:H structure and properties.

  19. 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

  20. 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

  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. Auxofuran, a Novel Metabolite That Stimulates the Growth of Fly Agaric, Is Produced by the Mycorrhiza Helper Bacterium Streptomyces Strain AcH 505†

    PubMed Central

    Riedlinger, Julia; Schrey, Silvia D.; Tarkka, Mika T.; Hampp, Rüdiger; Kapur, Manmohan; Fiedler, Hans-Peter

    2006-01-01

    The mycorrhiza helper bacterium Streptomyces strain AcH 505 improves mycelial growth of ectomycorrhizal fungi and formation of ectomycorrhizas between Amanita muscaria and spruce but suppresses the growth of plant-pathogenic fungi, suggesting that it produces both fungal growth-stimulating and -suppressing compounds. The dominant fungal-growth-promoting substance produced by strain AcH 505, auxofuran, was isolated, and its effect on the levels of gene expression of A. muscaria was investigated. Auxofuran and its synthetic analogue 7-dehydroxy-auxofuran were most effective at a concentration of 15 ?M, and application of these compounds led to increased lipid metabolism-related gene expression. Cocultivation of strain AcH 505 and A. muscaria stimulated auxofuran production by the streptomycete. The antifungal substances produced by strain AcH 505 were identified as the antibiotics WS-5995 B and C. WS-5995 B completely blocked mycelial growth at a concentration of 60 ?M and caused a cell stress-related gene expression response in A. muscaria. Characterization of these compounds provides the foundation for molecular analysis of the fungus-bacterium interaction in the ectomycorrhizal symbiosis between fly agaric and spruce. PMID:16672502

  3. The Association of PTPN22 R620W Polymorphism Is Stronger with Late-Onset AChR-Myasthenia Gravis in Turkey

    PubMed Central

    Kaya, Gizem A.; Co?kun, Ayse N.; Y?lmaz, Vuslat; Oflazer, Piraye; Gülsen-Parman, Ye?im; Aysal, Fikret; Disci, Rian; Direskeneli, Haner; Marx, Alexander; Deymeer, Feza; Saruhan-Direskeneli, Güher

    2014-01-01

    A functional single nucleotide polymorphism (SNP) of the PTPN22 gene encoding a protein tyrosine phosphatase has been associated with autoimmune disorders including myasthenia gravis (MG). As the PTPN22 R620W polymorphism has a wide variation of allele frequencies among different populations, this polymorphism was investigated in MG in Turkey. An emphasis is put on MG subgroups according to autoantibody (Abs) production and presence of thymoma. DNA samples from 416 patients with clinically diagnosed generalized MG (231 with Abs to acetylcholine receptor, AChR-MG), 53 with Abs to muscle-specific kinase (MuSK-MG), 55 patients with no detectable Abs (SN-MG), 77 patients with thymoma (TAMG) and 293 healthy controls (HC) were genotyped for the SNP (PTPN22 R620W, C1858T, rs2476601). The PTPN22 T allele was increased in AChR-MG patients (odds ratio [OR]: 2.5, 95%CI: 1.2–5.1). The association was stronger in late disease-onset AChR (LOMG, OR: 3.1, 95%CI: 1.2–8.2). MuSK-MG, SN-MG and TAMG groups did not carry the variant allele more frequently than the HC. In contrast to findings in other autoimmune diseases, the distribution of the PTPN22 polymorphism in this population provides a susceptibility marker for AChR-MG. The strongest association is detected in patients with LOMG. PMID:25119822

  4. Comparative study on the use of docking and Bayesian categorization to predict ligand binding to nicotinic acetylcholine receptors (nAChRs) subtypes.

    PubMed

    Kombo, David C; Bencherif, Merouane

    2013-12-23

    We have carried out a comparative study between docking into homology models and Bayesian categorization, as applied to virtual screening of nicotinic ligands for binding at various nAChRs subtypes (human and rat ?4?2, ?7, ?3?4, and ?6?2?3). We found that although results vary with receptor subtype, Bayesian categorization exhibits higher accuracy and enrichment than unconstrained docking into homology models. However, docking accuracy is improved when one sets up a hydrogen-bond (HB) constraint between the cationic center of the ligand and the main-chain carbonyl group of the conserved Trp-149 or its homologue (a residue involved in cation-? interactions with the ligand basic nitrogen atom). This finding suggests that this HB is a hallmark of nicotinic ligands binding to nAChRs. Best predictions using either docking or Bayesian were obtained with the human ?7 nAChR, when 100 nM was used as cutoff for biological activity. We also found that ligand-based Bayesian-derived enrichment factors and structure-based docking-derived enrichment factors highly correlate to each other. Moreover, they correlate with the mean molecular fractional polar surface area of actives ligands and the fractional hydrophobic/hydrophilic surface area of the binding site, respectively. This result is in agreement with the fact that hydrophobicity strongly contributes in promoting nicotinic ligands binding to their cognate nAChRs. PMID:24328365

  5. 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

  6. Anti-Allergic Role of Cholinergic Neuronal Pathway via ?7 Nicotinic ACh Receptors on Mucosal Mast Cells in a Murine Food Allergy Model

    PubMed Central

    Yamamoto, Takeshi; Kodama, Toshihisa; Lee, Jaemin; Utsunomiya, Naho; Hayashi, Shusaku; Sakamoto, Hiroshi; Kuramoto, Hirofumi; Kadowaki, Makoto

    2014-01-01

    The prevalence of food allergy (FA) has increased in developed countries over the past few decades. However, no effective drug therapies are currently available. Therefore, we investigated cholinergic anti-inflammatory pathway as a regulatory system to ameliorate disrupted mucosal immune homeostasis in the gut based on the pathophysiological elucidation of mucosal mast cells (MMCs) in a murine FA model. BALB/c mice sensitized with ovalbumin received repeated oral ovalbumin for the development of FA. FA mice developed severe allergic diarrhea and exhibited enhanced type 2 helper T (Th2) cell immune responses in both systemic immunity and mucosal immunity, along with MMCs hyperplasia in the colon. MMCs were localized primarily in the strategic position of the mucosal epithelium. Furthermore, the allergic symptoms did not develop in p85? disrupted phosphoinositide-3 kinase-deficient mice that lacked mast cells in the gut. Vagal stimulation by 2-deoxy-D-glucose and drug treatment with nicotinic ACh receptor (nAChR) agonists (nicotine and ?7 nAChR agonist GTS-21) alleviated the allergic symptoms in the FA mice. Nicotine treatment suppressed MMCs hyperplasia, enhanced MPO and upregulated mRNA expression of Th1 and Th2 cytokines in the FA mice colon. MMCs, which are negatively regulated by ?7 nAChRs, were often located in close proximity to cholinergic CGRP-immunoreactive nerve fibers in the FA mice colon. The present results reveal that the cholinergic neuroimmune interaction via ?7 nAChRs on MMCs is largely involved in maintaining intestinal immune homeostasis and can be a target for a new therapy against mucosal immune diseases with homeostatic disturbances such as FA. PMID:24454942

  7. Pharmacological stress is required for the anti-alcohol effect of the ?3?4* nAChR partial agonist AT-1001.

    PubMed

    Cippitelli, Andrea; Brunori, Gloria; Gaiolini, Kelly A; Zaveri, Nurulain T; Toll, Lawrence

    2015-06-01

    Alcohol and nicotine are often taken together. The mechanisms underlying this frequent co-abuse are not well known. Genetic and pharmacological evidence suggests that the nicotinic acetylcholine receptors (nAChRs) containing the ?3 and ?4 subunits play a role in alcohol as well as nicotine addiction. AT-1001 is a high affinity ?3?4 nAChR partial agonist recently found to block nicotine self-administration and relapse-like behavior in rats. Here, to study the involvement of ?3?4 nAChRs in the mechanisms that regulate alcohol abuse we evaluated the effects of AT-1001 on alcohol taking and seeking in Sprague-Dawley rats. AT-1001 reduced operant alcohol self-administration at the highest dose examined (3.0 mg/kg), an effect also observed for food self-administration. A dose of 1.5 mg/kg AT-1001, which had no effect on alcohol or food self-administration, essentially eliminated reinstatement of alcohol seeking induced by yohimbine (0.625 mg/kg) whereas, reinstatement induced by alcohol-associated cues was not altered, nor did AT-1001 induce reinstatement of extinguished self-administration on its own. Finally, AT-1001 showed an anxiolytic activity when measured in the presence or absence of yohimbine stress in the elevated plus maze paradigm. Together, these observations do not support a specific involvement of the ?3?4 nAChR in mediating alcohol reward or cue-induced relapse to alcohol seeking but rather indicate that the ?3?4 nAChR partial agonism may constitute an attractive approach for treating alcohol use disorders exacerbated by elevated stress response. PMID:25689019

  8. 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

  9. Engineering a4b2 nAChRs with reduced or increased nicotine sensitivity via selective disruption of consensus sites in the M3eM4

    E-print Network

    Lasalde Dominicc, Jose A. - Department of Biology, Universidad de Puerto Rico

    . Introduction Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand- gated ion channels that belong April 2015 Accepted 24 April 2015 Available online 6 May 2015 Keywords: Nicotinic acetylcholine receptor nicotinic acetylcholine receptor (nAChR) plays a crucial role in nicotine addiction. These receptors

  10. 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

  11. Geology of the quaternary volcanic centres of the east Anatolia

    NASA Astrophysics Data System (ADS)

    Y?lmaz, Y.; Güner, Y.; ?aro?lu, F.

    1998-10-01

    Following the collision along the Bitlis-Zagros suture, a north-south convergence between the Arabian Platform and Laurasia has continued uninterrupted until the present. As a result, the continental crust has been shortened, thickened and consequently elevated to form the Turkish-Iranian high plateau. On the high plateau volcanic activity began during the Neogene, intensified during the late Miocene-Pliocene and continued until historical times. Large volcanic centres have been developed during the Quaternary which form significant peaks above the Turkish-Iranian high plateau. Among the Quaternary volcanoes, the major volcanic centres are Ararat, Tendürek, Suphan and Nemrut. Ararat (A?ri Da?i) is the largest volcanic center and is a compound stratovolcano, consisting of Greater Ararat and lesser Ararat. The former represents the highest elevation of Anatolia reaching over 5000 m in height. Tendürek is a double-peaked shield volcano, which produced a voluminous amount of basalt lava as extensive pahoehoe, and aa flows. It has an ill-defined semi-caldera. Suphan is an isolated stratovolcano, capped by silicic dome. It represents the second highest topographic elevation in Anatolia, with a height of over 4000 m. A cluster of subsidiary cones and small domes surrounds the volcano. Nemrut is the largest member of a group of volcanoes, which trend north-south. It is a stratovolcano, having a well-defined collapse caldera and a caldera lake. Various volcanic ejecta have been extruded from these volcanic centres over the last 1 to 2 million years. The Quaternary volcanic centres, although temporally and spatially closely associated, display a wide range of lavas from basalt to rhyolite. The volcanoes have diverse compositional trends; Ararat is distinctly subalkaline, Suphan is mildly subalkaline, Nemrut is mildly alkaline and Tendürek is strongly alkaline. The major and trace element compositions together with the isotope ratios indicate that their magmas were generated from a heterogeneous mantle source. Each of the volcanic centres has undergone a partly different magmatic evolution.

  12. 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

  13. Quaternary geology and waste disposal in South Norfolk, England

    NASA Astrophysics Data System (ADS)

    Gray, J. M.

    South Norfolk is dominated by the till plain of the Anglian Glaciation in eastern England, and therefore there are very few disused gravel pits and quarries suitable for the landfilling of municipal waste. Consequently, in May 1991, Norfolk County Council applied for planning permission to develop an above ground or 'landraise' waste disposal site at a disused U.S. World War II Airfield at Hardwick in South Norfolk. The proposal involved excavating a pit 2-4 m deep into the Lowestoft Till and overfilling it to create a hill of waste up to 10 m above the existing till plain. In general, leachate containment was to be achieved by utilising the relatively low permeability till on the floor of the site, but with reworking of the till around the site perimeter because of sand lenses in the upper part of the till. This paper examines three aspects of the proposal and the wider issues relating to Quaternary geology and waste disposal planning in South Norfolk: (i) the suitability of the till as a natural leachate containment system; (ii) the appropriateness of the landraise landform; and (iii) alternative sites. A Public Inquiry into the proposals was held in January/February 1993 and notification of refusal of planning permission was published in August 1993. Among the grounds for refusal were an inadequate knowledge of the site's geology and hydrogeology and the availability of alternative sites. The paper concludes by stressing that a knowledge of Quaternary geology is crucial to both the planning and design of landfill sites in areas of glacial/Quaternary sediments.

  14. Recent Progress on the Stereoselective Synthesis of Cyclic Quaternary ?-Amino Acids

    PubMed Central

    Cativiela, Carlos; Ordóñez, Mario

    2010-01-01

    The most recent papers describing the stereoselective synthesis of cyclic quaternary ?-amino acids are collected in this review. The diverse synthetic approaches are classified according to the size of the ring and taking into account the bond that is formed to complete the quaternary skeleton. PMID:20300486

  15. Late Quaternary changes in biogenic opal uxes in the Southern Indian Ocean

    E-print Network

    Demouchy, Sylvie

    Late Quaternary changes in biogenic opal £uxes in the Southern Indian Ocean L. Dezileau a;Ã , J data. ß 2003 Elsevier B.V. All rights reserved. Keywords: Southern Ocean; Indian sector; biogenic opal 2003 Abstract Late Quaternary sedimentary and paleoenvironmental conditions in the southern Indian

  16. 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

  17. Maps of Quaternary Deposits and Liquefaction Susceptibility in the Central San Francisco Bay Region, California

    E-print Network

    Maps of Quaternary Deposits and Liquefaction Susceptibility in the Central San Francisco Bay Region.K., and Gans, K.D., 2006, Maps of Quaternary deposits and liquefaction susceptibility in the central San and Liquefaction Interpretation Additional products of this research include postscript and PDF files

  18. Quaternary history of sea ice in the western Arctic Ocean based on foraminifera

    E-print Network

    Quaternary history of sea ice in the western Arctic Ocean based on foraminifera Leonid Polyak a 4 February 2013 Keywords: Western Arctic Ocean Foraminifers Quaternary Mid-Pleistocene Transition Sea ice history a b s t r a c t Sediment cores from the Northwind Ridge, western Arctic Ocean

  19. Identification of Quaternary Shape Memory Alloys with Near-Zero Thermal Hysteresis and Unprecedented

    E-print Network

    Rubloff, Gary W.

    Identification of Quaternary Shape Memory Alloys with Near-Zero Thermal Hysteresis of quaternary Ti­Ni­Cu­Pd SMAs and the thermal hysteresis are tailored. Novel alloys with near-zero thermal hysteresis, as predicted by the geometric non- linear theory of martensite, are identified. The thin

  20. Charophytes as lacustrine biomarkers during the quaternary in North Africa

    NASA Astrophysics Data System (ADS)

    Soulié-Märsche, I.

    The use of charophytes as biomarkers is discussed with emphasis on the differences in study methods for cosmopolitan and ecotype species. A first extensive inventory of Quaternary deposits of charophytes in Africa north of the equator comprising 18 sites from Senegal to the Sudan is drawn up with data on spatial and temporal distribution. The existence of relatively deep cold lakes in the Holocene is shown by the frequent presence of specimens of cold flora no longer present in Africa today. All the original data show the complementary nature of the study of fossil Charophyta for the multidisciplinary reconstitution of palaeoenvironments.

  1. Differential Effects of Acetylcholinesterase Inhibitors on Clinical Responses and Cerebral Blood Flow Changes in Patients with Alzheimer's Disease: A 12-Month, Randomized, and Open-Label Trial

    PubMed Central

    Shimizu, Soichiro; Kanetaka, Hidekazu; Hirose, Daisuke; Sakurai, Hirohumi; Hanyu, Haruo

    2015-01-01

    Background/Aims The present study evaluated the differences in treatment outcomes and brain perfusion changes among 3 types of acetylcholinesterase inhibitors (AchEIs, i.e. donepezil, rivastigmine, and galantamine). Methods This was a prospective, longitudinal, randomized, open-label, 3-arm (donepezil, rivastigmine, or galantamine), parallel-group, 12-month clinical trial carried out in 55 patients with AD. Results At 6 months, the results of the Mini-Mental State Examination (MMSE) and the Trail Making Test (TMT)-Part A showed an improvement versus baseline in the donepezil treatment group. All groups showed a significant increase in regional cerebral blood flow (rCBF), mainly in the frontal lobe. Significant rCBF reduction was observed in the temporal lobe and cingulate gyrus in all 3 groups. Conclusion AchEI treatment prevents the progression of cognitive impairment and increases the relative rCBF in the frontal lobe. PMID:25999980

  2. 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

  3. Vesicular acetylcholine transporter (VAChT) in the brain of spontaneously hypertensive rats (SHR): effect of treatment with an acetylcholinesterase inhibitor.

    PubMed

    Tayebati, S K; Di Tullio, M A; Amenta, F

    2008-11-01

    The cholinergic marker vesicular acetylcholine transporter (VAChT) was investigated in different cerebral areas of spontaneously hypertensive rats (SHR) by immunochemistry (Western blot analysis) and by immunohistochemistry. SHR were used as an animal model of hypertensive brain damage. The sensitivity of manipulation of cholinergic system on VAChT was assessed in rats treated for four weeks with the acetylcholinesterase (AChE) inhibitor galantamine (3 mg/Kg/day). VAChT concentrations were increased in the brain of control SHR compared to age-matched normotensive Wistar-Kyoto rats. This increase probably represents an up-regulation of VAChT to oppose cholinergic deficits reported in SHR and is countered by galantamine administration. The possibility that cholinergic neurotransmission enhancement may represent a therapeutic strategy in cerebrovascular disease is discussed. PMID:19021024

  4. Late Quaternary geomorphology and soils in Crater Flat, Yucca mountain area, southern Nevada

    SciTech Connect

    Peterson, F.F.; Bell, J.W.; Ramelli, A.R.; Dorn, R.I.; Ku, T.L.

    1995-04-01

    Crater Flat is an alluvium-filled structural basin on the west side of Yucca Mountain, Nevada, which is under consideration for a high-level nuclear waste repository. North-trending, late Quaternary faults offset alluvium in Crater Flat both along the canyons of the western flanks of Yucca Mountain and out on the piedmont slope. We believe the initial lack of young offsets at Yucca Mountain was in part due to unrecognized late Quaternary stratigraphy. We hypothesize that alluviation in the Yucca Mountain region was more active during the late Quaternary than previously thought. Several techniques were tried to test this hypothesis. Results are compared with previous soils and surface-exposure dating studies, and correlated to stratigraphy of other late Quaternary units in the southern Nevada, Death Valley, and Mojave Desert areas, and provide new stratigraphic data relevant to understanding climatic-alluvial processes in the Basin and Range Province during the late Quaternary. 76 refs., 7 figs., 6 tabs.

  5. In Vitro and In Vivo Metabolism and Inhibitory Activities of Vasicine, a Potent Acetylcholinesterase and Butyrylcholinesterase Inhibitor

    PubMed Central

    Liu, Wei; Shi, Xiaoyuan; Yang, Yadi; Cheng, Xuemei; Liu, Qing; Han, Han; Yang, Baohua; He, Chunyong; Wang, Yongli; Jiang, Bo; Wang, Zhengtao; Wang, Changhong

    2015-01-01

    Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer’s disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-?-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity. PMID:25849329

  6. Cognitive effects of the acetylcholinesterase inhibitor, donepezil, in healthy, non-treatment seeking smokers: A pilot feasibility study

    PubMed Central

    Ashare, Rebecca L.; Ray, Riju; Lerman, Caryn; Strasser, Andrew A.

    2012-01-01

    Background There is a need to identify medications to aid in smoking cessation. Reducing withdrawal-related cognitive deficits represents a pharmacological target for new pharmacotherapies. Endogenous acetylcholine levels, which are modulated by acetylcholinesterase inhibitors (AChEIs), play an important role in smoking behavior and cognition. This pilot feasibility study tested whether an AChEI, donepezil, enhanced cognitive performance among healthy smokers. Methods Eighteen non-treatment seeking daily smokers (6 female) received either donepezil (5mg q.d) or placebo (double-blind; 2:1 allocation ratio) for four weeks. Smoking rate, side effects, and neurocognitive measures of working memory (Letter-N-back) and sustained attention (Penn Continuous Performance Task) were assessed weekly. Results For the working memory task, there was a significant group × load × time interaction (p=0.03) indicating that the donepezil group demonstrated an increase in true positives from baseline to week 4 at the highest working memory load (3-back). The placebo group showed no change in accuracy. For the sustained attention task, there was a marginal effect in the same direction for discriminability, or d', p=0.08. There were no significant effects on reaction time during either task. There was also a reduction in cigarettes per day in the placebo group, but not the donepezil group. Conclusions AChEIs, such as donepezil, may have pro-cognitive effects among healthy smokers while they continue to smoke as usual. Given the association between cognitive deficits and relapse, AChEIs should be explored as potential therapeutics for smoking cessation. PMID:22595038

  7. AC impedance spectroscopy - A dynamic tool for the design of corrosion inhibitors

    SciTech Connect

    Growcock, F.B.; Jasinski, R.J.

