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

PubMed Central

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

Zimmermann, M



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


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

Zimmermann, M



Electronic structure calculations toward new potentially AChE inhibitors  

NASA Astrophysics Data System (ADS)

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

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



Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with 'inverted' binding mode.  


Selective and nanomolar acetylcholinesterase inhibitors were obtained by connecting tri- and tetracyclic quinazolinones-previously described as moderately active and unselective cholinesterase (ChE) inhibitors-via a hydroxyl group in para position to an anilinic nitrogen with different amines linked via a three carbon atom spacer. These tri- and tetracyclic quinazolinones containing different alicyclic ring sizes and connected to tertiary amines were docked to a high-resolution hAChE crystal structure to investigate the preferred binding mode in relation to results obtained by experimental structure-activity relationships. While the 'classical orientation' locating the heterocycle in the active site was rarely found, an alternative binding mode with the basic aliphatic amine in the active center ('inverted' orientation) was obtained for most compounds. Analyses of extended SARs based on this inverted binding mode are able to explain the compounds' binding affinities at AChE. PMID:25047936

Darras, Fouad H; Wehle, Sarah; Huang, Guozheng; Sotriffer, Christoph A; Decker, Michael



Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE.  


A new series of donepezil-tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. These new hybrids combined a tacrine, 6-chlorotacrine or acridine unit as catalytic binding site and indanone (the heterocycle present in donepezil) or phthalimide moiety as peripheral binding site of the enzyme, connected through a different linker tether length. One of the synthesised compounds emerged as a potent and selective AChE inhibitor, which is able to displace propidium in a competition assay. These results seem to confirm the ability of this inhibitor to bind simultaneously to both sites of the enzyme and make it a promising lead for developing disease-modifying drugs for the future treatment of Alzheimer's disease. To gain insight into the molecular determinants that modulate the inhibitory activity of these compounds, a molecular modelling study was performed to explore their binding to the enzyme. PMID:16230018

Alonso, D; Dorronsoro, I; Rubio, L; Muñoz, P; García-Palomero, E; Del Monte, M; Bidon-Chanal, A; Orozco, M; Luque, F J; Castro, A; Medina, M; Martínez, A



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


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

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



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

SciTech Connect

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.

Zheng, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China) [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Li, Juan [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Qiu, Zhuibai [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China)] [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Xia, Zheng [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Li, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China)] [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Yu, Lining; Chen, Hailin; Chen, Jianxing [NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China)] [NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Xie, Qiong, E-mail: [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China)] [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Chen, Hongzhuan, E-mail: [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)



QSAR Models for the Reactivation of Sarin Inhibited AChE by Quaternary Pyridinium Oximes Based on Monte Carlo Method.  


For three random splits, one-variable models of oximes reactivation of sarin inhibited acetylcholinesterase (logarithm of the AChE reactivation percentage by oximes with concentration of 0.001 M) have been calculated with CORAL software. The total number of considered oximes was 42. Simplified molecular input line entry system (SMILES) and hydrogen-suppressed graph (HSG) are used to represent the molecular structure. Using CORAL software by means of the calculation with Monte Carlo optimization of the so called correlation weights for the molecular fragments, optimal SMILES-based descriptors were defined, which are correlated with an endpoint for the training set. The predictability of these descriptors for an external test are estimated. In this study hybrid representation HSG together with SMILES was used. The "classic" scheme (i.e. split data into the training set and test set) of building up quantitative structure-activity relationships was employed. Computational experiments indicated that this approach can satisfactorily predict the desired endpoint. Best model had following statistical characteristics n=32, r2= 0.6012, s= 0.279, F= 45 for training and n=10, r2= 0.9301, s= 0.076, Rm2=0.9206 for test set. PMID:25479380

Veselinovi?, Aleksandar M; Veselinovi?, Jovana B; Toropov, Andrey A; Toropova, Alla P; Nikoli?, Goran M



A Structure-Based Design Approach to the Development of Novel, Reversible AChE Inhibitors  

E-print Network

. Medicinally, it has been targeted in treatments for Alzheimer's disease, myasthenia gravis, and glaucoma focused on two key objectives, discovering (a) selective inhibitors of the mammalian enzyme for the effective treatment of Alzheimer's dis- ease, thereby avoiding the undesirable side effects

Sussman, Joel L.


Acetylshikonin, a Novel AChE Inhibitor, Inhibits Apoptosis via Upregulation of Heme Oxygenase-1 Expression in SH-SY5Y Cells  

PubMed Central

Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, and ?,?-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10??M. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells. PMID:24302971

Wang, Yan; Pan, Wen-Liang; Liang, Wei-Cheng; Law, Wai-Kit; Tsz-Ming Ip, Denis; Ng, Tzi-Bun; Miu-Yee Waye, Mary; Chi-Cheong Wan, David



Acetylshikonin, a Novel AChE Inhibitor, Inhibits Apoptosis via Upregulation of Heme Oxygenase-1 Expression in SH-SY5Y Cells.  


Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, and ?,?-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10??M. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells. PMID:24302971

Wang, Yan; Pan, Wen-Liang; Liang, Wei-Cheng; Law, Wai-Kit; Tsz-Ming Ip, Denis; Ng, Tzi-Bun; Miu-Yee Waye, Mary; Chi-Cheong Wan, David



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


The acetylcholinesterase (AChE)-knockout mouse is a new tool for identifying physiologically relevant targets of organophosphorus toxicants (OP). If AChE were the only important target for OP toxicity, then mice with zero AChE would have been expected to be resistant to OP. The opposite was found. AChE-/- mice were more sensitive to the lethality of DFP, chlorpyrifos oxon, iso-OMPA, and the nerve agent VX. A lethal dose of OP caused the same cholinergic signs of toxicity in mice with zero AChE as in mice with normal amounts of AChE. This implied that the mechanism of toxicity of a lethal dose of OP in AChE-/- mice was the same as in mice that had AChE, namely accumulation of excess acetylcholine followed by overstimulation of receptors. OP lethality in AChE-/- mice could be due to inhibition of BChE, or to inhibition of a set of proteins. A search for additional targets used biotinylated-OP as a marker. In vitro experiments found that biotinylated-OP appeared to label as many as 55 proteins in the 100,000×g supernatant of mouse brain. Chlorpyrifos oxon bound a set of proteins (bands 12, 41, 45) that did not completely overlap with the set of proteins bound by diazoxon (bands 9, 12, 41, 47) or dichlorvos (bands 12, 23, 24, 32, 44, 45, 51) or malaoxon (band 9). These results support the idea that a variety of proteins could be interacting with a given OP to give the neurotoxic symptoms characteristic of a particular OP. PMID:21783513

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



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


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

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



Quaternary ammonium sulfanilamide: a membrane-impermeant carbonic anhydrase inhibitor  

SciTech Connect

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

Henry, R.P.



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

Microsoft Academic Search

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

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



Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor.  


A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor. PMID:25562342

Fandrick, Keith R; Mulder, Jason A; Patel, Nitinchandra D; Gao, Joe; Konrad, Michael; Archer, Elizabeth; Buono, Frederic G; Duran, Adil; Schmid, Rolf; Daeubler, Juergen; Desrosiers, Jean-Nicolas; Zeng, Xingzhong; Rodriguez, Sonia; Ma, Shengli; Qu, Bo; Li, Zhibin; Fandrick, Daniel R; Grinberg, Nelu; Lee, Heewon; Bosanac, Todd; Takahashi, Hidenori; Chen, Zhidong; Bartolozzi, Alessandra; Nemoto, Peter; Busacca, Carl A; Song, Jinhua J; Yee, Nathan K; Mahaney, Paige E; Senanayake, Chris H



Arm ache.  


Both patients and providers hope for better management strategies for nonspecific activity-related upper limb pain (herein referred to as "arm ache"). The next innovation in the care of arm ache may arise from the strong evidence that mood, coping strategies (e.g., catastrophic thinking), and heightened illness concern-all very responsive to treatment with cognitive behavioral therapy-account for a large percentage of the variation in symptom intensity and magnitude of disability. This focus on treatments to reduce symptoms and disability represents a change in culture for patients and providers, both of whom are accustomed to the biomedical framework that anticipates a direct correspondence between illness (the state of being unwell) and disease (pathophysiology). Not all patients are ready for such an approach, but as a first step health providers can prioritize empathy; remain mindful that words, illness concepts, and treatments can reinforce ineffective coping strategies; and encourage curiosity about the human illness experience. PMID:24839415

Chabok, Hosein Ahmadzadeh; Ring, David



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


As a key enzyme that hydrolyzes the neurotransmitter acetylcholine in cholinergic synapses of both vertebrates and invertebrates, acetylcholinesterase (AChE) is strongly inhibited by organophosphates. AChE inhibition may induce the decrease of swimming ability. According to previous research, swimming behavior of different aquatic organisms could be affected by different chemicals, and there is a shortage of research on direct correlation analysis between swimming behavior and biochemical indicators. Therefore, swimming behavior and whole-body AChE activity of Daphnia magna under dichlorvos (DDVP) exposure were identified in order to clarify the relationship between behavioral responses and AChE inhibition in this study. In the beginning, AChE activity was similar in all treatments with the control. During all exposures, the tendency of AChE activity inhibition was the same as the behavioral responses of D. magna. The AChE activity of individuals without movement would decrease to about zero in several minutes. The correlation analysis between swimming behavior of D. magna and AChE activity showed that the stepwise behavioral response was mainly decided by AChE activity. All of these results suggested that the toxicity characteristics of DDVP as an inhibitor of AChE on the swimming behavior of organisms were the same, and the AChE activity inhibition could induce loss of the nerve conduction ability, causing hyperactivity, loss of coordination, convulsions, paralysis and other kinds of behavioral changes, which was illustrated by the stepwise behavioral responses under different environmental stresses. PMID:25112705