    1988-05-01

    Corrosion of steel during oil well acidizing or acid pickling treatments can be controlled effectively and economically with corrosion inhibitors. It is generally accepted that these additives function by forming an adherent barrier on the steel surface, the nature of which depends on various physiochemical properties of the inhibitor. Work to date has established that acetylenic alcohols first chemisorb and subsequently polymerize on steel surfaces. ..cap alpha.., BETA-Unsaturated aldehydes and ..cap alpha..-alkenylphenones behave in a similar manner. On the other hand, quaternary nitrogen salts adsorb electrostatically and do not appear to form macroscopic films. In this paper, the authors describe some AC impedance spectroscopy studies they have undertaken with the objective of elucidating the roles that adsorption and film formation play in the inhibition mechanisms of the compounds mentioned above.

  8. Benzoylurea Chitin Synthesis Inhibitors.

    PubMed

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs. PMID:26168369

  9. Quaternary extensional and compressional tectonics revealed from Quaternary landforms along Kosi River valley, outer Kumaun Lesser Himalaya, Uttarakhand

    NASA Astrophysics Data System (ADS)

    Luirei, Khayingshing; Bhakuni, S. S.; Kothyari, Girish Ch.; Tripathi, Kavita; Pant, P. D.

    2015-06-01

    A portion of the Kosi River in the outer Kumaun Lesser Himalaya is characterized by wide river course situated south of the Ramgarh Thrust, where huge thickness (~200 m) of the landslide deposits and two to three levels of unpaired fan terraces are present. Brittle normal faults, suggesting extensional tectonics, are recognized in the Quaternary deposits and bedrocks as further supported by surface morphology. Trending E-W, these faults measure from 3 to 5 km in length and are traced as discontinuous linear mini-horst and fault scarps (sackungen) exposed due to cutting across by streams. Active normal faults have displaced the coarsely laminated debris fan deposits at two sites located 550 m apart. At one of the sites, the faults look like bookshelf faulting with the maximum displacement of ~2 m and rotation of the Quaternary boulders along the fault plane is observed. At another site, the maximum displacement measures about 0.60 cm. Thick mud units deposited due to blocking of the streams by landslides are observed within and above the fan deposit. Landslide debris fans and terrace landforms are widely developed; the highest level of fan is observed ~1240 m above mean sea level. At some places, the reworking of the debris fans by streams is characterized by thick laminated sand body. Along the South Almora Thrust and Ramgarh Thrust zones, the valleys are narrow and V-shaped where Quaternary deposits are sparse due to relatively rapid uplift across these thrusts. Along the South Almora Thrust zone, three to four levels of fluvial terraces are observed and have been incised by river exposing the bedrocks due to recent movement along the RT and SAT. Abandoned channel, tilted mud deposits, incised meandering, deep-cut V-shaped valleys and strath terraces indicate rapid uplift of the area. Thick mud sequences in the Quaternary columns indicate damming of streams. A ~10-km-long north-south trending transverse Garampani Fault has offset the Ramgarh Thrust producing tectonic landforms.

  10. 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.

  11. Global warming: Perspectives from the Late Quaternary paleomammal record

    SciTech Connect

    Graham, R.W. )

    1993-03-01

    Global warming at the end of the Pleistocene caused significant environmental changes that directly and indirectly effected biotic communities. The biotic response to this global warming event can provide insights into the processes that might be anticipated for future climatic changes. The megafauna extinction may have been the most dramatic alteration of mammalian communities at the end of the Pleistocene. Late Quaternary warming also altered regional diversity patterns for some small mammal guilds without extinction. Reductions in body size for both small and large mammal species were also consequences of these environmental fluctuations. Geographic shifts in the distributions of individual mammal species resulted in changes in species composition of mammalian communities. The individualistic response of biota to environmental fluctuations define some boundary conditions for modeling communities. Understanding these boundary conditions is mandatory in planning for the preservation of biodiversity in the future. Finally, it is essential to determine how global warming will alter seasonal patterns because it is apparent from the paleobiological record that not all Quaternary warming events have been the same.

  12. Ecostratigraphic datums and sequence stratigraphy: Application to the marine Quaternary

    SciTech Connect

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

    1991-03-01

    The marine Quaternary is characterized by few evolutionary appearances and extinctions of planktonic foraminifera. Because climatic fluctuations are a fundamental characteristic of Pleistocene, however, better stratigraphic resolution of the marine Quaternary can be gained by the establishment of biozones based on climatically controlled foraminiferal assemblages. Utilizing relative abundances of the warm-water Globorotalia menardii complex and temperature-water G. inflata, supplemented by left- and right-coiling varieties of G. truncatulinoides, the authors have subdivided the prezone-W Pleistocene of the tropical Atlantic (Core V16-205), Caribbean Sea (DSDP Core 502B), and northeast Gulf of Mexico (ODP Core 625B, Eureka Core E67-135) into 17 subzones, each with an average duration of {approximately}100,000 yrs. The subzones appear to reflect water mass shifts and disjunct species distributions resulting from expansion and contraction of northern hemisphere ice sheets. Hence, subzonal boundaries should also reflect change in eustatic sea level and sequence boundaries. Indeed, graphic correlation of the subzones, along with biostratigraphic markers and paleomagnetic and oxygen isotope datums, reveals changes in sediment accumulation rate (especially on the continental slope) and missing section, as well as intervals of deformation (core breaks) that affect the occurrence of subzonal boundaries and biostratigraphic markers.

  13. 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

  14. 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.

  15. European quaternary refugia: a factor in large carnivore extinction?

    NASA Astrophysics Data System (ADS)

    O'Regan, Hannah J.; Turner, Alan; Wilkinson, David M.

    2002-12-01

    The extinction of large carnivores in Europe during the Quaternary is reviewed and the potential role of glacial refugia in these extinctions is investigated using the VORTEX model for population viability analysis. A model was built for a medium sized big cat similar to the extinct Panthera gombaszoegensis utilising life history data from the modern jaguar Panthera onca. This approach highlighted the potential importance of glacial refugia in the extinction process. Even model refugia the size of the Italian peninsula did not guarantee persistence of a population over a 1000 yr time span, illustrating the role of chance in survival in such a refugium. An area the size of the largest Mediterranean island was unable to support a big cat population for a period of 1000 yr. The models also demonstrated the importance of inbreeding as a mechanism for extinction in refugia. It is suggested that repeated genetic bottlenecks during successive glaciations would tend to remove lethal recessive alleles from the population, increasing the probability of survival in refugia in subsequent glaciations. The history of extinction of large carnivores in the European Quaternary is interpreted in the light of these results.

  16. Engineering ?4?2 nAChRs with reduced or increased nicotine sensitivity via selective disruption of consensus sites in the M3-M4 cytoplasmic loop of the ?4 subunit.

    PubMed

    Biaggi-Labiosa, Nilza M; Avilés-Pagán, Emir; Caballero-Rivera, Daniel; Báez-Pagán, Carlos A; Lasalde-Dominicci, José A

    2015-12-01

    The ?4?2 neuronal nicotinic acetylcholine receptor (nAChR) plays a crucial role in nicotine addiction. These receptors are known to desensitize and up-regulate after chronic nicotine exposure, but the mechanism remains unknown. Currently, the structure and functional role of the intracellular domains of the nAChR are obscure. To study the effect of subunit phosphorylation on ?4?2 nAChR function and expression, eleven residues located in the M3-M4 cytoplasmic loop were mutated to alanine and aspartic acid. Two-electrode voltage clamp and (125)I-labeled epibatidine binding assays were performed on Xenopus oocytes to assess agonist activation and receptor expression. When ACh was used as an agonist, a decrease in receptor activation was observed for the majority of the mutations. When nicotine was used as an agonist, four mutations exhibited a statistically significant hypersensitivity to nicotine (S438D, S469A, Y576A, and S589A). Additionally, two mutations (S516D and T536A) that displayed normal activation with ACh displayed remarkable reductions in sensitivity to nicotine. Binding assays revealed a constitutive up-regulation in these two nicotine mutations with reduced nicotine sensitivity. These results suggest that consensus phosphorylation residues in the M3-M4 cytoplasmic loop of the ?4 subunit play a crucial role in regulating ?4?2 nAChR agonist selectivity and functional expression. Furthermore, these results suggest that disruption of specific interactions at PKC putative consensus sites can render ?4?2 nAChRs almost insensitive to nicotine without substantial effects on normal AChR function. Therefore, these PKC consensus sites in the M3-M4 cytoplasmic loop of the ?4 nAChR subunit could be a target for smoking cessation drugs. PMID:25957813

  17. ACHS Conference 2009 PROCEEDINGS

    E-print Network

    Franklin, James

    allies. They had been surviving in basic camps as an unsolved minor problem of the early Cold War. 60 countries they had barely heard of and from which there had been virtually no migrants before? Let us step-American army in the West, neither of which was equipped to run civil governments. The Anglo-American army

  18. Oooh, Your Aching Head!

    MedlinePLUS

    ... too much time watching TV or using a computer . Strong odors , such as perfume, smoke, fumes, or the smell of a new car or carpet, can start a headache. Some foods can cause headaches in some kids, such as ...

  19. The reversible cholinesterase inhibitor physostigmine has channel-blocking and agonist effects on the acetylcholine receptor-ion channel complex.

    PubMed

    Shaw, K P; Aracava, Y; Akaike, A; Daly, J W; Rickett, D L; Albuquerque, E X

    1985-12-01

    The actions of the carbamate cholinesterase inhibitors, physostigmine (Phy) and physostigmine methiodide (MetPhy), were studied on the acetylcholine receptor-ion channel complex (AChR) of skeletal muscles. Low concentrations of these agents produced cholinesterase inhibition which resulted in potentiation of nerve-elicited muscle twitches and an increased peak amplitude and prolongation of the decay time constant (tau EPC) of endplate currents (EPCs) elicited in frog (Rana pipiens) sartorius muscles. However, increasing concentrations of Phy depressed the peak amplitude and shortened the decay phase of the EPC with an apparent loss in the voltage dependence of tau EPC. At higher concentrations and depolarized potentials, EPC decays were double exponential. The effects of both Phy and MetPhy on the postsynaptic AChR complex were also evident in preparations pretreated with diisopropylfluorophosphate. Under these conditions, a linear relationship between the reciprocal of tau EPC and the concentration of these agents was observed. Single channel studies revealed that Phy (20-600 microM) shortened channel lifetime and decreased channel conductance at very high concentrations. In addition, Phy (0.5 microM) induced the appearance of channel openings with conductance similar to that of acetylcholine. High concentrations (greater than 50 microM) of this agent activated channel openings with decreased conductance. Similar results were obtained with MetPhy. Thus, the reversible cholinesterase inhibitors Phy and MetPhy altered the properties of the AChR by interacting as agonists capable of inducing desensitization and blockade. PMID:2417099

  20. Quaternary Reorganization of North American Mid-continent Drainage Systems

    NASA Astrophysics Data System (ADS)

    Carson, E. C.; Rawling, J. E., III; Attig, J. W.; Bates, B. R.

    2013-12-01

    Identification of ancestral drainage systems in the North American mid-continent has been a topic of research and debate among geologists since the middle of the 19th Century. Over time our understanding of the significance of Quaternary glaciations in reshaping drainage patterns has grown. The ancestral Teays River, which drained large areas of the central Appalachians and flowed westward across Indiana and western Illinois, was dammed multiple times by Quaternary glaciers before finally being rerouted to the course of the modern central Ohio River. Similarly, the northward-flowing ancestral Pittsburgh River was dammed by pre-Illinoian glaciers; subsequent stream piracy converted this river system into the modern Allegheny, Monongahela and uppermost Ohio Rivers. Deposits and geomorphic features along the westward-flowing lower Wisconsin River indicate that the modern upper Mississippi River and Wisconsin River may have experienced a similar history of ice blockage, stream piracy, and radical rerouting. Coring into the Bridgeport strath terrace along the lower Wisconsin River reveals that the bedrock surface dips to the east, indicating the valley was cut by an eastward-flowing river. We believe the most likely scenario following this interpretation is that an ancestral river flowing along the modern upper Mississippi River valley made a sharp bend at Prairie du Chien, WI, and flowed eastward along the valley occupied by the modern lower Wisconsin River. This river, referred to here as the Wyalusing River, likely flowed northeastward into the Great Lakes (St. Lawrence) drainage until that path was blocked by ice advancing from the northwest. Subsequent stream piracy immediately south of the modern confluence of the Mississippi and Wisconsin Rivers rerouted these streams, converting them to the headwaters of the greater Mississippi drainage. The combined rerouting of these river systems into entirely different drainage basins necessitates significant fundamental changes to the total discharge of the St. Lawrence and Mississippi Rivers. While it is unclear if the Teays River ever flowed into the St. Lawrence drainage or developed as a westward-flowing tributary to the buried Mahomet valley in Illinois, both the ancestral Pittsburgh and Wyalusing Rivers originated as headwaters of the St. Lawrence basin before being rerouted as part of the Mississippi basin. The areas formerly drained by the Pittsburgh and Wyalusing Rivers comprise ~8% of the modern Mississippi River basin, and modern discharge from those areas represent ~14% of the mean annual discharge of the Mississippi River. The transfer of this drainage area and discharge to the Mississippi basin is mirrored by an equivalent loss from the St. Lawrence system during the Quaternary as a direct result of glacially-driven drainage system reorganization.

  1. 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.

  2. Synthesis of Lysine Methyltransferase Inhibitors

    NASA Astrophysics Data System (ADS)

    Ye, Tao; Hui, Chunngai

    2015-07-01

    Lysine methyltransferase which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and has emerged as a promising target for the development of various human diseases, including cancer, inflammation, and psychiatric disorders. However, inhibiting Lysine methyltransferases selectively has presented many challenges to medicinal chemists. During the past decade, lysine methyltransferase inhibitors covering many different structural classes have been designed and developed. In this review, we describe the development of selective, small-molecule inhibitors of lysine methyltransferases with an emphasis on their discovery and chemical synthesis. We highlight the current state of lysine methyltransferase inhibitors and discuss future directions and opportunities for lysine methyltransferase inhibitor discovery.

  3. [Kinase inhibitors and their resistance].

    PubMed

    Togashi, Yosuke; Nishio, Kazuto

    2015-08-01

    Kinase cascades are involved in all stages of tumorigenesis through modulation of transformation and differentiation, cell-cycle progression, and motility. Advances in molecular targeted drug development allow the design and synthesis of inhibitors targeting cancer-associated signal transduction pathways. Potent selective inhibitors with low toxicity can benefit patients especially with several malignancies harboring an oncogenic driver addictive signal. This article evaluates information on solid tumor-related kinase signals and inhibitors, including receptor tyrosine kinase or serine/threonine kinase signals that lead to successful application in clinical settings. In addition, the resistant mechanisms to the inhibitors is summarized. PMID:26281685

  4. Asynchronous extinction of late Quaternary sloths on continents and islands

    PubMed Central

    Steadman, David W.; Martin, Paul S.; MacPhee, Ross D. E.; Jull, A. J. T.; McDonald, H. Gregory; Woods, Charles A.; Iturralde-Vinent, Manuel; Hodgins, Gregory W. L.

    2005-01-01

    Whatever the cause, it is extraordinary that dozens of genera of large mammals became extinct during the late Quaternary throughout the Western Hemisphere, including 90% of the genera of the xenarthran suborder Phyllophaga (sloths). Radiocarbon dates directly on dung, bones, or other tissue of extinct sloths place their “last appearance” datum at ?11,000 radiocarbon years before present (yr BP) or slightly less in North America, ?10,500 yr BP in South America, and ?4,400 yr BP on West Indian islands. This asynchronous situation is not compatible with glacial–interglacial climate change forcing these extinctions, especially given the great elevational, latitudinal, and longitudinal variation of the sloth-bearing continental sites. Instead, the chronology of last appearance of extinct sloths, whether on continents or islands, more closely tracks the first arrival of people. PMID:16085711

  5. 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

  6. Quaternary prevention, an answer of family doctors to overmedicalization

    PubMed Central

    Jamoulle, Marc

    2015-01-01

    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

  7. Quaternary eustatic sedimentary accretion of southern Bahamas Archipelago

    SciTech Connect

    Mitchell, S.W.

    1985-02-01

    Surficial geologic mapping indicates that the southern half of the Bahamas Archipelago is forming by the accretion of discrete depositional sequences resulting from successive eustatic sea level changes: (1) multiple beach and dune ridges, (2) estuarine, (3) lacustrine, (4) shallow subtidal, (5) reef and reef rubble, and (6) megadune complexes. The lithologies are accreted along unconformable erosional-solutional contacts - marine terraces and subaerial caliche crusts. During periods of significant transgression, sequences 1-5 are accreted. Sediments are predominantly skeletal and peloid. During periods of significant regression, megadune complexes are accreted. Ooids are the dominant sediment. Erosional-solutional features reflect areas of subaerial exposure and/or coastline erosion. Terraces at 10, 20, and 40 ft elevations are preserved along arid eastern Great Inagua Island. The calichification of Bahamian Quaternary carbonates has concentrated insoluble residues (quartz, feldspar, heavy minerals, crandallite, micrometeorites). Insoluble residue analysis provides a basis for the correlation of accreted eustatic sedimentary sequences.

  8. Control of Quaternary sea-level changes on gas seeps

    NASA Astrophysics Data System (ADS)

    Riboulot, Vincent; Thomas, Yannick; Berné, Serge; Jouet, Gwénaël.; Cattaneo, Antonio

    2014-07-01

    Gas seeping to the seafloor through structures such as pockmarks may contribute significantly to the enrichment of atmospheric greenhouse gases and global warming. Gas seeps in the Gulf of Lions, Western Mediterranean, are cyclical, and pockmark "life" is governed both by sediment accumulation on the continental margin and Quaternary climate changes. Three-dimensional seismic data, correlated to multi-proxy analysis of a deep borehole, have shown that these pockmarks are associated with oblique chimneys. The prograding chimney geometry demonstrates the syn-sedimentary and long-lasting functioning of the gas seeps. Gas chimneys have reworked chronologically constrained stratigraphic units and have functioned episodically, with maximum activity around sea level lowstands. Therefore, we argue that one of the main driving mechanisms responsible for their formation is the variation in hydrostatic pressure driven by relative sea level changes.

  9. Terrestrial paleoenvironmental effects of a late quaternary-age supernova

    NASA Astrophysics Data System (ADS)

    Brakenridge, G. R.

    1981-04-01

    Over 120 radio-emitting galactic supernova remnants (SNRs) have been catalogued. It is possible to evaluate the possible terrestrial importance of specific inferred radiation events. Because radio SNRs expand with age, and become indistinguishable from the interstellar medium at mean diameters of approximately 65 pc (ages of roughly 45,000 years), only late Quaternary time can be examined. However, it is for this period that detailed and well-dated terrestrial paleoenvironmental records are available. Such records can provide tests of any predicted supernova effects. There is at present considerable evidence supporting the hypothesis that the Vela supernova caused short-term but possibly severe terrestrial environmental changes. The information presented suggests that the effects to be predicted for the Vela supernova did occur, and began shortly after 11,000 C-14 yr B.P.

  10. Expanded record of Quaternary oceanographic change: Amerasian Arctic Ocean

    USGS Publications Warehouse

    Ishman, S.E.; Polyak, L.V.; Poore, R.Z.

    1996-01-01

    Four sediment cores collected from the Northwind and Mendeleyev ridges, Arctic Ocean, from 1089 m to 1909 m water depth, provide an oceanographic record extending back into the Matuyama reversed polarity chron. Benthic foraminiferal analyses show four prominent assemblage zones: Bolivina arctica, Cassidulina teretis, Bulimina aculeata, and Oridorsalis tener from the upper Matuyama reversed polarity chronozone through the Brunhes normal polarity chronozone. These assemblage zones represent depth-dependent benthic foraminiferal biofacies changes associated with oceanographic events that occurred in the Amerasian basin at ??? 780 and 300 ka, and indicate oceanographic influence from the North Atlantic. Recognition of these benthic assemblage zones in Arctic cores from the Alpha Ridge indicates that the benthic foraminiferal zonations in intermediate to deep water (>1000 m) Arctic cores may be more useful than preexisting lithostratigraphic zonations and should provide important information pertaining to the Quaternary paleoceanographic evolution of the Arctic Ocean.

  11. The Use of Quaternary Ammonium to Combat Dental Caries

    PubMed Central

    Ge, Yang; Wang, Suping; Zhou, Xuedong; Wang, Haohao; Xu, Hockin H. K.; Cheng, Lei

    2015-01-01

    Resin composites and adhesives are increasingly popular in dental restorations, but secondary caries is one of the main reasons for restoration failure. Quaternary ammonium monomers (QAMs) have an anti-microbial effect and are widely used in many fields. Since the concept of the immobilized antibacterial effect was put forward, dental restorations containing QAMs have been studied to reduce secondary caries. Previous studies have been struggling to develop novel anti-caries materials which might have triple benefits: good mechanical properties, antibacterial effects and remineralization potentials. Different kinds of QAMs have been proven to be effective in inhibiting the growth and metabolism of biofilms. Combination of QAMs and other nanoparticles in resin composites and adhesives could enhance their anti-caries capability. Therefore, QAMs are promising to show significant impact on the future of restorative and preventive dentistry. PMID:26635932

  12. 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.

  13. Seismic stratigraphy and quaternary evolution of the New York Bight Inner Continental Shelf 

    E-print Network

    Lotto, Linda L

    2000-01-01

    over the New York Bight Apex on the U. S. Atlantic inner continental shelf were analyzed to develop a better understanding of the Quaternary evolution of this inner continental shelf environment. Interpretation of the subbottom data reveals several...

  14. 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.

  15. 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.

  16. 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.

  17. INTRODUCTION For much of the past century, the Quaternary record of the

    E-print Network

    Pederson, Joel L.

    the Pleistocene glaciations. Second, the unique Geological Society of America Field Guide 6 2005 From cirques.L., and Carson, E.C., 2005, From cirques to canyon cutting: New Quaternary research in the Uinta Mountains

  18. Quaternary volcano-lacustrine patterns and palaeobotanical data in southern Armenia

    E-print Network

    Utrecht, Universiteit

    imprints, pollen, insects and mammal bones) are related to major volcanic activity, basaltic flows and tectono-orogenic movements that occurred during the Quaternary period. The recent discovery of indicators

  19. Species-specific responses of Late Quaternary megafauna to climate and humans

    E-print Network

    Lorenzen, Eline D.; Nogué s-Bravo, David; Orlando, Ludovic; Weinstock, Jaco; Binladen, Jonas; Marske, Katharine A.; Ugan, Andrew; Borregaard, Michael K.; Gilbert, M. Thomas P.; Nielsen, Rasmus; Ho, Simon Y.W.; Goegel, Ted; Graf, Kelly E.; Byers, David; Stenderup, Jesper T.; Rasmussen, Morten; Campos, Paula F.; Leonard, Jennifer A.; Koepfli, Klaus-Peter; Froese, Duane; Zazula, Grant; Stafford, Thomas W. Jr.; Aaris-Sø rensen, Kim; Batra, Persaram; Haywood, Alan M.; Singarayer, Joy S.; Valdes, Paul J.; Boeskorov, Gennady; Burns, James A.; Davydov, Sergey P.; Haile, James; Jenkins, Dennis L.; Kosintsev, Pavel; Kuznetsova, Tatyana; Lai, Xulong; Martin, Larry D.; McDonald, H. Gregory; Mol, Dick; Meldgaard, Morten; Munch, Kasper; Stephan, Elisabeth; Sablin, Mikhail; Sommer, Robert S.; Sipko, Taras; Scott, Eric; Suchard, Marc A.; Tikhonov, Alexei; Willerslev, Rane; Wayne, Robert K.; Cooper, Alan; Hofreiter, Michael; Sher, Andrei; Shapiro, Beth; Rahbek, Carsten; Willerslev, Eske

    2014-11-17

    Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary remain contentious. We use ancient DNA, species distribution models and the human fossil record...

  20. Quaternary geologic and geomorphic framework for neotectonic analysis of the northeastern Franklin Mountains, El Paso, Texas 

    E-print Network

    Scherschel, Craig A.

    1995-01-01

    The Quaternary geology and geomorphology of a 45 km2 area along the northeastern Franklin Mountains near El Paso, Texas was characterized as part of a paleoseismic evaluation of the East Franklin Mountains fault. The East Franklin Mountains fault...

  1. Diatom-based Late Quaternary precipitation record for lowland tropical South America 

    E-print Network

    Fitzpatrick, Katharine Anne

    2012-06-25

    The late Quaternary palaeoclimatic history of the lowland Southern Hemisphere Tropics of South America (SHTSA) has been little studied and analysis of key climatic events, such as the Last Glacial Maximum (centred ~ ...

  2. Anthranilamide inhibitors of factor Xa.

    PubMed

    Mendel, David; Marquart, Angela L; Joseph, Sajan; Waid, Philip; Yee, Ying K; Tebbe, Anne Louise; Ratz, Andrew M; Herron, David K; Goodson, Theodore; Masters, John J; Franciskovich, Jeffry B; Tinsley, Jennifer M; Wiley, Michael R; Weir, Leonard C; Kyle, Jeffrey A; Klimkowski, Valentine J; Smith, Gerald F; Towner, Richard D; Froelich, Larry L; Buben, John; Craft, Trelia J

    2007-09-01

    SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays. PMID:17624775

  3. Kinase dysfunction and kinase inhibitors.

    PubMed

    London, Cheryl A

    2013-02-01

    With recent advances in molecular biology, abnormalities in cancer cells that contribute to dysregulation of cell survival and proliferation are being characterized with greater precision. Through this process, key abnormalities in cancer cells involving proteins that regulate signal transduction, migration, mitosis and other critical processes have been identified. Such abnormalities often involve a class of proteins called kinases that act to phosphorylate other proteins in the cell, resulting in activation of these proteins in the absence of appropriate stimulation/regulation. Given their role in tumour biology, substantial effort has been directed at blocking the function of these proteins. Several approaches have been used, including monoclonal antibodies and small molecule inhibitors. While antibodies are primarily directed at cell surface proteins, small molecule inhibitors, also known as kinase inhibitors, target proteins throughout the cell. A variety of kinase inhibitors have been approved for the treatment of human cancers. In some instances, these inhibitors have exhibited significant clinical efficacy, and it is likely that their biological activity will be further enhanced as combination regimens with standard treatment modalities are explored. The use of kinase inhibitors in dogs and cats is relatively recent, although two inhibitors, toceranib (Palladia; Pfizer Animal Health, Madison, NJ, USA) and masitinib (Kinavet; Catalent Pharma Solutions, Somerset, NJ, USA) have been approved by the Federal Drug Administration (USA) for use in dogs. This article reviews the biology of protein kinase dysfunction in human and animal cancers, and the application of specific kinase inhibitors to veterinary cancer patients. PMID:23331696

  4. Biological abatement of cellulase inhibitors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

  5. 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

  6. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes.

    PubMed

    Gudernova, Iva; Vesela, Iva; Balek, Lukas; Buchtova, Marcela; Dosedelova, Hana; Kunova, Michaela; Pivnicka, Jakub; Jelinkova, Iva; Roubalova, Lucie; Kozubik, Alois; Krejci, Pavel

    2016-01-01

    Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation. In contrast, TKI treatment of newborn mice did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. In cell-free kinase assays as well as in vitro and in vivo cell assays, none of the tested TKIs demonstrated selectivity for FGFR3 over three other FGFR tyrosine kinases. In addition, the TKIs exhibited significant off-target activity when screened against a panel of 14 unrelated tyrosine kinases. This was most extensive in SU5402 and AZD1480, which inhibited DDR2, IGF1R, FLT3, TRKA, FLT4, ABL and JAK3 with efficiencies similar to or greater than those for FGFR. Low target specificity and toxicity of FGFR TKIs thus compromise their use for treatment of ACH. Conceptually, different avenues of therapeutic FGFR3 targeting should be investigated. PMID:26494904

  7. Intravenous proton pump inhibitors.

    PubMed

    Baker, Danial E

    2006-01-01

    Intravenous (IV) administration of a proton pump inhibitor (PPI) is a faster way to achieve gastric acid suppression than oral administration of the same agent. Peak suppression after IV administration occurs within hours, compared with several days later after oral administration. Thus the IV route of administration offers a faster onset of gastric suppression, achievement of intragastric pH closer to neutrality, and better bioavailability. The PPIs that have IV formulations in the United States (esomeprazole, lansoprazole, and pantoprazole) are approved for different indications; the key differences among them relate to their ability to reach specific gastric pH, time to maintain a specific gastric pH, and ease of use of the IV formulation (eg, reconstitution, requirement of inline filters, infusion times). PMID:16520709

  8. 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

  9. The Quaternary impact record from the Pampas, Argentina

    NASA Astrophysics Data System (ADS)

    Schultz, Peter H.; Zárate, Marcelo; Hames, Bill; Koeberl, Christian; Bunch, Theodore; Storzer, Dieter; Renne, Paul; Wittke, James

    2004-03-01

    Loess-like deposits cover much of central Argentina and preserve a rich record of impacts since the late Miocene. The present contribution focuses on two localities containing Quaternary impact glasses: along the coastal sequences near Centinela del Mar (CdM) and from near Rio Cuarto (RC). These highly vesicular glasses contain clear evidence for an impact origin including temperatures sufficient to melt most mineral constituents (1700°C) and to leave unique quench products such as ?-cristobolite. The CdM glasses occur within a relatively narrow horizon just below a marine transgression expressed by a series of coastal paleo-dunes and systematic changes in the underlying sediments. High-resolution 40Ar/39Ar dating methods yielded an age of 445±21 ka (2?). Glasses were also recovered from scattered occurrences lower in the section but were dated to 230±40 ka. This inconsistency between stratigraphic and radiometric age is most likely related to a nearby outcrop of glass that had been exposed and locally re-deposited in coastal lagoons during the last marine transgression at 125 ka. Sediments containing the original impact glass layer are now missing due to an unconformity, perhaps related to subsequent marine transgressions after the impact (410 ka and 340 ka) and hiatuses in deposition. Two different types of impact glasses from RC yield two distinct dates. High-resolution 40Ar/39Ar dating of fresher-appearing glasses (well-preserved tachylitic sheen) indicates an age of 6±2 ka (2?). Independent fission track analyses yielded a similar age of 2.3±1.6 ka (2?). More weathered glasses, however, gave significantly older ages of 114±26 ka (2?). Consequently, materials from two separate Quaternary impacts have been recovered at Rio Cuarto. The younger glasses are consistent with previously reported carbon dates for materials on the floor of one of the large elongate structures. The depths of excavation for the RC and CdM impacts are very different. While the RC glasses are largely derived from near-surface materials, the CdM glasses from the upper level contain added components consistent with Miocene marine evaporites at a depth of about 400-500 m (e.g., high CaO and P2O5). The CdM glasses also incorporated older loess-like sediments from depth based on the geochemistry. Several ratios of key trace and rare earth elements of sediments of different ages from the Miocene to the Holocene indicate a systematic compositional change through time. Such changes calibrate the observed differences in glass composition from their host sediments and further indicate incorporation of materials from depth. Consequently, the Argentine loess-like sediments preserve evidence for at least four separate Quaternary impacts. Based on foreign components in the glasses, the CdM impact very likely produced a crater (now buried or eroded) once as large as 6 km in diameter. The younger RC glasses, however, are consistent with shallower excavation consistent with an oblique impact.

  10. Identification of the Chemical Bonding Prompting Adhesion of a-C:H Thin Films on Ferrous Alloy Intermediated by a SiCx:H Buffer Layer.

    PubMed

    Cemin, F; Bim, L T; Leidens, L M; Morales, M; Baumvol, I J R; Alvarez, F; Figueroa, C A

    2015-07-29

    Amorphous carbon (a-C) and several related materials (DLCs) may have ultralow friction coefficients that can be used for saving-energy applications. However, poor chemical bonding of a-C/DLC films on metallic alloys is expected, due to the stability of carbon-carbon bonds. Silicon-based intermediate layers are employed to enhance the adherence of a-C:H films on ferrous alloys, although the role of such buffer layers is not yet fully understood in chemical terms. The chemical bonding of a-C:H thin films on ferrous alloy intermediated by a nanometric SiCx:H buffer layer was analyzed by X-ray photoelectron spectroscopy (XPS). The chemical profile was inspected by glow discharge optical emission spectroscopy (GDOES), and the chemical structure was evaluated by Raman and Fourier transform infrared spectroscopy techniques. The nature of adhesion is discussed by analyzing the chemical bonding at the interfaces of the a-C:H/SiCx:H/ferrous alloy sandwich structure. The adhesion phenomenon is ascribed to specifically chemical bonding character at the buffer layer. Whereas carbon-carbon (C-C) and carbon-silicon (C-Si) bonds are formed at the outermost interface, the innermost interface is constituted mainly by silicon-iron (Si-Fe) bonds. The oxygen presence degrades the adhesion up to totally delaminate the a-C:H thin films. The SiCx:H deposition temperature determines the type of chemical bonding and the amount of oxygen contained in the buffer layer. PMID:26135943

  11. Antidepressants and Cdk inhibitors

    PubMed Central

    Chesnokova, Vera; Pechnick, Robert N.

    2010-01-01

    It is now clear that neurogenesis occurs in the brain of adult mammals. Many studies have attempted to establish relationships among neurogenesis, depression and the mechanism of action of antidepressant drugs. Therapeutic effects of antidepressants appear to be linked to increased neurogenesis in the hippocampus. Cdk inhibitors are expressed in multiple brain regions, presumably maintaining quiescence in differentiated neurons. Recently, the abundant expression of p21Cip1 was found in neuroblasts and in newly developing neurons in the subgranular zone of the hippocampus, a region where adult neurogenesis occurs. Chronic treatment with the tricyclic antidepressant imipramine markedly decreased p21Cip1 mRNA and protein levels and stimulated neurogenesis in this region. These results suggest that p21Cip1 restrains neurogenesis in the hippocampus, and antidepressant-induced stimulation of neurogenesis might be a consequence of decreased p21Cip1 expression, with the subsequent release of neuronal progenitor cells from the blockade of proliferation. These findings suggest the potential for new therapeutic strategies for the treatment of depression that target cell cycle proteins. However, there is a possibility that long-term stimulation of neurogenesis might exhaust the proliferation potentials of neuronal progenitors. PMID:18682686

  12. Quaternary benzyltriethylammonium ion binding to the Na,K-ATPase: a tool to investigate extracellular K+ binding reactions.

    PubMed

    Peluffo, R Daniel; González-Lebrero, Rodolfo M; Kaufman, Sergio B; Kortagere, Sandhya; Orban, Branly; Rossi, Rolando C; Berlin, Joshua R

    2009-09-01

    This study examined how the quaternary organic ammonium ion, benzyltriethylamine (BTEA), binds to the Na,K-ATPase to produce membrane potential (V(M))-dependent inhibition and tested the prediction that such a V(M)-dependent inhibitor would display electrogenic binding kinetics. BTEA competitively inhibited K(+) activation of Na,K-ATPase activity and steady-state (86)Rb(+) occlusion. The initial rate of (86)Rb(+) occlusion was decreased by BTEA to a similar degree whether it was added to the enzyme prior to or simultaneously with Rb(+), a demonstration that BTEA inhibits the Na,K-ATPase without being occluded. Several BTEA structural analogues reversibly inhibited Na,K-pump current, but none blocked current in a V(M)-dependent manner except BTEA and its para-nitro derivative, pNBTEA. Under conditions that promoted electroneutral K(+)-K(+) exchange by the Na,K-ATPase, step changes in V(M) elicited pNBTEA-activated ouabain-sensitive transient currents that had similarities to those produced with the K(+) congener, Tl(+). pNBTEA- and Tl(+)-dependent transient currents both displayed saturation of charge moved at extreme negative and positive V(M), equivalence of charge moved during and after step changes in V(M), and similar apparent valence. The rate constant (k(tot)) for Tl(+)-dependent transient current asymptotically approached a minimum value at positive V(M). In contrast, k(tot) for pNBTEA-dependent transient current was a "U"-shaped function of V(M) with a minimum value near 0 mV. Homology models of the Na,K-ATPase alpha subunit suggested that quaternary amines can bind to two extracellularly accessible sites, one of them located at K(+) binding sites positioned between transmembrane helices 4, 5, and 6. Altogether, these data revealed important information about electrogenic ion binding reactions of the Na,K-ATPase that are not directly measurable during ion transport by this enzyme. PMID:19621894

  13. Causal link between Quaternary paleoclimatic changes and volcanic islands evolution

    NASA Astrophysics Data System (ADS)

    Quidelleur, X.; Hildenbrand, A.; Samper, A.

    2006-12-01

    High precision radiometric ages of large-volume volcanic flank collapses indicate a causal relationship between the evolution of volcanic islands from different geodynamic contexts and global climatic changes. We present a compilation of previously well-dated events within the last 1 Myr from Tahiti, Hawaii, Canary Islands, together with new ages from Guadeloupe and Martinique (Lesser Antilles). Ages of major flank collapses show a strong correlation with Quaternary climate changes evidenced by a global stack of benthic d18O records. Effectively, most collapses occurred within a glacial to interglacial termination. The ages reported here favor the hypothesis that for the last 900 kyr major flank collapse events occurred during the onset of glacial to interglacial transitions when a sudden influx of melt water from polar ice caps results in rapid sea level rise. Thus, it can be inferred that, when geological causes such as regional tectonics or edifice strength reduction due to volcanic processes are also present, rapid sea level rise can favor large mass wasting events. We propose that following a sub aerial erosion interval during low sea level stands, rapid sea level rise induces enhanced coastal erosion and sudden changes of pore pressure conditions within basal layers, which favor edifice failure. Since these events can trigger tsunamis and can initiate periods of increased volcanic activity, we show here that global warming may result in an increased likelihood of certain geologic hazards, such as large landslides of up to several hundreds cubic kilometers.

  14. Liquid chromatography of hydrocarbonaeous quaternary amines on cyclodextrin bonded silica

    USGS Publications Warehouse

    Abidi, S.L.

    1986-01-01

    Mixtures of n-alkylbenzyldimethylammonium chloride (ABDAC) were resolved into homologous components by high-performance liquid chromatography (HPLC) with a cyclodextrin-bonded silica stationary phase. With a few exceptions, results from this study are similar to those obtained from traditional reversed-phase HPLC. It was found that the presence of electrolytes in aqueous mobile phases is not a critical factor in determining the success of HPLC separation. Under normal HPLC conditions, a mobile phase consisting of either methanol–water (50:50) or acetonitrile–water (30:70) was employed for obtaining adequate resolution of the quaternary ammonium mixtures. Although the percent organic modifier–water profiles were similar to those in previous studies with these compounds, resolution (R) and selectivity (?) parameters were found to be quite susceptible to changes in the mobile phase solvent composition. The retention behavior of the cationic analytes in the homologous series is consistent with the hydrophobic-interaction concept proposed for the retention mechanism via dominant inclusion complex formation. Several electrolytes were chosen for a study of the counter ion effect on the chromatographic characteristics of ABDAC components. Among the electrolytes examined, the perchlorate ion was found most likely to act as an ion-pairing counter ion for ammonium cations in the HPLC system studied. A correlation study established linear relationships between the chain length of ABDAC and the logarithmic capacity factor (k2). The analytical utility of the HPLC method was demonstrated by the analysis of various unknown mixtures.

  15. Effects of late quaternary climate change on Palearctic shrews.

    PubMed

    Prost, Stefan; Klietmann, Johannes; van Kolfschoten, Thijs; Guralnick, Robert P; Waltari, Eric; Vrieling, Klaas; Stiller, Mathias; Nagel, Doris; Rabeder, Gernot; Hofreiter, Michael; Sommer, Robert S

    2013-06-01

    The Late Quaternary was a time of rapid climatic oscillations and drastic environmental changes. In general, species can respond to such changes by behavioral accommodation, distributional shifts, ecophenotypic modifications (nongenetic), evolution (genetic) or ultimately face local extinction. How those responses manifested in the past is essential for properly predicting future ones especially as the current warm phase is further intensified by rising levels of atmospheric carbon dioxide. Here, we use ancient DNA (aDNA) and morphological features in combination with ecological niche modeling (ENM) to investigate genetic and nongenetic responses of Central European Palearctic shrews to past climatic change. We show that a giant form of shrew, previously described as an extinct Pleistocene Sorex species, represents a large ecomorph of the common shrew (Sorex araneus), which was replaced by populations from a different gene-pool and with different morphology after the Pleistocene Holocene transition. We also report the presence of the cold-adapted tundra shrew (S. tundrensis) in Central Europe. This species is currently restricted to Siberia and was hitherto unknown as an element of the Pleistocene fauna of Europe. Finally, we show that there is no clear correlation between climatic oscillations within the last 50 000 years and body size in shrews and conclude that a special nonanalogous situation with regard to biodiversity and food supply in the Late Glacial may have caused the observed large body size. PMID:23505017

  16. Patterns of late Quaternary shelf-margin sedimentation, southwest Louisiana

    SciTech Connect

    Suter, J.R.; Berryhill, H.L.

    1986-09-01

    Late Quaternary extension of the continental shelf in the northern Gulf of Mexico has been largely accomplished by deposition at the shelf margin during sea level lowstands. The distribution and geometry of facies suggest that delta progradation during sea level fall and lowstand is a principal process for shelf accretion. Along the shelf margin of southwest Louisiana, sets of deltaic deposits corresponding to the last two lowstands of sea level have been mapped from high-resolution seismic profiles. Individual deltas extend farther than 5000 m/sup 2/ and are more than 160 m thick. Diapirism has had a controlling effect on sedimentation patterns of the shelf-margin deltas throughout their depositional histories. Shelf-margin deltas have also been the loci for the transfer of large volumes of sediment from the shelf to the upper slope by mass transport, with buried submarine troughs formed by retrogressive shelf-edge failure in association with major streams acting as conduits for sediment movement. In southwest Louisiana, mass transport deposits follow depressions formed by salt diapirism rather than creating broad aprons on the slope.

  17. Effects of Quaternary Ammonium Chain Length on Antibacterial Bonding Agents

    PubMed Central

    Li, F.; Weir, M.D.; Xu, H.H.K.

    2013-01-01

    The objectives of this study were to synthesize new quaternary ammonium methacrylates (QAMs) with systematically varied alkyl chain lengths (CL) and to investigate, for the first time, the CL effects on antibacterial efficacy, cytotoxicity, and dentin bond strength of bonding agents. QAMs were synthesized with CL of 3 to 18 and incorporated into Scotchbond Multi-Purpose (SBMP) bonding agent. The cured resins were inoculated with Streptococcus mutans. Bacterial early attachment was investigated at 4 hrs. Biofilm colony-forming units (CFU) were measured after 2 days. With CL increasing from 3 to 16, the minimum inhibitory concentration and minimum bactericidal concentration were decreased by 5 orders of magnitude. Incorporating QAMs into SBMP reduced bacterial early attachment, with the least colonization at CL = 16. Biofilm CFU for CL = 16 was 4 log lower than SBMP control (p < .05). All groups had similar dentin bond strengths (p > .1). The new antibacterial materials had fibroblast/odontoblast viability similar to that of commercial controls. In conclusion, increasing the chain length of new QAMs in bonding agents greatly increased the antibacterial efficacy. A reduction in Streptococcus mutans biofilm CFU by 4 log could be achieved, without compromising bond strength and cytotoxicity. New QAM-containing bonding agents are promising for a wide range of restorations to inhibit biofilms. PMID:23958761

  18. Ligand exchange in quaternary alloyed nanocrystals--a spectroscopic study.

    PubMed

    Gabka, Grzegorz; Bujak, Piotr; Giedyk, Kamila; Kotwica, Kamil; Ostrowski, Andrzej; Malinowska, Karolina; Lisowski, Wojciech; Sobczak, Janusz W; Pron, Adam

    2014-11-14

    Exchange of initial, predominantly stearate ligands for pyridine in the first step and butylamine (BA) or 11-mercaptoundecanoic acid (MUA) in the second one was studied for alloyed quaternary Cu-In-Zn-S nanocrystals. The NMR results enabled us to demonstrate, for the first time, direct binding of the pyridine labile ligand to the nanocrystal surface as evidenced by paramagnetic shifts of the three signals attributed to its protons to 7.58, 7.95 and 8.75 ppm. XPS investigations indicated, in turn, a significant change in the composition of the nanocrystal surface upon the exchange of initial ligands for pyridine, which being enriched in indium in the 'as prepared' form became enriched in zinc after pyridine binding. This finding indicated that the first step of ligand exchange had to involve the removal of the surface layer enriched in indium with simultaneous exposure of a new, zinc-enriched layer. In the second ligand exchange step (replacement of pyridine with BA or MUA) the changes in the nanocrystal surface compositions were much less significant. The presence of zinc in the nanocrystal surface layer turned out necessary for effective binding of pyridine as shown by a comparative study of ligand exchange in Cu-In-Zn-S, Ag-In-Zn-S and CuInS2, carried out by complementary XPS and NMR investigations. PMID:25252174

  19. Quaternary geochronology using the U-Th-Pb method

    SciTech Connect

    Getty, S.R.; DePaolo, D.J.

    1995-08-01

    We describe a method of uranium-thorium-lead (U-Th-Pb) isotopic age dating for Quaternary rocks. The approach uses an instrumental mass discrimination correction for lead isotope ratios, which allows small enrichments of radiogenic {sup 206}Pb and {sup 208}Pb to be detected at the level of 0.001%. Igneous rocks hosting minerals with a range in {sup 238}U/{sup 204}Pb values of 100 can be dated with uncertainties of approximately {+-}15-20 kyr. A Quarternary rhyolite dated at 1.19 Ma by K-Ar yields a {sup 238}U-{sup 206}Pb age of 1.03{+-}0.10 Ma. A Holocene dacite (9.5 ka) has uniform {sup 206}Pb/{sup 207}Pb to within {+-}0.0015% in groundmass phases, but 1 mm plagioclase phenocrysts have lower {sup 206}Pb/{sup 207}Pb by 0.105{+-}0.002% indicating contamination of the magma after plagioclase crystallization. High precision {sup 206}Pb/{sup 207}Pb ratios may be a useful new tool for petrogenetic studies.

  20. Formation of Late Quaternary paleoshorelines in Crete, Eastern Mediterranean

    NASA Astrophysics Data System (ADS)

    Mouslopoulou, Vasiliki; Begg, John; Nicol, Andrew; Oncken, Onno; Prior, Christine

    2015-12-01

    Paleoshorelines of Late Quaternary age in western Crete do not exclusively increase in age with rising altitude as is generally observed worldwide. At numerous sites, for example, Late-Holocene paleoshorelines decrease in age with increasing altitude while in other cases paleoshorelines at similar altitude vary in age by tens of thousands of years. We propose that the observed paleoshoreline altitude-age relationships can be accounted for by eustatic sea-level changes and tectonic rock uplift without requiring substantial errors on radiocarbon ages or tectonic subsidence, as has been previously proposed. To test this model we use a dataset consisting of altitude and age data for 71 individual paleoshorelines sampled from 21 sites distributed along the entire Cretan coastline. These data include radiocarbon ages of marine biota (40 new dates) within beachrock resting on paleoshorelines ranging up to 48 kyr BP in age and ?20 m above present sea-level. We find that paleoshoreline formation reflects Late Holocene tectonic rock uplift in western Crete, preceded by eustatic sea-level rise and by >10 kyr BP rock uplift along the entire island. Our observations contravene existing models as they suggest that some paleoshorelines, and their associated lithified beachrock, survived passage through the wave-zone multiple times and formed throughout the sea-level cycle (i.e., preservation is not restricted to highstand deposits). These results may have application globally in regions where erosion-resistant carbonate beachrock mantles paleoshorelines.

  1. Carnivore size and quaternary climatic change in southern Africa

    NASA Astrophysics Data System (ADS)

    Klein, Richard G.

    1986-07-01

    The relationship between carnassial length and latitude south is analyzed for 17 African carnivore species to determine if individuals tend to be larger in cooler climates, as predicted by Bergmann's Rule. With modern data in support, middle and late Quaternary temperatures might then be inferred from mean carnassial length in fossil samples, such as those from Equus Cave, Elandsfontein, Sea Harvest. Duinefontein, and Swartklip in the Cape Province of South Africa. One problematic aspect of the study is the use of carnassial length and latitude as necessary but imperfect substitutes for body size and temperature, respectively. For some species, another difficulty is the relatively small number of available modern specimens, combined with their uneven latitudinal spread. Still, in 14 of the species, carnassial length does tend to increase with latitude south, while mean carnassial length in the same species tends to be greater in those fossil samples which accumulated under relatively cool conditions, as inferred from sedimentologic, palynological, or geochemical data. Given larger modern samples from a wide variety of latitudes, refinement of the mathematical relationship between carnassial length and latitude in various species may even permit quantitative estimates of past temperatures in southern Africa.

  2. Kinetics of synthesizing polymer-supported quaternary ammonium catalysts.

    PubMed

    Wu, Ho-Shing; Lo, Chi-Wei

    2006-01-01

    This study attempted to synthesize the optimum quaterary ammonium poly(styrene-co-methylstyrene) catalyst using the combinatorial chemistry method. The catalyst was synthesized by a mix-split method. A phase-transfer catalyst library with 25 kinds of polystyrene-supported quaternary ammonium salt catalyst was the the result of the reaction of five kinds of chloromethylated crosslinked polystyrene with five tert-amines. The allylation of phenol and the oxidation of benzyl alcohol were used as the probing reaction to screen out the most active catalyst for the reaction using the iterative deconvolution method. The screening conditions included teritary amine and organic solvent. The structure of the most active catalyst in the allylation of phenol shows 20 mol % ring substitution and 0.177-0.25-mm pellet size activated with trihexylamine. For oxidation of benzyl alcohol, the reaction conditions of the most active catalyst included a resin of 20% ring substitution and pellet size of 0.177-0.25 mm, activated with triethylamine reacting in an organic solvent of n-hexane. PMID:17096574

  3. Interhemispheric dynamics of the African rainbelt during the late Quaternary

    NASA Astrophysics Data System (ADS)

    Singarayer, Joy S.; Burrough, Sallie L.

    2015-09-01

    The spatial pattern of precipitation variability in tropical and subtropical Africa over the late Quaternary has long been debated. Prevailing hypotheses variously infer (1) insolation-controlled asymmetry of wet phases between hemispheres, (2) symmetric contraction and expansion of the tropical rainbelt, and (3) independent control on moisture available in Southern Africa via sea surface temperatures in the Indian Ocean. In this study we use climate-model simulations covering the last glacial cycle (120 kyr) with HadCM3 and the multi-model ensembles from PMIP3 (the Palaeoclimate Model Intercomparison Project) to investigate the long-term behaviour of the African rainbelt, and test these simulations against existing empirical palaeohydrological records. Through regional model-data comparisons we find evidence for the validity of several hypotheses, with various proposed processes occurring concurrently but with different regional emphasis (e.g. asymmetric shifts at the seasonal extremes and symmetric expansions/contractions towards West equatorial regions). Crucially, variations in rainfall are associated with multiple forcing mechanisms that vary in their dominance both spatially and temporally over the glacial cycle; an important consideration when interpreting and extrapolating from often relatively short palaeoenvironmental records.

  4. Late Quaternary environments, vegetation and agriculture in northern New Zealand

    NASA Astrophysics Data System (ADS)

    Horrocks, M.; Nichol, S. L.; Augustinus, P. C.; Barber, I. G.

    2007-03-01

    A sedimentological and plant microfossil history of the Late Quaternary is preserved in two sediment cores from early Polynesian ditch systems on southern Aupouri Peninsula. The study places human activities into a geomorphological and ecological context and allows comparison of natural and anthropogenic effects on two different geological settings: a floodplain and a relatively closed peat swamp. The data fill part of the current gap in the environmental record from northern New Zealand, namely MIS 3 (57k-26k yr BP). There is evidence for an increase in fire frequency in the region after 40k 14C yr BP, suggesting a shift to drier (and cooler) conditions. Pollen records show that conifer-hardwood forest dominated by podocarps (especially Dacrydium) prevailed prior to Polynesian arrival and deforestation within the last millennium, with Fuscopsora insignificant throughout. Both cores show sections with gaps in deposition or preservation, possible flood-stripping of peat during the pre-Holocene and mechanical disturbance by early Polynesians. The identification of prehistoric starch grains and other microremains of introduced Colocasia esculenta (taro) in both cores supports indirect evidence that the ditch systems of far northern New Zealand were used for the extensive cultivation of this crop. Copyright

  5. Regulated assembly and disassembly of the yeast telomerase quaternary complex

    PubMed Central

    Tucey, Timothy M.

    2014-01-01

    The enzyme telomerase, which elongates chromosome termini, is a critical factor in determining long-term cellular proliferation and tissue renewal. Hence, even small differences in telomerase levels can have substantial consequences for human health. In budding yeast, telomerase consists of the catalytic Est2 protein and two regulatory subunits (Est1 and Est3) in association with the TLC1 RNA, with each of the four subunits essential for in vivo telomerase function. We show here that a hierarchy of assembly and disassembly results in limiting amounts of the quaternary complex late in the cell cycle, following completion of DNA replication. The assembly pathway, which is driven by interaction of the Est3 telomerase subunit with a previously formed Est1–TLC1–Est2 preassembly complex, is highly regulated, involving Est3-binding sites on both Est2 and Est1 as well as an interface on Est3 itself that functions as a toggle switch. Telomerase subsequently disassembles by a mechanistically distinct pathway due to dissociation of the catalytic subunit from the complex in every cell cycle. The balance between the assembly and disassembly pathways, which dictate the levels of the active holoenzyme in the cell, reveals a novel mechanism by which telomerase (and hence telomere homeostasis) is regulated. PMID:25240060

  6. Quaternary heteroaromatic salts with prophylactic and antidotal activity towards soman

    SciTech Connect

    Sundberg, R.J.; Dalvie, D.; Cordero, J.; Sabat, M.

    1993-05-13

    A series of quaternary heteroaromatic salts has been prepared and evaluated for prophylactic and antidotal activity towards the lethal toxicity of soman. One series of compounds contains 2-, 3-, or 4-(dimethylaminocarbonyloxy)phenoxymethyl substituents at the 2 position of the following rings: 1,3-dimethylimidazolium, 1-methylpyridinium, 1-methylquinolinium, 1,3-dimethylbenzimidazolium and 1-methylimidazo1,2-Apyridinium. The compounds were evaluated both in vitro, by determining the IC50 for electric eel acetylcholinesterase, and in vivo, using both antidotal and prophylactic assays in mice. Compound 2b was most active in the in vitro assay (IC50 = 0.01 M). However, its toxicity is high and compound la is more effective in vivo with 80-100% protective activity against 2 LD50 of soman at 6.2 to 62.5 mg/kg. A second series of compounds consisted of 6-substituted 2'-, 3'-, and 4'-(dimethylaminocarbonyloxy) phenylimidazo (1,2-a) pyridinium salts (8).

  7. Quaternary glaciation of the Tashkurgan Valley, Southeast Pamir

    NASA Astrophysics Data System (ADS)

    Owen, Lewis A.; Chen, Jie; Hedrick, Kathyrn A.; Caffee, Marc W.; Robinson, Alexander C.; Schoenbohm, Lindsay M.; Yuan, Zhaode; Li, Wenqiao; Imrecke, Daniel B.; Liu, Jinfeng

    2012-07-01

    The Quaternary glacial history of Tashkurgan valley, in the transition between the Pamir and Karakoram, in Xinjiang Province, China was examined using remote sensing, field mapping, geomorphic analysis of landforms and sediments, and 10Be terrestrial cosmogenic nuclide dating. Moraines were assigned to four glacial stages: 1) the Dabudaer glacial stage that dates to the penultimate glacial cycle and/or earlier, and may represent one or more glaciations; 2) the Tashkurgan glacial stage that dates to early last glacial, most likely Marine Oxygen Isotope Stage (MIS) 4; 3) the Hangdi glacial stage that dates to MIS 2, possibly early MIS 2; and 4) the Kuzigun glacial stage that dates to the MIS 2, possibly the global Last Glacial Maximum, and is younger than the Hangdi glacial stage. Younger moraines and rock glaciers are present at the heads of tributary valleys; but these were inaccessible because they are located close to politically sensitive borders with Pakistan, Afghanistan and Tajikistan. Glaciers during the Dabudaer glacial stage advanced into the central part of the Tashkurgan valley. During the Tashkurgan glacial stages, glaciers advanced several kilometers beyond the mouths of the tributary valleys into the Tashkurgan valley. Glaciers during the Hangdi and Kuzigun glacial stages advanced just beyond the mouths of the tributary valleys. Glaciation in this part of the Himalayan-Tibetan orogen is likely strongly controlled by northern hemisphere climate oscillations, although a monsoonal influence on glaciation cannot be ruled out entirely.

  8. Latest quaternary volcanism in the St. George Basin, southwestern Utah

    SciTech Connect

    Millings, V.T. III; Green, J.D.; Nusbaum, R.L. . Dept. of Geology)

    1993-03-01

    The St. George Basin was the site of mafic volcanism from about 6 Ma to 1 ka. The nature of latest Quaternary volcanism is of interest because the Basin is recognized as a low temperature (< 90C) geothermal resource area and it is part of the transition zone between the Basin and Range Province and the Colorado Plateau. The authors have studied the geochemistry, mineralogy, and aerial distribution of two of the youngest eruptions centers: (1) Veyo Volcano; and (2) the Diamond Valley scoria cones (DVSC). Veyo Volcano erupted basaltic andesite, beginning with an explosive stage marked by a 0.5 m basal Plinian layer. Later eruptions alternated between quiescent and Strombolian-styles. Phenocrysts include clear plagioclase, sieve-texture plagioclase, olivine and rare augite. The DVSC and associated Santa Clara lava flow are tholeiitic basalt, consisting of olivine phenocrysts, and rare plagioclase phenocrysts. Based on preliminary geochemical data, Diamond Valley rocks exhibit lower incompatible element ratios compared to mafic rocks on the Markagunt Plateau and transition zone rocks. In contrast, Veyo Volcano rocks are similar to transition zone mafic rocks with regard to incompatible element abundances.

  9. A Quaternary volcanic ash deposit in western Missouri

    SciTech Connect

    Emerson, J.W. )

    1993-03-01

    Quaternary volcanic ash has been found in more than fifty localities in the midwest. The most widespread deposits originated from the Long Valley caldera, California; the Jemez calderas, New Mexico; or the Yellowstone caldera, Wyoming. Fission track dating has grouped the deposits into six separate ash falls ranging from 700,000--2,000,000 years old. A small volcanic ash deposit in western Missouri may be correlative with those found along the Kansas and Marais de Cygnes rivers in eastern Kansas. The ash deposit is in Northwest Bates County Missouri, exposed along a tributary to Miami Creek, four miles east of the Kansas state line. The ash layer is interbedded with alluvial terrace deposits and ranges from fifteen to thirty inches in thickness. It is inferred to have been deposited in a pond or oxbow lake. The color is white with a pale yellow tinge (Munsell 10YR 8/2). Shard examination shows that about 70% are flat bubble-wall types, about 20% have straight ridges, less than 10% are bubble-junction, and only a trace are vesicular. The closest known volcanic ash occurrence is an ash outcropping in a Kansas river terrace near DeSoto, KS, forty-five miles to the northwest. The DeSoto deposit has been identified as the .62 m.y. Lava Creek B ash from the Yellowstone caldera. A preliminary correlation of the Missouri ash with the DeSoto ash is based on similar shard morphology and color.

  10. Cellular uptake of polyurethane nanocarriers mediated by gemini quaternary ammonium.

    PubMed

    Ding, Mingming; He, Xueling; Wang, Zhigao; Li, Jiehua; Tan, Hong; Deng, Hua; Fu, Qiang; Gu, Qun

    2011-12-01

    The effective passage of drug formulations into tumor cells is a key factor in the development of nanoscale delivery systems. However, rapid cellular uptake with reduced toxicity remains a great challenge for efficient and safe delivery. In this study, we first use gemini quaternary ammonium (GQA) as a cell internalization promoter to enhance the cellular uptake of drug nanocarriers. It is found that a twenty times faster cell internalization could be achieved by introducing GQA into biodegradable multiblock polyurethane nanomicelles, as confirmed by flow cytometry and confocal laser scanning microscopy (CLSM) studies. Meanwhile, an added methoxyl-poly(ethylene glycol) (mPEG) outer corona could protect these cationic micelles from cytotoxicity at high concentrations, as verified by methyl tetrazolium (MTT) assay. Moreover, GQA not only acts as an enhancer for rapid cellular entry, but also plays an important role in controlled self-assembly and high drug loading capacity. Our work offers a new understanding on the role of cationic surfactants; and provides a facile and economical approach for the design of versatile drug nanocarriers to achieve efficient delivery and good biocompatibility. PMID:21907404

  11. Coupled micromorphological and stable isotope analysis of Quaternary calcrete development

    NASA Astrophysics Data System (ADS)

    Adamson, Kathryn; Candy, Ian; Whitfield, Liz

    2015-09-01

    Pedogenic calcretes are widespread in arid and semi-arid regions. Using calcrete profiles from four river terraces of the Rio Alias in southeast Spain, this study explores the potential of using detailed micromorphological and stable isotopic analysis to more fully understand the impacts of Quaternary environmental change on calcrete development. The four profiles increase in carbonate complexity with progressive age, reflecting calcretisation over multiple glacial-interglacial cycles since MIS 9 (c. 300 ka). Calcrete profiles contain a mixture of Alpha (non-biogenic) and Beta (biogenic) microfabrics. Alpha fabrics have higher ?13C and ?18O values. The profiles contain a range of crystal textures, but there is little difference between the ?13C and ?18O values of spar, microspar, and micrite cements. Strong positive covariance between ?13C and ?18O suggests that both isotopes are responding to the same environmental parameter, which is inferred to be relative aridity. The study reveals that the detailed co-analysis of calcrete micromorphology and stable isotope signatures can allow patterns of calcrete formation to be placed into a wider palaeoclimatic context. This demonstrates the potential of this technique to more reliably constrain the palaeoenvironmental significance of secondary carbonates in dryland settings where other proxy records may be poorly preserved.

  12. Interaction of ochratoxin A with quaternary ammonium beta-cyclodextrin.

    PubMed

    Poór, Miklós; Kunsági-Máté, Sándor; Szente, Lajos; Matisz, Gergely; Secenji, Györgyi; Czibulya, Zsuzsanna; K?szegi, Tamás

    2015-04-01

    Ochratoxin A (OTA) is a widely spread nephrotoxic food contaminant mycotoxin. Unfortunately, attenuation or prevention of the toxic effects of OTA is still an unresolved problem. Molecular inclusion of OTA by cyclodextrins (CDs) results in complexes with low stability. In the human organism, OTA exists mostly in the dianionic state (OTA(2-)). Therefore, our major goal was to develop a chemically modified cyclodextrin which gives a more stable complex with OTA than the previously published derivatives and which shows stronger preference towards OTA(2-). In our fluorescence spectroscopic study we demonstrate that quaternary ammonium beta-cyclodextrin (QABCD) fulfils both of these requirements. The calculated stability constant of the QABCD-OTA(2-) complex was 28,840 M(-1) (about 200-fold higher than that of the ?-CD-OTA(2-) complex). We hypothesize, that QABCD may be a suitable tool for the decontamination of different OTA-contaminated drinks; furthermore, for alleviation of the toxic effects of OTA, such complex formation may reduce its absorption from the intestine. PMID:25442535

  13. Late Quaternary sea-level changes of the Persian Gulf

    NASA Astrophysics Data System (ADS)

    Lokier, Stephen W.; Bateman, Mark D.; Larkin, Nigel R.; Rye, Philip; Stewart, John R.

    2015-07-01

    Late Quaternary reflooding of the Persian Gulf climaxed with the mid-Holocene highstand previously variously dated between 6 and 3.4 ka. Examination of the stratigraphic and paleoenvironmental context of a mid-Holocene whale beaching allows us to accurately constrain the timing of the transgressive, highstand and regressive phases of the mid- to late Holocene sea-level highstand in the Persian Gulf. Mid-Holocene transgression of the Gulf surpassed today's sea level by 7100-6890 cal yr BP, attaining a highstand of > 1 m above current sea level shortly after 5290-4570 cal yr BP before falling back to current levels by 1440-1170 cal yr BP. The cetacean beached into an intertidal hardground pond during the transgressive phase (5300-4960 cal yr BP) with continued transgression interring the skeleton in shallow-subtidal sediments. Subsequent relative sea-level fall produced a forced regression with consequent progradation of the coastal system. These new ages refine previously reported timings for the mid- to late Holocene sea-level highstand published for other regions. By so doing, they allow us to constrain the timing of this correlatable global eustatic event more accurately.

  14. New urethane oligodimethacrylates with quaternary alkylammonium for formulating dental composites.

    PubMed

    Buruiana, Tinca; Melinte, Violeta; Popa, Ionela D; Buruiana, Emil C

    2014-04-01

    The aim of this study was to prepare urethane dimethacrylates containing quaternary alkyl (C16, C12) ammonium and polyethylene glycol short sequences (Mn, 400 g/mol) and to investigate their behaviour in some experimental formulations in order to evaluate their potential applicability in the dental composites field. The structure of urethane dimethacrylates has been confirmed by (1)H ((13)C) NMR and FTIR spectra, as well as by electrospray ionization tandem mass spectroscopy, and gel permeation chromatography measurements. The effects of the cationic macromers on the properties of the filled/non-filled composites were examined through FTIR, photoDSC, and specific measurements as volumetric polymerization shrinkage, water sorption/solubility, contact angle, mechanical parameters, and morphology. The monomer compositions based on cationic dimethacrylate (6.88-27.52 wt%), BisGMA-analogue (48.18-68.82 wt%) and TEGDMA (23.3 wt%) showed a good photoreactivity in terms of double bond conversion (DC, 50.07-68.81 %) and polymerization rate (Rp, 0.099-0.141 s(-1)) measured by photoDSC compared to a control sample (BisGMA-1/TEGDMA: DC, 45.91 %; Rp, 0.162 s(-1)), while the polymerization shrinkage increased in acceptable limits (5.37-7.74 vol%). The mechanical properties (compressive, flexural and diametral tensile strength) of the composite resin incorporating 70 wt% silanized zirconium silicate micro/nanopowder can be modulated by the initial co-monomer concentrations. PMID:24435527

  15. Radiolysis of simple quaternary ammonium salt components of Amberlite resin

    NASA Astrophysics Data System (ADS)

    Dhiman, Surajdevprakash B.; LaVerne, Jay A.

    2013-05-01

    The radiation chemical yields of gaseous products, H2 and CH4, in the radiolysis of dry methylammonium chloride, dimethylammonium chloride, trimethylammonium chloride, tetramethylammonium chloride and benzyl trimethylammonium chloride by ?-rays and 5 MeV helium ions have been investigated. Some of these amines are the different components of the quaternary ammonium resin Amberlite, which is a strongly basic anion exchange resin based on a polystyrene divinylbenzene copolymer. Molecular hydrogen yields with ?-radiolysis range from a high of 4.43 molecules per 100 eV for trimethylammonium chloride to 0.07 and 0.05 molecules per 100 eV for tetramethylammonium chloride and benzyl trimethylammonium chloride, respectively. Yields of methane gas are generally negligible except for trimethylammonium chloride and tetramethylammonium chloride, 0.26 and 0.02 molecules per 100 eV, respectively. Isotopic labeling studies suggest that the first step in H2 production is the breakage of the Nsbnd H bond followed by abstraction of Hrad atom from the methyl groups. EPR analysis shows the formation of both N and C centered radicals. A comparison is made between the radiolysis of Amberlite and its various components.

  16. Epiguruk: a late Quaternary environmental record from northwestern Alaska

    USGS Publications Warehouse

    Hamilton, T.D.; Ashley, G.M.

    1993-01-01

    Epiguruk, a prominent bluff along the Kobuk River in northwestern Alaska, exposes a rich depositional record of Quaternary eolian and fluvial sand, with associated loess, paleosols, and periglacial features. Three major complexes of alluvial and eolian deposits are separated by two conspicuous organic-rich paleosols which formed during cool-moist interstadial intervals. Sediments between the two paleosols include eolian, channel, and floodplain deposits that formed during alluviation of the Kobuk River to a height of about 12m above the present level. The youngest depositional complex, which overlies the upper paleosol, is divisible into late Wisconsinan and Holocene components and into fluvial-channel, flood-plain, eolian-dune, sand-sheet, loess, and pond facies. Eolian sand from the active Kobuk sand sea overloaded the river during late Wisconsinan time, causing it to alluviate to about 13m above its modern level. The Holocene record reflects erosion and deposition by a small southern Tributary to the Kobuk River, downcutting by the Kobuk River toward its modern level, and subsequent erosion across a meander belt nearly 8km wide. 66 radiocarbon ages, many from rooted shrubs, provide a firm chronology for the past 35 k.y. at Epiguruk. -from Authors

  17. Quaternary geology of the Rhode Island inner shelf

    USGS Publications Warehouse

    Needell, S. W.; O'Hara, C. J.; Knebel, H. J.

    1983-01-01

    Five sedimentary units and three erosional unconformities identified in high-resolution seismic-reflection profiles reveal the stratigraphic framework and Quaternary history of the inner continental shelf south of Narragansett Bay, Rhode Island. Late Tertiary to early Pleistocene rivers eroded the pre-Mesozoic bedrock and the Upper Cretaceous to lower Tertiary coastal plain and continental shelf strata to form a lowland and cuesta having a north-facing escarpment. The lowland and landward flanks of the cuesta were modified by glaciers during Pleistocene time and subsequently were overlain by drift and end moraine deposits of the late Wisconsinan ice advance. During deglaciation, freshwater lakes formed between the retreating ice and end moraines. Prior to sea-level rise, the drift and older deposits were cut by streams flowing south and southwestward toward Block Island Sound. As sea level rose, postglacial valleys were partly filled by fluvial, freshwater-peat, estuarine and salt-marsh deposits. Transgressing seas eroded the sea floor, exposing bedrock and coastal plain outcrops, and deposited marine sediments. ?? 1983.

  18. Scientists Identify New Quaternary Materials for Solar Cell Absorbers (Fact Sheet), NREL Highlights, Science

    SciTech Connect

    Not Available

    2011-10-01

    Research provides insight for exploring use of earth-abundant quaternary semiconductors for large-scale solar cell applications. For large-scale solar electricity generation, it is critical to find new material that is Earth abundant and easily manufactured. Previous experimental studies suggest that Cu{sub 2}ZnSnS{sub 4} could be a strong candidate absorber materials for large-scale thin-film solar cells due to its optimal bandgap, high adsorption coefficient, and ease of synthesis. However, due to the complicated nature of the quaternary compound, it is unclear whether other quaternary compounds have physical properties suitable for solar cell application. Researchers at the National Renewable Energy Laboratory (NREL), Fudan University, and University College London have performed systematic searches of quaternary semiconductors using a sequential cation mutation method in which the material properties of the quaternary compounds can be derived and understood through the evolution from the binary, to ternary, and to quaternary compounds. The searches revealed that in addition to Cu{sub 2}ZnSnS{sub 4}, Cu{sub 2}ZnGeSe{sub 4} and Cu{sub 2}ZnSnSe{sub 4} are also suitable quaternary materials for solar cell absorbers. Through the extensive study of defect and alloy properties of these materials, the researchers propose that to maximize solar cell performance, growth of Cu{sub 2}ZnSnS{sub 4} under Cu-poor/Zn-rich conditions will be optimal and the formation of Cu{sub 2}ZnSn(S,Se){sub 4} alloy will be beneficial in improving solar cell performance.

  19. Selective Inhibitors of Protein Methyltransferases

    PubMed Central

    2015-01-01

    Mounting evidence suggests that protein methyltransferases (PMTs), which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and human diseases. In particular, PMTs have been recognized as major players in regulating gene expression and chromatin state. PMTs are divided into two categories: protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs). There has been a steadily growing interest in these enzymes as potential therapeutic targets and therefore discovery of PMT inhibitors has also been pursued increasingly over the past decade. Here, we present a perspective on selective, small-molecule inhibitors of PMTs with an emphasis on their discovery, characterization, and applicability as chemical tools for deciphering the target PMTs’ physiological functions and involvement in human diseases. We highlight the current state of PMT inhibitors and discuss future directions and opportunities for PMT inhibitor discovery. PMID:25406853

  20. Notch Inhibitors for Cancer Treatment

    PubMed Central

    Espinoza, Ingrid; Miele, Lucio

    2013-01-01

    Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been developed. Most of these inhibitors had shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical drugs still under study in different clinical trials. In this review, we describe the basics of Notch signaling and the role of Notch in normal and cancer stem cells as a logic way to develop different Notch inhibitors and their current stage of progress for cancer patient’s treatment. PMID:23458608

  1. Synthesis of lysine methyltransferase inhibitors

    PubMed Central

    Hui, Chunngai; Ye, Tao

    2015-01-01

    Lysine methyltransferase which catalyze methylation of histone and non-histone proteins, play a crucial role in diverse biological processes and has emerged as a promising target for the development of various human diseases, including cancer, inflammation, and psychiatric disorders. However, inhibiting lysine methyltransferases selectively has presented many challenges to medicinal chemists. During the past decade, lysine methyltransferase inhibitors covering many different structural classes have been designed and developed. In this review, we describe the development of selective, small-molecule inhibitors of lysine methyltransferases with an emphasis on their discovery and chemical synthesis. We highlight the current state of lysine methyltransferase inhibitors and discuss future directions and opportunities for lysine methyltransferase inhibitor discovery. PMID:26258118

  2. Gravity anomalies, Quaternary vents, and Quaternary faults in the southern Cascade Range, Oregon and California: Implications for arc and backarc evolution

    USGS Publications Warehouse

    Blakely, R.J.; Christiansen, R.L.; Guffanti, M.; Wells, R.E.; Donnelly-Nolan, J. M.; Muffler, L.J. Patrick; Clynne, M.A.; Smith, James G.

    1997-01-01

    Isostatic residual gravity anomalies in the southern Cascade Range of northern California and southern Oregon are spatially correlated with broad zones of Quaternary magmatism as reflected by the total volume of Quaternary volcanic products, the distribution of Quaternary vents, and the anomalously low teleseismic P wave velocities in the upper 30 km of crust. The orientation of Quaternary faults also appears to be related to gravity anomalies and volcanism in this area, trending generally north-south within the magmatic regions and northwest-southeast as they enter the neighboring amagmatic zones to the north and south. The relationship between gravity anomalies, vent density, and fault orientations may indicate in a broad sense the strength of the middle and upper crust. The southern Cascade Range occupies a transition zone where horizontal stress is transferred from the northwest-southeast dextral shear of the Walker Lane belt to the east-west extension characteristic of the Cascade arc in central Oregon. Faulting along north-south strikes in the volcanically active areas indicates the east-west extensional stresses in thermally weakened crust, whereas northwest faulting between the volcanically active areas reflects the northwest trending, right lateral shear strain of the Walker Lane belt. The segmentation of the arc reflected in Quaternary magmatism may be caused by differential extension behind crustal blocks of the forearc rotating clockwise with respect to North America. In this view the volcanic centers at Mount Shasta, Medicine Lake volcano, and Lassen Peak in northern California are situated along the southern parts of the trailing edges of two distinct segments of the forearc where additional extension is implied by their differential clockwise rotation. U.S. copyright. Published in 1997 by the American Geophysical Union.

  3. Morphology, optical and electrical properties of Cu-Ni nanoparticles in a-C:H prepared by co-deposition of RF-sputtering and RF-PECVD

    NASA Astrophysics Data System (ADS)

    Ghodselahi, T.; Vesaghi, M. A.; Gelali, A.; Zahrabi, H.; Solaymani, S.

    2011-11-01

    We report optical and electrical properties of Cu-Ni nanoparticles in hydrogenated amorphous carbon (Cu-Ni NPs @ a-C:H) with different surface morphology. Ni NPs with layer thicknesses of 5, 10 and 15 nm over Cu NPs @ a-C:H were prepared by co-deposition of RF-sputtering and RF-Plasma Enhanced Chemical Vapor Deposition (RF-PECVD) from acetylene gas and Cu and Ni targets. A nonmetal-metal transition was observed as the thickness of Ni over layer increases. The surface morphology of the sample was described by a two dimensional (2D) Gaussian self-affine fractal, except the sample with 10 nm thickness of Ni over layer, which is in the nonmetal-metal transition region. X-ray diffraction profile indicates that Cu NPs and Ni NPs with fcc crystalline structure are formed in these films. Localized Surface Plasmon Resonance (LSPR) peak of Cu NPs is observed around 600 nm in visible spectra, which is widen and shifted to lower wavelengths as the thickness of Ni over layer increases. The variation of LSPR peak width correlates with conductivity variation of these bilayers. We assign both effects to surface electron delocalization of Cu NPs.

  4. A novel 4/6-type alpha-conotoxin ViIA selectively inhibits nAchR ?3?2 subtype.

    PubMed

    Li, Liang; Liu, Na; Ding, Rong; Wang, Shuo; Liu, Zhuguo; Li, Haiying; Zheng, Xing; Dai, Qiuyun

    2015-12-01

    Conotoxins (CTxs) are typically small peptides composed of 12-50 amino acid residues with 2-5 disulfide bridges. Most of them potently and selectively target a wide variety of ion channels and membrane receptors. They are highly valued as neuropharmacological probes and in pharmaceutical development. In this work, a novel ?4/6-CTx named ViIA (RDCCSNPPCAHNNPDC-NH2) was identified from a cDNA library of the venom ducts of Conus virgo (C. virgo). ViIA was then synthesized chemically and its disulfide connectivity was identified as 'C(1)-C(3), C(2)-C(4)'. Its molecular targets were further assessed using two-electrode voltage clamping. The results indicated that ViIA selectively inhibited nicotinic acetylcholine receptor (nAChR) ?3?2 subtype with an IC50 of 845.5 nM, but did not target dorsal root ganglion sodium (Na(+))-, potassium (K(+))- or calcium (Ca(2+))-ion channels. Further structure-activity relationship analysis demonstrated that Arg(1) and His(11) but not Asp(2) were the functional residues. To the best of our knowledge, ViIA is the first 4/6 ?-CTx that selectively inhibits nAChR ?3?2 subtype. This finding expands the knowledge of targets of ?4/6-family CTxs. PMID:26511093

  5. Delimiting the binding site for quaternary ammonium lidocaine derivatives in the acetylcholine receptor channel.

    PubMed

    Pascual, J M; Karlin, A

    1998-11-01

    The triethylammonium QX-314 and the trimethylammonium QX-222 are lidocaine derivatives that act as open-channel blockers of the acetylcholine (ACh) receptor. When bound, these blockers should occlude some of the residues lining the channel. Eight residues in the second membrane-spanning segment (M2) of the mouse-muscle alpha subunit were mutated one at a time to cysteine and expressed together with wild-type beta, gamma, and delta subunits in Xenopus oocytes. The rate constant for the reaction of each substituted cysteine with 2-aminoethyl methanethiosulfonate (MTSEA) was determined from the time course of the irreversible effect of MTSEA on the ACh-induced current. The reactions were carried out in the presence and absence of ACh and in the presence and absence of QX-314 and QX-222. These blockers had no effect on the reactions in the absence of ACh. In the presence of ACh, both blockers retarded the reaction of extracellularly applied MTSEA with cysteine substituted for residues from alphaVal255, one third of the distance in from the extracellular end of M2, to alphaGlu241, flanking the intracellular end of M2, but not with cysteine substituted for alphaLeu258 or alphaGlu262, at the extracellular end of M2. The reactions of MTSEA with cysteines substituted for alphaLeu258 and alphaGlu262 were considerably faster in the presence of ACh than in its absence. That QX-314 and QX-222 did not protect alphaL258C and alphaE262C against reaction with MTSEA in the presence of ACh implies that protection of the other residues was due to occlusion of the channel and not to the promotion of a less reactive state from a remote site. Given the 12-A overall length of the blockers and the alpha-helical conformation of M2 in the open state, the binding site for both blockers extends from alphaVal255 down to alphaSer248. PMID:9806969

  6. Mineralogical characteristics of the superlarge Quaternary bauxite deposits in Jingxi and Debao counties, western Guangxi, China

    NASA Astrophysics Data System (ADS)

    Liu, Xuefei; Wang, Qingfei; Zhang, Qizuan; Feng, Yuewen; Cai, Shuhui

    2012-06-01

    In recent decades, more than 0.5 billion tons of ores scattered in the Quaternary laterite in western Guangxi, China have been explored. The ores were derived from a bauxite horizon in Permian via physical break-up and re-sediment process. Utilizing various test methods, i.e., XRD, DTA, TG/DTG, SEM/EDS and EPMA, the mineralogical characteristics of the Quaternary bauxite ores in Jingxi and Debao counties were investigated. XRD was used together with TG/DTG to obtain relatively accurate ore mineral abundance. Diaspore is the major phase, whereas hematite, kaolinite, anatase, chamosite, gibbsite, goethite, illite and rutile are minor. Diaspore is characterized by a small particle size, low degrees of crystallinity and complex chemical composition. Both gibbsite and goethite have a varied particle size, and goethite crystals contain high Al substitution and Si. It is clarified that diaspore, chamosite and anatase were formed in a mildly reduced and alkaline depositional environment in Permian, while gibbsite, hematite, goethite and part kaolinite were precipitated from Al3+-, Si4+- and Fe3+-enriched solutions within an Quaternary oxidized environment. The ions Al3+, Si4+ and Fe3+ are mostly released from chamosite in its dissolution process. The different physicochemical conditions between the Permian depositional and the Quaternary weathering periods resulted in a complex mineral assemblage in the Quaternary bauxite.

  7. Quaternary glaciations : from observations to theories (Milankovic Medal Lecture)

    NASA Astrophysics Data System (ADS)

    Paillard, Didier

    2013-04-01

    Since the mid-nineteenth century, the idea that climate may change through time has been substantiated by the observation of past glacial periods. During this time, two alternative views of glaciations have dominated the scientific debates : astronomical theories and geochemical ones involving changes in greenhouse gas concentrations. In the last decades, the validity of the Milankovitch theory has been clearly demonstrated, though several problems have been pointed out, most notably the difficulty to explain the 100-kyr cycles in simple versions of this theory. Besides, changes in atmospheric CO2 concentration have been documented, and they appear tightly linked to glaciation cycles. A central question of Quaternary Climate Sciences is therefore to understand the respective roles of the astronomical and geochemical changes, and how they can be dynamically combined in order to explain paleoclimatic observations. After some historical background, I will address this question from the viewpoint of conceptual models. I will highlight their predictive power and their limitations. Most importantly, these models are helping us to formulate hypotheses in order to unravel the required dynamical structure of the astronomical-glaciological-geochemical-climatical problem. I will discuss in some details how the model of Paillard (1998) leads naturally to the counter-intuitive idea that full glaciations should trigger oceanic CO2 degassing and thus to the model of Paillard and Parrenin (2004), by using the underlying mechanism of brine rejection during sea ice formation around Antarctica. Then I will present results from a more complex model (CLIMBER-2) that validate this mechanism through the comparison of simulated and observed paleoclimatic tracer distributions of 13C and 14C (Bouttes et al., 2011; Mariotti et al. 2013). The model simulation of the last deglaciation (Bouttes et al., 2012) predicts that, when brine formation is stopped, atmospheric CO2 and Antarctic temperatures should start rising together at the exact same time. This fact has now been confirmed from Antarctic ice core analysis (Parrenin et al, 2013). It seems therefore that we are getting closer to a full synthesis of the astronomical and geochemical theories of Quaternary Climate. Paillard D. (1998) The timing of Pleistocene glaciations from a simple multiple-state climate model. Nature, vol. 391 pp. 378-381. Paillard D., Parrenin F. (2004) The Antarctic ice-sheet and the triggering of deglaciations. Earth Planet. Sci. Lett. ,vol. 227 (3-4) pp. 263-271. Bouttes N. et al. (2011) Last Glacial Maximum CO2 and ?13C successfully reconciled. Geophys. Res. Lett., vol. 38 (2) pp. 1-5. Bouttes N. et al. (2012) Impact of oceanic processes on the carbon cycle during the last termination. Clim Past, vol. 8 (1) pp. 149-170. Mariotti V. et al., (accepted) Simulated Last Glacial Maximum ?14CATM and the deep glacial ocean carbon reservoir, Radiocarbon. Parrenin F. et al., (in press) Synchronous change of atmospheric CO2 and Antarctic temperature during the last deglacial warming, Science.

  8. Summary of Quaternary Stratigraphy and history, Eastern Canada

    NASA Astrophysics Data System (ADS)

    Fulton, R. J.; Karrow, P. F.; LaSalle, P.; Grant, D. R.

    Deposits of three Wisconsinan substages, Sangamonian Stage, and older Quaternary stratigraphic units are recognized in Eastern Canada. The age assignment of these units is based on radiocarbon dating and correlation of events. Quaternary deposits older than Sangamonian are recognized locally in Eastern Canada. In southern Ontario glacial deposits directly underlie Sangamonian sediments and are referred to as Illinoian in age. In other areas the ages of older sediments are largely unknown. Offshore core stratigraphy suggests that a major glaciation took place about 436 ka and that the Illinoian (oxygen isotope stage 6) was also a time of extensive glaciation. In this report Sangamonian is used as the name for the chronostratigraphic stage that includes all of deep-sea oxygen isotope stage 5 and consequently, on a regional basis, it includes warm interglacial deposits, glacial deposits and cool interglacial deposits. In southern Ontario the warm interglacial deposits are represented by the Don Formation, the stadial deposits by the Scarborough Formation and the cool interglacial deposits by the Pottery Road Formation. Warm interglacial deposits have not been recognized in Quebec (unless they are part of the pre-Johnville Sediments); the Bécancour Till is included as glacial Sangamonian sediments, and the St. Pierre Sediments are recognized as cool interglacial sediments. The Early Wisconsinan appears to have been the time of maximum Wisconsinan glaciation in Eastern Canada with ice moving south of the International Boundary and well out onto the continental shelf. The Middle Wisconsinan was primarily a nonglacial period in southern Ontario and a glacial stade elsewhere in Eastern Canada. In southern Ontario the Middle Wisconsinan record has been subdivided into two interstades (Port Talbot and Plum Point), separated by a stade (Cherrytree). The Port Talbot Interstade began before the limit of radiocarbon dating (before 48 ka) and ended about 40 ka; glacial or near glacial conditions of the Cherrytree Stage lasted from about 40 to 35 ka ago, and the Plum Point Interstade was from about 35 to 23 ka ago. Central St. Lawrence Lowland was occupied by ice throughout the Middle Wisconsinan, but southeastern Quebec and the Montreal area were briefly deglaciated. Scattered evidence in Atlantic Canada suggests local deglaciation of coastal areas during Middle Wisconsinan but extensive ice remained on the continental shelf and ice from centres located on the shelf flowed onto land in at least two areas. Glacial conditions predominated throughout Eastern Canada during the Late Wisconsinan. At the Late Wisconsinan maximum, through-moving ice deposited the Catfish Creek Drift in southern Ontario but ice lobes, which developed in the basins of the Great Lakes after 15.5 ka, controlled ice flow during a period of ice margin oscillation and retreat. A calving bay developed in lower St. Lawrence valley, after the Late Wisconsinan maximum, causing a reversal of flow on the south shore of the St. Lawrence and replacing ice in the valley with the Champlain Sea about 12 ka. Late Wisconsinan glaciers were largely limited to land areas in Atlantic Canada. Local ice caps dominated with complicated patterns of flow and retreat developing as centres of accumulation shifted and competing ice centres achieved dominance. The period of Late Wisconsinan retreat in Atlantic Canada appears to have lasted from about 14 to 10 ka.

  9. Quaternary tectonic setting of South-Central coastal California

    USGS Publications Warehouse

    Lettis, William R.; Hanson, Kathryn L.; Unruh, Jeffrey R.; McLaren, Marcia; Savage, William U.; Keller, Margaret A.

    2004-01-01

    Recent geodetic, geologic, and seismologic studies show that the south-central coast of California is a region of active Quaternary deformation. Northeast-directed crustal shortening is occurring in a triangular-shaped region between the Hosgri-San Simeon fault system on the west, the Southern Coast Ranges on the northeast, and the western Transverse Ranges on the south. We informally call this region the Los Osos domain. In this study, we conducted detailed geological, seismological, and geophysical investigations to characterize the nature and rates of deformation in the domain. Locations of active and potentially active faults and folds are compiled at a scale of 1:250,000 for the entire domain based primarily on onshore geologic data and offshore geophysical data. Crustal shortening in the domain is accommodated by a series of prominent northwest-trending reverse faults and localized folding. The reverse faults separate distinct structural blocks that have little or no internal deformation. Hangingwall blocks are being uplifted at rates of up to 0.2 mm/yr. Footwall blocks are either static or slowly subsiding at rates of 0.1 mm/yr or less, except for localized areas of concentrated subsidence directly adjacent to some faults. The cumulative rate of crustal shortening is about 1 to 2 mm/yr across the northern part of the domain based on observed geologic deformation. Cumulative shortening across the central and southern parts of the domain is poorly constrained by geologic data and may approach 2 to 3 mm/yr. Historical and instrumental seismicity generally are spatially associated with the uplifted blocks and bordering reverse faults to depths of about 10 km. Together with near-surface geological data and deeper crustal geophysical imaging that show high-angle faulting, the seismicity data indicate that the reverse faults probably extend to the base of the seismogenic crust. The base of the seismogenic crust may correspond with a mid-crustal detachment or decollement surface into which the reverse faults root. We speculate that the detachment may coincide, in part, with the top of a northeast-dipping slab of oceanic crust that extends beneath the western margin of the continent or with the brittle-ductile transition above the subducted slab. The Los Osos domain of north-northeast/south-southwest crustal shortening is structurally detached from the offshore Hosgri Fault Zones. Both the pattern and regional extent of deformation in the Los Osos domain contrast sharply with that of the offshore Santa Maria Basin. The basin is undergoing minor east-northeast/west-southwest crustal shortening at rates of less than 0.1 mm/yr and is moving northwestward at a rate of about 1 to 3 mm/yr relative to the Los Osos domain along the San Simeon and Hosgri Fault Zones. Geodetic data and the kinematics of north-northeast-directed crustal shortening of the Los Osos domain east of the Hosgri Fault Zone show that the rate and cumulative amount of right-slip along the Hosgri Fault Zone progressively decrease southward. Quaternary deformation within the Los Osos domain is related to distributed dextral simple shear associated with Pacific-North American plate motion. Paleomagnetic data show that clockwise rotation of the western Transverse Ranges has occurred along the southern boundary of the domain during the past 6 m.y. During this time, the Salinian crustal block, which forms the eastern boundary of the Los Osos domain, has remained relatively stable. Internal shortening of the Los Osos domain has accommodated the relative motions of these bordering crustal blocks, particularly the rotation of the western Transverse Ranges.

  10. Europe's Neogene and Quaternary lake gastropod diversity - a statistical approach

    NASA Astrophysics Data System (ADS)

    Neubauer, Thomas A.; Georgopoulou, Elisavet; Harzhauser, Mathias; Mandic, Oleg; Kroh, Andreas

    2014-05-01

    During the Neogene Europe's geodynamic history gave rise to several long-lived lakes with conspicuous endemic radiations. However, such lacustrine systems are rare today as well as in the past compared to the enormous numbers of "normal" lakes. Most extant European lakes are mainly results of the Ice Ages and are due to their (geologically) temporary nature largely confined to the Pleistocene-Holocene. As glacial lakes are also geographically restricted to glacial regions (and their catchment areas) their preservation potential is fairly low. Also deposits of streams, springs, and groundwater, which today are inhabited by species-rich gastropod assemblages, are rarely preserved. Thus, the pre-Quaternary lacustrine record is biased towards long-lived systems, such as the Late Miocene Lake Pannon, the Early to Middle Miocene Dinaride Lake System, the Middle Miocene Lake Steinheim and several others. All these systems have been studied for more than 150 years concerning their mollusk inventories and the taxonomic literature is formidable. However, apart from few general overviews precise studies on the ?-diversities of the post-Oligocene European lake systems and the shifting biodiversity in European freshwater systems through space and time are entirely missing. Even for the modern faunas, literature on large-scale freshwater gastropod diversity in extant lakes is scarce and lacks a statistical approach. Our preliminary data suggest fundamental differences between modern and pre-Pleistocene freshwater biogeography in central Europe. A rather homogenous central European Pleistocene and Holocene lake fauna is contrasted by considerable provincialism during the early Middle Miocene. Aside from the ancient Dessaretes lakes of the Balkan Peninsula, Holocene lake faunas are dominated by planorbids and lymnaeids in species numbers. This composition differs considerably from many Miocene and Pliocene lake faunas, which comprise pyrgulid-, hydrobiid-, viviparid-, melanopsid- and planorbid-dominated lakes. Nevertheless, several pre-Holocene lakes, such as the early Middle Miocene Lake Rein (Styrian Basin, Austria), several Middle Miocene lakes in Hungary and some Pliocene ones in France, are strikingly "modern" in their generic inventory and genus/species relations. This suggests that the modern composition is not necessarily a young pattern, explained only by the glacial bottleneck. Nevertheless, an overall turnover from melanopsid-pyrgulid-dominated faunas towards planorbid-viviparid-dominated lake faunas from Miocene to Pliocene seems to be reflected in the data on central Europe. This rule of thumb, however, is contradicted by melanopsid-dominated faunas on the Aegean islands during the Pliocene. The FreshGEN project (Freshwater Gastropods of the European Neogene) is currently collecting data for providing the first detailed assessment of the composition of the European freshwater gastropod fauna during the Neogene and Quaternary at species level, with emphasis on lake faunas. This includes revealing shifts in the overall ?-biodiversity, changing evolutionary hotspots, faunal gradients, and the evolution of endemic radiations. The results will be discussed in terms of regional and global patterns and will be related to regional and large-scale climatic changes during the Neogene.

  11. An Atlas of Submarine Glacial Landforms: Modern, Quaternary and Ancient

    NASA Astrophysics Data System (ADS)

    Jakobsson, M.; Dowdeswell, J. A.; Canals, M.; Todd, B. J.; Dowdeswell, E. K.; Hogan, K. A.

    2014-12-01

    In the past two decades there have been several advances that make the production of an atlas of submarine glacial landforms timely. First is the development of high-resolution imaging technologies; multi-beam echo-sounding or swath bathymetry that allows the detailed mapping of the sea floor at water depths of tens to thousands of metres across continental margins, and 3-D seismic methods that enable the visualisation of palaeo-continental shelves in Quaternary sediments and ancient palaeo-glacial rocks (e.g. Late Ordovician of Northern Africa). A second technological development is that of ice-breaking or ice-strengthened ships that can penetrate deep into the ice-infested waters of the Arctic and Antarctic, to deploy the multibeam systems. A third component is that of relevance - through both the recognition that the polar regions, and especially the Arctic, are particularly sensitive parts of the global environmental system and that these high-latitude margins (both modern and ancient) are likely to contain significant hydrocarbon resources. An enhanced understanding of the sediments and landforms of these fjord-shelf-slope systems is, therefore, of increasing importance to both academics and industry. We are editing an Atlas of Submarine Glacial Landforms that presents a series of individual contributions that describe, discuss and illustrate features on the high-latitude, glacier-influenced sea floor. Contributions are organised in two ways: first, by position on a continental margin - from fjords, through continental shelves to the continental slope and rise; secondly, by scale - as individual landforms and assemblages of landforms. A final section provides discussion of integrated fjord-shelf-slope systems. Over 100 contributions by scientists from many countries contain descriptions and interpretation of swath-bathymetric data from both Arctic and Antarctic margins and use 3D seismic data to investigate ancient glacial landforms. The Atlas will be published in late 2015 in the Memoir Series of the Geological Society of London.

  12. Late Quaternary land-sea correlations, northern Labrador, Canada

    SciTech Connect

    Clark, P.; Josenhans, H.

    1985-01-01

    Late Quaternary glacial and postglacial units in the Torngat Mountains, northern Labrador, are correlated with units identified on the adjacent continental shelf. The late Wisconsinan Laurentide Ice Sheet drained through major valleys of the Torngat Mountains as outlet glaciers, depositing the Saglek Moraines. These are of regional extent and have been mapped from Saglek Fiord north to Noodleook Fiord. A C-14 date of 18,210 +/- 1900 BP on total organic matter (TOM) from lake sediment dammed by a segment of the Saglek Moraines is interpreted as a maximum date for deposition of the Saglek Moraine system because of possible contamination. Glacial sediments comprising the Saglek Moraines are correlated with upper till mapped in troughs and saddles on the continental shelf. Outlet glaciers depositing a late Wisconsinan unit flowed through Labrador fiords and onto the shelf at low basal shear stresses, particularly on the shelf where, although grounded, they were hydrostatically buoyed up and moved principally by sliding. A glaciomarine unit conformably overlies late Wisconsinan till on the shelf and on the land. This unit is a gravelly clayey silt, contains abundant foraminifera, and has up to 60% limestone in the pebble fraction. C-14 dates suggest deposition of this unit began ca. 10,000 BP on the shelf and 9000 BP on the land, an ended by 8000 BP. Limestone pebbles in this unit suggest a source in part from sediment-laden icebergs and pack-ice from the north. Marine deposition from ca. 8000-0 BP is characterize by basinal sedimentation.

  13. Late Quaternary Productivity Records from Coccolith Sr/Ca

    NASA Astrophysics Data System (ADS)

    Stoll, H. M.; Burke, A.; Mejia Ramirez, L. M.; Shimizu, N.; Ziveri, P. P. I.

    2014-12-01

    The Sr/Ca of coccoliths has been proposed as an indicator of productivity on the basis of correlation with export production in sediment traps and across upwelling productivity gradients, although the mechanism responsable for this relationship is not clear. For diverse oceanographic settings in the Late Quaternary, we compare coccolith Sr/Ca productivity records with those of other productivity indicators and proxies for mechanisms of productivity forcing. For the Somalia Basin in the Arabian Sea, coccolith Sr/Ca shows a large variation coherent with precessional forcing of wind strength as a mechanism for productivity regulation. During the glacial, the Sr/Ca peak is decoupled from productivity indicators based on organic C accumulation rate. For the Northern Bay of Bengal, coccolith Sr/Ca, Ba/Ti, and relative abundance of G. bulloides, all suggest greater productivity during the interglacial periods, consisted with Nd isotopic evidence for greater riverine nutrient inputs. In the Andaman Sea, coccolith Sr/Ca is highest during precessional maxima in the summer monsoon, consistent with proxies for chemical weathering in the Irawaddy rivershed. In the Eastern Mediterranean, coccolith Sr/Ca is on average low, and peaks during the E. Holocene interval characterized by deposition of sapropel S1. The peak in Sr/Ca however is comparable to the level maintained throughout the Holocene in the Western Mediterranean, where no sapropel occurs, implicating deepwater oxygen levels as a significant contributor to sapropel formation. Finally, on the Agulhas Bank, minima in coccolith Sr/Ca occur during obliquity minima which are periods of anomalous equatorward deposition of IRD in the Southern Ocean. Northward explansion of the westerly wind field during these cold intervals, block upwelling on the Agulhas Bank and result in low productivity.

  14. Tetracalcium phosphate composite containing quaternary ammonium dimethacrylate with antibacterial properties

    PubMed Central

    Cheng, Lei; Weir, Michael D.; Limkangwalmongkol, Penwadee; Hack, Gary D.; Xu, Hockin H. K.; Chen, Qianming; Zhou, Xuedong

    2012-01-01

    Tooth caries is a carbohydrate-modified bacterial infectious disease, and recurrent caries is a frequent reason for restoration failure. The objective of this study was to develop a novel antibacterial composite using tetracalcium phosphate (TTCP) fillers and bis(2-methacryloyloxy-ethyl) dimethyl-ammonium bromide, which is a quaternary ammonium dimethacrylate (QADM). QADM was synthesized using 2-(N,N-dimethylamino)ethyl methacrylate and 2-bromoethyl methacrylate and incorporated into a resin. The resin was filled with 40% TTCP and 30% glass particles. The following QADM mass fractions in the composite were tested: 0%, 6%, 12%, and 18%. Streptococcus mutans biofilms were formed on the composites and the colony-forming units (CFUs), metabolic activity, and lactic acid production were measured. The TTCP-QADM composite had flexural strength and elastic modulus similar to those of two commercial composites (p > 0.1). Increasing the QADM content in TTCP composite greatly decreased the bacteria growth and biofilm matrix production. There were significantly more dead bacteria with increasing QADM content. TTCP composite containing 18% QADM had biofilm CFU, metabolic activity, and acid production about half of those without QADM. Inversely linear relationships were established between QADM mass fraction and S. mutans biofilm CFU, metabolic activity, and acid production, with correlation coefficients R2 ? 0.98. In conclusion, TTCP-QADM composites were developed and the effect of QADM mass fraction on the antibacterial properties of the composite was determined for the first time. The novel TTCP-QADM composites possessing a strong antibacterial capability, together with calcium phosphate ion release and good mechanical properties, are promising for dental restorations to reduce biofilm growth and recurrent caries. PMID:22190356

  15. Late Quaternary depositional history of the Albemarle Embayment, NC

    SciTech Connect

    Riggs, S.R.; Klingman, C.R.; Wyrick, R.A. . Dept. of Geology)

    1993-03-01

    The depositional history of Albemarle Embayment documents deep fluvial incisement by the Roanoke River system during glacial episodes and subsequent infilling by fluvial-estuarine-barrier island sediment sequences during interglacial transgressions. Unraveling the Holocene time slice will help reconstruct complex Quaternary records of multiple incisement and backfilling. A network of drill holes, vibracores, and seismic data suggest a four-phase infill history over the last 12,000 years. (1) Lower Roanoke River: (a) Bedload-charged, braided fluvial systems deposited basal sequences of sand and gravel prior to [approximately]5,000 BP. (b) Aggradational, swamp-forest floodplains developed [approximately]5,000 BP and bound the modern incised channels characterized by minimal bedload sedimentation. (2) Albemarle sound: (a) In the central basin, the basal channel sand sequence is overlain by an open estuarine, highly interlaminated sand and mud sequence that accumulated between [approximately]12,000 BP and [approximately]2,000 BP. (b) Depositional patterns within this unit suggest multiple oscillations of Holocene sea level that caused channel reincisement and subsequent backfilling. (c) Present estuarine marsh sedimentation began in protected coastal areas [approximately]5,000 BP. (3) Outer banks: (a) Barrier islands first influenced sedimentation in the area after [approximately]5,000 BP producing a semi-enclosed Albemarle Sound. (b) Deposition within the central basin shifted to uniform organic-rich muds that grade eastward into overwash and inlet sands. (4) Modern man: (a) colonial development within the drainage basins in the early 1700's AD produced a wedge of orange mud in inner Albemarle Sound. (b) Dam construction in the 1950's terminated orange mud deposition and the central basin reverted to organic-rich mud sedimentation.

  16. Use of P450 cytochrome inhibitors in studies of enokipodin biosynthesis

    PubMed Central

    Ishikawa, Noemia Kazue; Tahara, Satoshi; Namatame, Tomohiro; Farooq, Afgan; Fukushi, Yukiharu

    2013-01-01

    Enokipodins A, B, C, and D are antimicrobial sesquiterpenes isolated from the mycelial culture medium of Flammulina velutipes, an edible mushroom. The presence of a quaternary carbon stereocenter on the cyclopentane ring makes enokipodins A-D attractive synthetic targets. In this study, nine different cytochrome P450 inhibitors were used to trap the biosynthetic intermediates of highly oxygenated cuparene-type sesquiterpenes of F. velutipes. Of these, 1-aminobenzotriazole produced three less-highly oxygenated biosynthetic intermediates of enokipodins A-D; these were identified as (S)-(?)-cuparene-1,4-quinone and epimers at C-3 of 6-hydroxy-6-methyl-3-(1,2,2-trimethylcyclopentyl)-2-cyclohexen-1-one. One of the epimers was found to be a new compound. PMID:24688524

  17. 2334 IEEE TRANSACTIONS ON VEHICULAR TECHNOLOGY, VOL. 57, NO. 4, JULY 2008 Multicode MIMO Systems With Quaternary

    E-print Network

    No, Jong-Seon

    With Quaternary LCZ and ZCZ Sequences Jae-Dong Yang, Xianglan Jin, Kyoung-Young Song, Jong-Seon No, Member, IEEE-output (MIMO) systems with quaternary low-correlation zone (LCZ) and zero-correlation zone (ZCZ) sequences between these sequences are within the predetermined correlation zone, and thus, the multi- user

  18. Synthesis of Quaternary Ammonium Salts of Tricyclic Cationic Drugs: A One-Pot Synthesis for the Bioorganic Chemistry Laboratory

    ERIC Educational Resources Information Center

    Brunauer, Linda S.; Mogannam, Abid C.; Hwee, Won B.; Chen, James Y.

    2007-01-01

    A one-pot conversion of tricyclic cationic drugs to their quaternary ammonium forms is described for a widely used bioactive drug: chlorpromazine, a phenothiazine-based antipsychotic. After conversion to its free base, the parent drug was methylated using substoichiometric amounts of methyl iodide dissolved in ether; the charged quaternary

  19. Thickness effects on optical and photoelectric properties of PbSeTeO quaternary thin films prepared by magnetron

    E-print Network

    Volinsky, Alex A.

    Thickness effects on optical and photoelectric properties of PbSeTeO quaternary thin films prepared, indicating that increasing the thickness is an effective method to expand the absorption range of the sputtered PbSeTeO quaternary thin films. The photoelectric sensi- tivity increased almost linearly

  20. Paleo-erosion rates in Central Asia since 9 Ma: A transient increase at the onset of Quaternary glaciations?

    E-print Network

    Avouac, Jean-Philippe

    Paleo-erosion rates in Central Asia since 9 Ma: A transient increase at the onset of Quaternary.M. Harrison Keywords: Quaternary glaciation erosion rates Tianshan cosmogenic nuclide magnetostratigraphy 10 Be Erosion is a fundamental player of the interactions existing between internal geodynamics and climate

  1. Magnetic Properties of Quaternary Deposits, Kenai Peninsula, Alaska -- Implications for Aeromagnetic Anomalies of Upper Cook Inlet

    USGS Publications Warehouse

    Saltus, R.W.; Haeussler, P.J.

    2004-01-01

    We measured magnetic susceptibilities of exposed Quaternary deposits on several beach cliffs and river banks on the Kenai Peninsula near Soldotna, Alaska. Data, descriptions, and photos from nine sites are included in this report. The mean susceptibility for Quaternary materials in this region is approximately 2.5 x 10-3 SI units. This is sufficiently magnetic to produce subtle aeromagnetic anomalies such as those observed to correlate with topographic features in the region of the measurements. The highest susceptibilities measured (greater than 20 x 10-3 SI units) may help, at least in part, to explain moderate amplitude aeromagnetic anomalies observed elsewhere in Cook Inlet, particularly those relating to structures showing Quaternary movement. Comparison of measured beach cliff susceptibility and susceptibility predicted from idealized formulas and two-dimensional cliff models suggests that measured susceptibilies underestimate true bulk susceptibility by 20 percent to 50 percent in this region.

  2. Atmospheric effects on Quaternary polarization encoding for free space communication, laboratory simulation

    E-print Network

    Soorat, Ram

    2015-01-01

    We have simulated atmospheric effects such as fog and smoke in laboratory environment to simulate depolarisation due to atmospheric effects during a free space optical communi- cation. This has been used to study noise in two components of quaternary encoding for polarization shift keying. Individual components of a Quaternary encoding, such as vertical and horizontal as well as 45$^\\circ$ and 135$^\\circ$ , are tested separately and indicates that the depo- larization effects are different for these two situation. However, due to a differential method used to extract information bits, the protocol shows extremely low bit error rates. The information obtained is useful during deployment of a fully functional Quaternary encoded PolSK scheme in free space.

  3. Construction of multiple, contiguous quaternary stereocenters in acyclic molecules by lithiation-borylation.

    PubMed

    Watson, Charlotte G; Balanta, Angelica; Elford, Tim G; Essafi, Stéphanie; Harvey, Jeremy N; Aggarwal, Varinder K

    2014-12-17

    Lithiation of carbamates followed by borylation provides a powerful method for the homologation of boron reagents. However, when applied to hindered systems (secondary carbamates with tBu-boronic esters) for the construction of two quaternary centers, this methodology fails. Instead, using mixed boranes (tBuBMe2), the synthesis of adjacent quaternary stereogenic centers with full stereocontrol was successful. The process can be repeated two or three times in one pot leading to carbon chains bearing multiple contiguous quaternary stereogenic centers. The boranes were converted into tertiary alcohols or C-tertiary amines using chloramine. The origin of the high selectivity for alkyl over Me group migration was determined computationally. PMID:25469619

  4. Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops

    SciTech Connect

    Kwon, Young Do; Finzi, Andrés; Wu, Xueling; Dogo-Isonagie, Cajetan; Lee, Lawrence K.; Moore, Lucas R.; Schmidt, Stephen D.; Stuckey, Jonathan; Yang, Yongping; Zhou, Tongqing; Zhu, Jiang; Vicic, David A.; Debnath, Asim K.; Shapiro, Lawrence; Bewley, Carole A.; Mascola, John R.; Sodroski, Joseph G.; Kwong, Peter D.

    2013-03-04

    The HIV-1 envelope (Env) spike (gp120{sub 3}/gp41{sub 3}) undergoes considerable structural rearrangements to mediate virus entry into cells and to evade the host immune response. Engagement of CD4, the primary human receptor, fixes a particular conformation and primes Env for entry. The CD4-bound state, however, is prone to spontaneous inactivation and susceptible to antibody neutralization. How does unliganded HIV-1 maintain CD4-binding capacity and regulate transitions to the CD4-bound state? To define this mechanistically, we determined crystal structures of unliganded core gp120 from HIV-1 clades B, C, and E. Notably, all of these unliganded HIV-1 structures resembled the CD4-bound state. Conformational fixation with ligand selection and thermodynamic analysis of full-length and core gp120 interactions revealed that the tendency of HIV-1 gp120 to adopt the CD4-bound conformation was restrained by the V1/V2- and V3-variable loops. In parallel, we determined the structure of core gp120 in complex with the small molecule, NBD-556, which specifically recognizes the CD4-bound conformation of gp120. Neutralization by NBD-556 indicated that Env spikes on primary isolates rarely assume the CD4-bound conformation spontaneously, although they could do so when quaternary restraints were loosened. Together, the results suggest that the CD4-bound conformation represents a 'ground state' for the gp120 core, with variable loop and quaternary interactions restraining unliganded gp120 from 'snapping' into this conformation. A mechanism of control involving deformations in unliganded structure from a functionally critical state (e.g., the CD4-bound state) provides advantages in terms of HIV-1 Env structural diversity and resistance to antibodies and inhibitors, while maintaining elements essential for entry.

  5. Comparison of the efficacy of four cholinesterase inhibitors in combination with memantine for the treatment of Alzheimer’s disease

    PubMed Central

    Shao, Zi-Qiang

    2015-01-01

    Background: Combined use of memantine and acetylcholinesterase inhibitors (AChEIs) has shown improved outcomes in patients with Alzheimer’s disease (AD). However, it is not clear which AChEI is the optimal for the combined treatment with memantine. Methods: A total of 110 AD patients were randomized to receive memantine and one of the following add-on drugs: placebo, donepezil, rivastigmine, galantamine, and huperzine A for 24 weeks (n=22). At baseline, 12 weeks, and 24 weeks, the patients were evaluated using mini-mental state examination (MMSE) and Alzheimer Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scales. Adverse events were recorded to analyze the safety profile. Results: The MMSE scores were significantly increased and the ADL scores were significantly decreased at 12 weeks and 24 weeks in all five groups compared with baseline (all P<0.01). At 24 weeks, patients treated with memantine+huperzine A showed better MMSE and ADL scores than those treated with memantine+placebo. Conclusions: Huperzine A may be an optimal choice for the combined therapy with memantine in treating AD. PMID:25932260

  6. The influence of inhibitors and other factors on cholinesterases.

    PubMed

    Bajgar, J

    1991-01-01

    Literature survey dealing with cholinesterases and effects of highly toxic organophosphorus compounds suitable for use as chemical weapons is given in introductory part of this work. There are nerve paralytical agents (NPA)--sarin, soman, VX and a model compound O-ethyl-S-(2-dimethylaminoethyl)-methyl-phosphonothioate (EDMM). On the base of described scheme of intoxication with NPA, inhibition effect on cholinesterases, preferably on AChE as the most important factor involved in the mechanism of acute intoxication with NPA was studied. Intoxication of mice or rats with sarin and soman (2 x LD50) showed that time course of poisoning is faster than that for VX or EDMM. Inhibition of AChE in the blood was in good correlation with symptoms of intoxication and also with inhibition of AChE in the brain. The differences between inhibition effect of soman preferably uniform character of inhibition in the brain parts) and sarin (selective inhibition in the brain parts, with maximum in the frontal cortex and pontomedullar area) were observed. This selectivity was most marked for VX and EDMM intoxication (maximal inhibition in the part of the pontomedullar area containing reticular formation). The dose causing inhibition effect in the brain was assessed to be about 1% of the dose administered. The study of the effect of antidotal therapy (combination of atropine and reactivator) in vivo showed in mice and rats intoxicated with sarin non-uniform increase of AChE activity in the pontomedullar part depending on the dose and type of reactivator. The most marked effect was observed for methoxime. It was demonstrated that there exists good correlation between survival of experimental animals and the rest AChE activity in the pontomedullar part of the brain. AChE activity level critical for survival or death of the organism poisoned with NPA was assessed from these experiments; it was about 1-5% of normal values. By means of original method allowing continual monitoring of AChE activity in the blood, similar AChE reactivation was demonstrated, with highest effect for trimedoxime and methoxime. Using continual determination of the blood AChE activity following sarin, soman, VX and EDMM intoxication demonstrated that only a part of the dose administered caused inhibition effect in the blood; this part was determined to be practically 100% (i. v. administration); for other routes of administration this ratio was as follows: 50-80% (i. m.), 20-40% (i. p.), 6-16% (p. o.) and 1-5% (p. c.), respectively. Using this continual monitoring, the detoxication of sarin and soman was demonstrated. Detoxication of VX and EDMM was not observed.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1759111

  7. Dynamic Covalent Chemistry of Nucleophilic Substitution Component Exchange of Quaternary Ammonium Salts.

    PubMed

    Kulchat, Sirinan; Lehn, Jean-Marie

    2015-11-01

    Dynamic covalent libraries (DCLs) of quaternary ammonium cations were set up by reversible nucleophilic substitution (SN 2' and SN 2) exchange reactions of ammonium salts and tertiary amines. The reactions were conducted at 60?°C to generate thermodynamically and kinetically controlled mixtures of quaternary ammonium compounds and tertiary amines, and were accelerated by using iodide as a nucleophilic catalyst. Microwave irradiation was used to assist the exchange reaction between the pyridinium salts and pyridine derivatives. Finally, experiments towards the generation of dynamic ionic liquids were performed. The results of this study pave the way for the extension of dynamic combinatorial chemistry to nucleophilic substitution reactions. PMID:26213320

  8. Synthetic Studies on Perphoramidine and the Communesins: Construction of the Vicinal Quaternary Stereocenters

    PubMed Central

    Seo, Jae Hong; Artman, Gerald D.; Weinreb, Steven M.

    2008-01-01

    An efficient synthetic strategy for installation of the two vicinal quaternary carbon centers of the communesins is reported. Key steps include the O-allylation/Claisen rearrangement of spirolactone systems, which are formed by tandem intramolecular Heck cyclization/carbonylation. Substituent and solvent effects on the stereochemical outcome of the Claisen rearrangements have been examined. The stereochemical assignment of the allyl spirolactone previously reported as 17 has now been revised to 32, which has the communesin relative configuration at the quaternary carbons. Key C-allyl spirolactone 59 bearing functional handles required for the communesin core has been constructed with a 9.8:1 diastereomer ratio. PMID:17081020

  9. Corrosion inhibitors from expired drugs.

    PubMed

    Vaszilcsin, Nicolae; Ordodi, Valentin; Borza, Alexandra

    2012-07-15

    This paper presents a method of expired or unused drugs valorization as corrosion inhibitors for metals in various media. Cyclic voltammograms were drawn on platinum in order to assess the stability of pharmaceutically active substances from drugs at the metal-corrosive environment interface. Tafel slope method was used to determine corrosion rates of steel in the absence and presence of inhibitors. Expired Carbamazepine and Paracetamol tablets were used to obtain corrosion inhibitors. For the former, the corrosion inhibition of carbon steel in 0.1 mol L(-1) sulfuric acid solution was about 90%, whereas for the latter, the corrosion inhibition efficiency of the same material in the 0.25 mol L(-1) acetic acid-0.25 mol L(-1) sodium acetate buffer solution was about 85%. PMID:22561212

  10. Positron emitter labeled enzyme inhibitors

    SciTech Connect

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.; Langstrom, B.

    1990-04-03

    This invention involves a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography.

  11. Electrochemical studies of corrosion inhibitors

    NASA Technical Reports Server (NTRS)

    Danford, M. D.

    1990-01-01

    The effect of single salts, as well as multicomponent mixtures, on corrosion inhibition was studied for type 1010 steel; for 5052, 1100, and 2219-T87 aluminum alloys; and for copper. Molybdate-containing inhibitors exhibit an immediate, positive effect for steel corrosion, but an incubation period may be required for aluminum before the effect of a given inhibitor can be determined. The absence of oxygen was found to provide a positive effect (smaller corrosion rate) for steel and copper, but a negative effect for aluminum. This is attributed to the two possible mechanisms by which aluminum can oxidize. Corrosion inhibition is generally similar for oxygen-rich and oxygen-free environments. The results show that the electrochemical method is an effective means of screening inhibitors for the corrosion of single metals, with caution to be exercised in the case of aluminum.

  12. Positron emitter labeled enzyme inhibitors

    DOEpatents

    Fowler, Joanna S. (Bellport, NY); MacGregor, Robert R. (Sag Harbor, NY); Wolf, Alfred P. (Setauket, NY); Langstrom, Bengt (Upsala, SE)

    1990-01-01

    This invention involves a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography.

  13. Positron emitter labeled enzyme inhibitors

    DOEpatents

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

    1987-05-22

    This invention involved a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide in activators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

  14. Solution conformation of a neuronal nicotinic acetylcholine receptor antagonist {alpha}-conotoxin OmIA that discriminates {alpha}3 vs. {alpha}6 nAChR subtypes

    SciTech Connect

    Chi, Seung-Wook; Kim, Do-Hyoung; Olivera, Baldomero M.; McIntosh, J. Michael; Han, Kyou-Hoon . E-mail: khhan600@kribb.re.kr

    2006-06-23

    {alpha}-Conotoxin OmIA from Conus omaria is the only {alpha}-conotoxin that shows a {approx}20-fold higher affinity to the {alpha}3{beta}2 over the {alpha}6{beta}2 subtype of nicotinic acetylcholine receptor. We have determined a three-dimensional structure of {alpha}-conotoxin OmIA by nuclear magnetic resonance spectroscopy. {alpha}-Conotoxin OmIA has an '{omega}-shaped' overall topology with His{sup 5}-Asn{sup 12} forming an {alpha}-helix. Structural features of {alpha}-conotoxin OmIA responsible for its selectivity are suggested by comparing its surface characteristics with other functionally related {alpha}4/7 subfamily conotoxins. Reduced size of the hydrophilic area in {alpha}-conotoxin OmIA seems to be associated with the reduced affinity towards the {alpha}6{beta}2 nAChR subtype.

  15. STAT inhibitors for cancer therapy

    PubMed Central

    2013-01-01

    Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds. PMID:24308725

  16. Covalent-Allosteric Kinase Inhibitors.

    PubMed

    Weisner, Jörn; Gontla, Rajesh; van der Westhuizen, Leandi; Oeck, Sebastian; Ketzer, Julia; Janning, Petra; Richters, André; Mühlenberg, Thomas; Fang, Zhizhou; Taher, Abu; Jendrossek, Verena; Pelly, Stephen C; Bauer, Sebastian; van Otterlo, Willem A L; Rauh, Daniel

    2015-08-24

    Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homology (PH) domain-dependent covalent-allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chemical biology and medicinal chemistry research. PMID:26110718

  17. Optimisation and establishment of separation conditions of organic acids from Usnea longissima Ach. by pH-zone-refining counter-current chromatography: Discussion of the eluotropic sequence.

    PubMed

    Sun, Changlei; Liu, Feng; Sun, Jie; Li, Jia; Wang, Xiao

    2016-01-01

    The major bioactive constituents of Usnea longissima Ach. are organic acids. However, few recent literatures involve the preparative separation of these organic acids. In the present study, pH zone-refining counter-current chromatography is used to separate organic acids from crude sample of U. longissima Ach. The crude extract was separated with the two-phase solvent system Pet-EtAc-MeOH-H2O (5:5:3:7, v/v) with 10mM TFA in organic stationary phase and different concentration of the eluter in aqueous mobile phase for the screening of the most suitable separation conditions. From the crude extract (1.2g), 74.0mg of orsellinic acid at 92.7% purity, 55.5mg of 4-O-methylorsellinic acid at 97.7% purity, 353.5mg of evernic acid at 93.8% purity, 102.0mg of barbatic acid at 94.8% purity, 19.4mg of diffractaic acid at 92.2% purity, and 44.9mg of usnic acid at 95.7% purity were obtained using the selected conditions in which the concentration of TFA in stationary phase was 10mM and the concentration of NaOH in mobile phase was 10-20mM. The purities of the separated organic acids were measured by HPLC. And the data of electrospray ionization-liquid chromatography/mass spectrometry (ESI-LC/MS), (1)H NMR, and (13)C NMR were used for confirming chemical structures. PMID:26686561

  18. Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5

    PubMed Central

    Wilson, Michael D.; Riemer, Cathy; Martindale, Duane W.; Schnupf, Pamela; Boright, Andrew P.; Cheung, Tony L.; Hardy, Daniel M.; Schwartz, Scott; Scherer, Stephen W.; Tsui, Lap-Chee; Miller, Webb; Koop, Ben F.

    2001-01-01

    Chromosome 7q22 has been the focus of many cytogenetic and molecular studies aimed at delineating regions commonly deleted in myeloid leukemias and myelodysplastic syndromes. We have compared a gene-dense, GC-rich sub-region of 7q22 with the orthologous region on mouse chromosome 5. A physical map of 640 kb of genomic DNA from mouse chromosome 5 was derived from a series of overlapping bacterial artificial chromosomes. A 296 kb segment from the physical map, spanning Ache to Tfr2, was compared with 267 kb of human sequence. We identified a conserved linkage of 12 genes including an open reading frame flanked by Ache and Asr2, a novel cation-chloride cotransporter interacting protein Cip1, Ephb4, Zan and Perq1. While some of these genes have been previously described, in each case we present new data derived from our comparative sequence analysis. Adjacent unfinished sequence data from the mouse contains an orthologous block of 10 additional genes including three novel cDNA sequences that we subsequently mapped to human 7q22. Methods for displaying comparative genomic information, including unfinished sequence data, are becoming increasingly important. We supplement our printed comparative analysis with a new, Web-based program called Laj (local alignments with java). Laj provides interactive access to archived pairwise sequence alignments via the WWW. It displays synchronized views of a dot-plot, a percent identity plot, a nucleotide-level local alignment and a variety of relevant annotations. Our mouse–human comparison can be viewed at http://web.uvic.ca/~bioweb/laj.html. Laj is available at http://bio.cse.psu.edu/, along with online documentation and additional examples of annotated genomic regions. PMID:11239002

  19. Maintenance of immune tolerance to a neo-self AChR antigen with aging: Implications for late-onset autoimmunity

    PubMed Central

    Stacy, Sue; Williams, Earlanda L.; Standifer, Nathan E.; Pasquali, Amanda; Krolick, Keith A.; Infante, Anthony J.; Kraig, Ellen

    2010-01-01

    Age-related changes in immune regulation are likely to account for the age-associated increase in serum autoantibody levels and in certain autoimmune disorders, like myasthenia gravis (MG). To demonstrate directly a loss of immune tolerance in older individuals, responses to the acetylcholine receptor (AChR), the autoantigen in MG, were assessed in transgenic mice expressing the Torpedo californica AChR (TAChR) ?-chain as a neo-self antigen. T cells from young transgenic mice had been shown to be tolerant to p146-162, the TAChR ?-chain peptide that dominated young nontransgenic T-cell responses in vitro. The immunodominance of p146-162 was not lost with age; fine specificity was preserved. Moreover, T-cell tolerance to p146-162, as well as to other epitopes of the TAChR ? chain extracellular domain, was maintained in old transgenic mice. Even multiple TAChR immunizations coupled with the MG-enhancing cytokine, IL-12, did not break tolerance. Additionally, T cells exhibiting CD4 upregulation, an early activation marker, were reduced in frequency equivalently in old and young transgenic animals suggesting that immune regulation in this model was not impacted by aging. Moreover, B-cell tolerance was also maintained with age. The persistence of immune tolerance was accompanied by an increase in the proportion of Tregs; it is speculated that this may compensate for deficiencies in central tolerance that occur due to thymic involution. In summary, our study reveals, for the first time, that some immune tolerance mechanisms do survive aging; this suggests that certain late onset autoimmune disorders may be induced by a specific insult that disrupts immune homeostasis. PMID:20435934

  20. The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor.

    PubMed

    Papke, Roger L; Bagdas, Deniz; Kulkarni, Abhijit R; Gould, Timothy; AlSharari, Shakir D; Thakur, Ganesh A; Damaj, M Imad

    2015-04-01

    The ?7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of neurological disorders including chronic pain and inflammatory diseases. Since ?7 can function as a ligand-gated ion channel, drug development initially focused on ligands that were selective activators of the ?7 ion channel. However, the best ?7 drugs for chronic pain and inflammation indications may not be ion channel activators but rather "silent agonists", which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is NS6740. We show that NS6740 selectively induces prolonged desensitization of ?7 nAChRs. There are two forms of ?7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations, NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form. NS6740 was tested in several pain models after in vivo administration in the mouse. Although it had no effects in acute thermal pain, NS6740 induced significant dose- and time-dependent antinociceptive activity in formalin- and acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for neuropathic pain. The antinociceptive activity of NS6740 in these models was ?7-dependent. In addition, NS6740 administration reversed pain-induced aversion, an important affective component of pain. The time and concentration dependence of the effects were consistent with NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for analgesia is accomplished by ?7 receptors in that conformation. PMID:25497451

  1. Quaternary Tectonic and Climatic Processes shaping the Central Andean hyperarid forearc (southern Peru)

    NASA Astrophysics Data System (ADS)

    Audin, Laurence; Benavente, Carlos; Zerathe, Swann; Saillard, Marianne; Hall, Sarah R.; Farber, Daniel L.

    2015-04-01

    Understanding the forearc structure and processes related to Quaternary evolution and uplift of the Western Andean Cordillera remains an outstanding scientific issue. Models of Andean Plateau evolution based on Tertiary volcanic stratigraphy since 5Ma suggest that the deformation was focused along the eastern margin of the plateau and that minimal uplift occurred along the Pacific margin. On the contrary, new tectonic data and Quaternary surface 10Be dating highlight the presence of recently active deformation, incision and alluvial processes within the upper Andean forearc together with a regional uplift of the coastal zone. Additionally, the high obliquity observed in the northern Arica Bend region makes it an ideal target to discuss whether partitioning of the oblique convergence is accommodated by the neotectonic features that dissect the Quaternary forearc. Our goals are both to decipher the Quaternary tectonic and climatic processes shaping the hyperarid forearc along strike and across strike. Finally, we aim to quantify the respective influence of these factors in the overall uplift of the Western Andes. Indeed, sequences of pediment surfaces, landslide products, paleolake deposits and marine terraces found along the oblique Peruvian margin are a unique set of datable markers that can be used to quantify the rates of Quaternary processes. In this study, we focus on the southern Peru hyperarid Atacama area where regional surfaces and tectonic markers (scarps, folds, temporary streams and paleolake levels offsets…) are well preserved for the Quaternary timescale. Numerous landsliding events align on the major fault segments and reflect Plio-Pleistocene climatic and tectonic activity together with filled and strath terraces. As the present day sea-level is one of the highest levels recorded for Quaternary time span, any emerged marine terrace is preserved by tectonic coastal uplift. In particular, the geomorphic and chronologic correlation between marine and continental planation surfaces or terraces permit to deduce net vertical rates and suggests that the along strike uplift affected not only the coast but also the overall ~50 km-wide forearc of the Western Andes. We produced a chronology of remnant low-relief surfaces and a new neotectonic map of the Central Andean forearc between ~14° and 18°S based on detailed field mapping and 10Be cosmogenic dating. We address 1) the spatial and temporal correlations of various markers, and 2) the correlation of the surface abandonment ages to various regional climatic events and 3) the description of neotectonic activity accommodating both uplift and partitioning. Multiple markers yield 10Be surface abandonment ages that spanning 35 ka to >2 Ma. Erosion surfaces >2 Ma yield low erosion rates of <0.1mm/yr. However uplift rates of ~0.1-1mm/yr and multiple surfaces dated at ~35 ka suggest that the hyperarid forearc landscape has been recently modified through Quaternary surface uplift and climatic events, contradicting the Miocene fossil forearc hypothesis. Generally, surface abandonment ages and activated landslides periods tend to correlate with cold wet periods preceding Plio Pleistocene deglaciation on the Altiplano. Finally, neotectonic oblique faults connecting at depth participate to topography building in the Arica Bend region and suggest that Quaternary surface abandonment is the result of both surface uplift in the forearc and specific high-discharge climate periods in the high Andes. Obtained Quaternary regional uplift rates and individual slip-rates suggest that the Andean forearc may accommodate as much as 0.5 to 1 mm/yr of regional uplift for the Quaternary time period.

  2. Analysis of a Global Database on Quaternary Explosive Volcanism

    NASA Astrophysics Data System (ADS)

    Ortiz, N.; Sparks, R. S.; Hobbs, L.

    2009-12-01

    Large volcanic eruptions, despite their low frequency of occurrence, have the potential to cause massive loss of life and affect the health of humans and animals and cause major economic losses. The knowledge of the evolution of past volcanic processes is key to mitigate the effects of future eruptions. Field studies along with application of diverse techniques of analysis generate volcanic data, such as, eruption ages, petrological classification, estimates of ejected volume, intensity and magnitude. The design of databases on volcano data constitutes a tool for experts in charge of identifying places at risk, forecasting volcano activity, and scientists interested in finding the relation between volcanic eruptions and climate change. A global database on Quaternary explosive on explosive volcanism has been developed as part of the VOGRIPA project and implemented which main aim is to facilitate accessing data on volcanic eruptions for the scientific community. An explosive eruption is included in the database if its magnitude is 4 or above and if it has been dated. Also at least one measure of the eruption magnitude, such as erupted mass, erupted volume or Volcano Explosivity Index (VEI) is required. The use of the age data is examined for periods of time according to the nature of the age data and also considering major Earth events such as glaciations and interglacials. As we go back in the time, peaks in volcanic activity most likely reflect biases of data; however is an increase in the number of explosive eruptions in the 7th to 10th century and in the past 650 years in the global database on explosive volcanism as well as ice core records. Statistical analyses are applied to eruption records to test the linked hypothesis that the volcanism has been constant over the time interval chosen and that there is not under-recording. The hypothesis is in agreement for the period between 15,000 and 45,000 years BP, and for the whole period including only eruptions with Magnitude 7. Number of explosive eruptions with M>4 and active volcanoes back to 40,000 years BP in 2,500 year intervals

  3. Quaternary borocarbides: Relatively high Tc intermetallic superconductors and magnetic superconductors

    NASA Astrophysics Data System (ADS)

    Mazumdar, Chandan; Nagarajan, R.

    2015-07-01

    Discovery of superconductivity in Y-Ni-B-C (Tc ? 13 K) gave rise to the class of quaternary rare earth transition metal borocarbide superconductors. Before the discovery of Fe-based arsenide superconductors, this was the only class of materials containing a magnetic element, viz., Ni, yet exhibiting Tcs > 5 K. Many members of this class have high Tc (>10 K). Tc of ?23 K in Y-Pd-B-C system equaled the record Tc known then, for intermetallics. Another feature that sets this class apart, is the occurrence of the exotic phenomenon of coexistence of superconductivity and magnetism at temperatures >5 K. Availability of large and electronically 'clean' single crystals and large Ginzburg-Landau (G-L) parameter, ?, have enabled detailed investigation of nonlocal effects of superconductivity. Intermediate value of upper critical field Hc2, has enabled detailed investigation of superconductivity in this class, over the complete H-T plane. This has revealed details of anisotropy of superconductivity (e.g., a fourfold symmetry in the square a-b plane is found) and raised questions on the symmetry of order parameter. After a brief outline of the discovery, this article gives a summary of the materials and highlights of superconducting properties of this class of materials. Interesting results from studies, using various techniques, on YNi2B2C (Tc ? 15 K) and LuNi2B2C (Tc ? 16 K) are presented, including observation of unusual square vortex lattice and its structural transformation with H and T. With conduction electrons involved in the magnetic order of this class of superconductors, the interplay of superconductivity and magnetism is intimate in these magnetic superconductors. With Tc (?11 K) > TN (?6 K) in ErNi2B2C, Tc (?8 K) = TN (?8 K) in HoNi2B2C and Tc (?6 K) < TN (?11 K) in DyNi2B2C, and with other parameters being favorable as mentioned earlier, this class of magnetic superconductors have become ideal materials to investigate the coexistence phenomenon. A few major results on these are presented.

  4. Ternary and quaternary oxides of Bi, Sr and Cu

    NASA Technical Reports Server (NTRS)

    Casais, M. T.; Millan, P.; Rasines, I.; Campa, J. A.

    1991-01-01

    Before the discovery of superconductivity in an oxide of Bi, Sr, and Cu, the system Bi-Sr-Cu-O had not been studied, although several solid phases had been identified in the two-component regions of the ternary system Bi2O3-Si-O-CuO. The oxides Sr2CuO3, SrCu2O2, SrCuO2, and Bi2CuO4 were then well known and characterized, and the phase diagram of the binary system Bi2O3-SrO had been established in the temperature range 620 to 1000 C. Besides nine solutions of compositions Bi(2-2x) Sr(x) O(3-2x) and different symmetries, this diagram includes three definite compounds of stoichiometries Bi(2)BrO4. Bi2Sr2O5, and Bi2Sr3O6 (x - 0.50, 0.67 and 0.75 respectively), only the second of which with known unit-cell of orthorhombic symmetry, dimensions (A) a = 14.293(2), b = 7.651(2), c = 6.172(1), and z = 4. The first superconducting oxide in the system Bi-Sr-Cu-O was initially formulated as Bi2Sr2Cu2O(7+x), with an orthorhombic unit-cell of parameters (A) a = 5.32, b = 26.6, c = 48.8. In a preliminary study the same oxide was formulated with half the copper content, Bi(2)Sr(2)CuO(6+x), and index its reflections assuming an orthorhombic unit-cell of dimensions (A) a = 5.390(2), b = 26.973(8), c = 24.69(4). Subsequent studies by diffraction techniques have confirmed the composition 2:2:1. A new family of oxygen-deficient perovskites, was characterized, after identifying by x ray diffraction the phases present in the products of thermal treatments of about 150 mixtures of analytical grade Bi2O3, Sr(OH)2-8H2O and CuO at different molar ratios. X ray diffraction data are presented for some other oxides of Bi and Sr, as well as for various quaternary oxides, among them an oxide of Bi, Sr, and Cu.

  5. Synthetic lipopeptide inhibitors of RAS oncoproteins

    Cancer.gov

    It is well known that overactive Ras signaling is linked to many forms of cancer, and despite intensive efforts worldwide to develop effective inhibitors of Ras, to date there is no anti-Ras inhibitor in clinical use.

  6. Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

    PubMed Central

    ?olovi?, Mirjana B; Krsti?, Danijela Z; Lazarevi?-Pašti, Tamara D; Bondži?, Aleksandra M; Vasi?, Vesna M

    2013-01-01

    Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases. PMID:24179466

  7. Biocatalysts with enhanced inhibitor tolerance

    DOEpatents

    Yang, Shihui; Linger, Jeffrey; Franden, Mary Ann; Pienkos, Philip T.; Zhang, Min

    2015-12-08

    Disclosed herein are biocatalysts for the production of biofuels, including microorganisms that contain genetic modifications conferring tolerance to growth and fermentation inhibitors found in many cellulosic feedstocks. Methods of converting cellulose-containing materials to fuels and chemicals, as well as methods of fermenting sugars to fuels and chemicals, using these biocatalysts are also disclosed.

  8. Bivalent Inhibitors of Protein Kinases

    PubMed Central

    Gower, Carrie M.; Chang, Matthew E. K.; Maly, Dustin J.

    2015-01-01

    Protein kinases are key players in a large number of cellular signaling pathways. Dysregulated kinase activity has been implicated in a number of diseases, and members of this enzyme family are of therapeutic interest. However, due to the fact that most inhibitors interact with the highly conserved ATP-binding sites of kinases, it is a significant challenge to develop pharmacological agents that target only one of the greater than 500 kinases present in humans. A potential solution to this problem is the development of bisubstrate and bivalent kinase inhibitors, in which an active site-directed moiety is tethered to another ligand that targets a location outside of the ATP-binding cleft. Because kinase signaling specificity is modulated by regions outside of the ATP-binding site, strategies that exploit these interactions have the potential to provide reagents with high target selectivity. This review highlights examples of kinase interaction sites that can potentially be exploited by bisubstrate and bivalent inhibitors. Furthermore, an overview of efforts to target these interactions with bisubstrate and bivalent inhibitors is provided. Finally, several examples of the successful application of these reagents in a cellular setting are described. PMID:24564382

  9. Overexpression of acetylcholinesterase gene in rice results in enhancement of shoot gravitropism.

    PubMed

    Yamamoto, Kosuke; Shida, Satoshi; Honda, Yoshihiro; Shono, Mariko; Miyake, Hiroshi; Oguri, Suguru; Sakamoto, Hikaru; Momonoki, Yoshie S

    2015-09-25

    Acetylcholine (ACh), a known neurotransmitter in animals and acetylcholinesterase (AChE) exists widely in plants, although its role in plant signal transduction is unclear. We previously reported AChE in Zea mays L. might be related to gravitropism based on pharmacological study using an AChE inhibitor. Here we clearly demonstrate plant AChE play an important role as a positive regulator in the gravity response of plants based on a genetic study. First, the gene encoding a second component of the ACh-mediated signal transduction system, AChE was cloned from rice, Oryza sativa L. ssp. Japonica cv. Nipponbare. The rice AChE shared high homology with maize, siratro and Salicornia AChEs. Similar to animal and other plant AChEs, the rice AChE hydrolyzed acetylthiocholine and propionylthiocholine, but not butyrylthiocholine. Thus, the rice AChE might be characterized as an AChE (E.C.3.1.1.7). Similar to maize and siratro AChEs, the rice AChE exhibited low sensitivity to the AChE inhibitor, neostigmine bromide, compared with the electric eel AChE. Next, the functionality of rice AChE was proved by overexpression in rice plants. The rice AChE was localized in extracellular spaces of rice plants. Further, the rice AChE mRNA and its activity were mainly detected during early developmental stages (2 d-10 d after sowing). Finally, by comparing AChE up-regulated plants with wild-type, we found that AChE overexpression causes an enhanced gravitropic response. This result clearly suggests that the function of the rice AChE relate to positive regulation of gravitropic response in rice seedlings. PMID:26277389

  10. The HIV entry inhibitors revisited.

    PubMed

    Leonard, J Thomas; Roy, Kunal

    2006-01-01

    The new generation of antiviral drugs intended to counter HIV-1 entry into susceptible cells is emerging swiftly. The antiviral agents that inhibit HIV entry to the target cells (denoted as HIV entry inhibitors) are already in different phases of clinical trials. Operating early in the viral life cycle, they prevent viral entry, and have a novel, highly specific mechanism of action with a low toxicity profile. Entry inhibitors have different toxicity and resistance profiles than the existing reverse transcriptase and protease inhibitors. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, thus offering the rationale for their combination in therapies for HIV-infected individuals. It is worth focusing on recent developments in HIV entry inhibitors, as most of the current drug regimens suffer from the events of developing resistance against existing combination therapies. Recent advances in the understanding of the cellular and molecular mechanisms of HIV-1 entry provide the basis for novel therapeutic strategies that prevent viral penetration of the target cell-membrane, while reducing detrimental virus and treatment effects on cells and prolonging virion exposure to immune defenses. A number of potential sites for therapeutic intervention become accessible during the narrow window between virus attachment and the subsequent fusion of viral envelope with the cell membrane. The HIV-1 coreceptors are particularly attractive from the perspective of identifying new antiviral compounds, since they are seven-transmembrane motif G protein-coupled receptors (GPCRs), a family of proteins that is a well-validated target for drug development. Among the many chemokine receptors that can mediate HIV-1 entry in vitro, only CCR5 and CXCR4 are of frontline pharmacological importance. In particular, CCR5 is essential for viral transmission and replication during the early and clinically latent phase of disease. Several small-molecule antagonists of CCR5 and CXCR4 that block chemokine binding and HIV-1 entry have been identified in recent years. Considerable advances have been made in the last years in the design of derivatives acting as inhibitors of HIV entry. The molecular mechanism involved in viral entry, the structural and functional aspects of entry inhibitors are reviewed here. We have also summarized the recent insights into how small-molecule antagonists interact with CCR5 and CXCR4, focusing on drug development programs that are well documented in the scientific literature. An overview of the entry inhibitors that are in preclinical or early clinical development, and the Quantitative Structure-Activity Relationships (QSAR) studies reported for the coreceptor antagonists are also be presented. PMID:16611075

  11. Structural Studies of the HIV-1 Integrase Protein: Compound Screening and Characterization of a DNA-Binding Inhibitor

    PubMed Central

    Hassounah, Said; Mesplède, Thibault; Wainberg, Mark A.

    2015-01-01

    Understanding the HIV integrase protein and mechanisms of resistance to HIV integrase inhibitors is complicated by the lack of a full length HIV integrase crystal structure. Moreover, a lentiviral integrase structure with co-crystallised DNA has not been described. For these reasons, we have developed a structural method that utilizes free software to create quaternary HIV integrase homology models, based partially on available full-length prototype foamy virus integrase structures as well as several structures of truncated HIV integrase. We have tested the utility of these models in screening of small anti-integrase compounds using randomly selected molecules from the ZINC database as well as a well characterized IN:DNA binding inhibitor, FZ41, and a putative IN:DNA binding inhibitor, HDS1. Docking studies showed that the ZINC compounds that had the best binding energies bound at the IN:IN dimer interface and that the FZ41 and HDS1 compounds docked at approximately the same location in integrase, i.e. behind the DNA binding domain, although there is some overlap with the IN:IN dimer interface to which the ZINC compounds bind. Thus, we have revealed two possible locations in integrase that could potentially be targeted by allosteric integrase inhibitors, that are distinct from the binding sites of other allosteric molecules such as LEDGF inhibitors. Virological and biochemical studies confirmed that HDS1 and FZ41 share a similar activity profile and that both can inhibit each of integrase and reverse transcriptase activities. The inhibitory mechanism of HDS1 for HIV integrase seems to be at the DNA binding step and not at either of the strand transfer or 3' processing steps of the integrase reaction. Furthermore, HDS1 does not directly interact with DNA. The modeling and docking methodology described here will be useful for future screening of integrase inhibitors as well as for the generation of models for the study of integrase drug resistance. PMID:26046987

  12. Millennial-scale ocean acidification and late Quaternary decline of cryptic bacterial crusts in tropical reefs

    E-print Network

    Riding, Robert

    Millennial-scale ocean acidification and late Quaternary decline of cryptic bacterial crusts, Spain ABSTRACT Ocean acidification by atmospheric carbon dioxide has increased almost continuously since occurring 12 000­ 10 000 years ago. We interpret this as an early effect of deglacial ocean acidification

  13. Quaternary Science Reviews 26 (2007) 17901809 Understanding the origin and analysis of sediment-charcoal records

    E-print Network

    2007-01-01

    Quaternary Science Reviews 26 (2007) 1790­1809 Understanding the origin and analysis of sediment-charcoal; received in revised form 15 March 2007; accepted 21 March 2007 Abstract Interpreting sediment-charcoal records is challenging because there is little information linking charcoal production from fires

  14. Salt diapirs in the Dead Sea basin and their relationship to Quaternary extensional tectonics

    E-print Network

    ten Brink, Uri S.

    Salt diapirs in the Dead Sea basin and their relationship to Quaternary extensional tectonics, USA b US Geological survey, Woods Hole Field Center, 384 Woods Hole Road, Woods Hole, MA 02543, USA extension of a brittle overburden and underlying salt causes differential loading that is thought

  15. Spontaneous Quaternary and Tertiary T-R Transitions of Human Hemoglobin in Molecular Dynamics Simulation

    E-print Network

    de Groot, Bert

    Spontaneous Quaternary and Tertiary T-R Transitions of Human Hemoglobin in Molecular Dynamics human hemoglobin (Hb) A under physiological conditions, starting from the R, R2, and T state-R Transitions of Human Hemoglobin in Molecular Dynamics Simulation. PLoS Comput Biol 6(5): e1000774. doi:10

  16. The insect response to climate change: Perspectives from the Quaternary record

    SciTech Connect

    Ashworth, A.C.; Schwert, D.P. . Quaternary Entomology Lab.)

    1993-03-01

    Data based on museum collections of insects are generally inadequate to answer questions related to the response of insects to recent and potential changes in climate. The most important source of information for this purpose is the late Quaternary fossil record. Abundant, well-preserved, [sup 14]C-dated assemblages of insect fossils provide information with which to answer the following questions: (1) will climate change result in speciation--all evidence suggests that species are constant through the climate changes of the late Quaternary, future climate change would not be expected to result in accelerated rates of speciation; (2) will climate change result in extinction--few species became extinct as a result of the large-scale changes in climate and physical environment during the quaternary, although large-scale extirpation might occur, future climate change would not be expected to result in widespread extinction of species; (3) will climate change result in changes in geographic distribution--species survived late Quaternary climatic change through the ability of individuals to disperse into suitable habitats. The result was large changes in geographic distribution of species, as exemplified by the succession of faunal changes that occurred in response to the climatic changes of the late Wisconsinan in the midcontinent, future climate change would be expected to result in significant range changes of species.

  17. Ligand-Enabled ?-C–H Olefination and Carbonylation: Construction of ?-Quaternary Carbon Centers

    PubMed Central

    2015-01-01

    Monoselective ?-C–H olefination and carbonylation of aliphatic acids has been accomplished by using a combination of a quinoline-based ligand and a weakly coordinating amide directing group. The reaction provides a new route for constructing richly functionalized all-carbon quaternary carbon centers at the ?-position of aliphatic acids. PMID:24666182

  18. Quaternary International 120 (2004) 185194 The distribution of salt marsh foraminifera at Little Dipper Harbour

    E-print Network

    Patterson, Timothy

    2004-01-01

    Quaternary International 120 (2004) 185­194 The distribution of salt marsh foraminifera at Little content at both 0­1 and 0­10 cm from a transect collected across the salt marsh at Little Dipper Harbour across the marsh at Little Dipper Harbour, New Brunswick. Only the 0­1 cm surface samples produce

  19. Quaternary Science Reviews 23 (2004) 561580 Recent environmental change and prehistoric human activity in

    E-print Network

    Nicoll, Kathleen

    2004-01-01

    Quaternary Science Reviews 23 (2004) 561­580 Recent environmental change and prehistoric human of Oxford, Mansfield Road, Oxford OX13TB, UK Received 21 March 2003; accepted 11 October 2003 Abstract rights reserved. 1. Introduction Converging lines of evidence from various geoarch- aeological

  20. Author's personal copy Beryllium-10 terrestrial cosmogenic nuclide surface exposure dating of Quaternary

    E-print Network

    Frankel, Kurt L.

    Terrestrial cosmogenic nuclides Optically stimulated luminescence Alluvial fans Shore lines Lake Manly Quaternary alluvial fans, and shorelines, spits and beach bars were dated using 10 Be terrestrial cosmogenic. Comparisons of 10 Be TCN ages on alluvial fan surfaces with chronostratigraphies based on soil development