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



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

SciTech Connect

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.

Xia Menghang, E-mail: [NIH Chemical Genomics Center, National Institutes of Health, Bethesda, MD (United States); Shahane, Sampada A.; Huang, Ruili; Titus, Steven A. [NIH Chemical Genomics Center, National Institutes of Health, Bethesda, MD (United States); Shum, Enoch; Zhao Yong [Cerep, Inc., Redmond, WA (United States); Southall, Noel; Zheng, Wei [NIH Chemical Genomics Center, National Institutes of Health, Bethesda, MD (United States); Witt, Kristine L.; Tice, Raymond R. [National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States); Austin, Christopher P. [NIH Chemical Genomics Center, National Institutes of Health, Bethesda, MD (United States)



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...


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

PubMed Central

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.

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



Centrally acting oximes in reactivation of tabun-phosphoramidated AChE.  


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

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



Centrally Acting Oximes in Reactivation of Tabun-Phosphoramidated AChE  

PubMed Central

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

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



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

PubMed Central

Acetylcholinesterase (AChE; EC plays a crucial role in the rapid hydrolysis of the neurotransmitter acetylcholine, in the central and peripheral nervous system and might also participate in non-cholinergic mechanism related to neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-? (A?) peptide accumulation and synaptic alterations. We have previously shown that AChE is able to accelerate the A? peptide assembly into Alzheimer-type aggregates increasing its neurotoxicity. Furthermore, AChE activity is altered in brain and blood of Alzheimer’s patients. The enzyme associated to amyloid plaques changes its enzymatic and pharmacological properties, as well as, increases its resistant to low pH, inhibitors and excess of substrate. Here, we reviewed the effects of IDN 5706, a hyperforin derivative that has potential preventive effects on the development of AD. Our results show that treatment with IDN 5706 for 10?weeks increases brain AChE activity in 7-month-old double transgenic mice (APPSWE–PS1) and decreases the content of AChE associated with different types of amyloid plaques in this Alzheimer’s model. We concluded that early treatment with IDN 5706 decreases AChE–A? interaction and this effect might be of therapeutic interest in the treatment of AD. PMID:21949501

Carvajal, Francisco J.; Inestrosa, Nibaldo C.



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

PubMed Central

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

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



Reaction Gorge Fluctuation in Acetylcholinesterase (AChE)  

NSDL National Science Digital Library

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

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



In vitro reactivation kinetics of paraoxon- and DFP-inhibited electric eel AChE using mono- and bis-pyridinium oximes.  


Oxime-assisted reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a crucial step in the post-inhibitory treatment of OP intoxication. The limited efficacy of oxime reactivators for all OP nerve agents and pesticides led to the development of various novel oximes and their thorough kinetic investigations. Hence, in the present investigation, we have tested 10 structurally different pyridinium oxime-based reactivators for their in vitro potency to reactivate paraoxon- and DFP-inhibited electric eel AChE. From structure activity relationship point of view, various oximes such as mono-quaternary (2-PAM, K100, K024) and bis-quaternary symmetric (obidoxime, TMB-4) and asymmetric (K027, K048, K203, K618, K628) oximes bearing different connecting linkers (oxybismethylene, trimethylene, propane, butane, butene, and xylene) have been studied. The observed kinetic data demonstrate that not only the position of oxime group is decisive for the increased reactivation ability of oximes, but the role of connecting linker is also significant. Oximes with aliphatic linkers are superior reactivators than the oximes with unsaturated and aromatic linkers. The optimal chain length for plausible reactivation ability for paraoxon- and DFP-inhibited AChE is 3 or 4 carbon-carbon connecting linker between prydinium rings. PMID:24065055

Gupta, Bhanushree; Sharma, Rahul; Singh, Namrata; Kuca, Kamil; Acharya, J R; Ghosh, Kallol K



In Silico Studies in Probing the Role of Kinetic and Structural Effects of Different Drugs for the Reactivation of Tabun-Inhibited AChE  

PubMed Central

We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ?2.5 kcal/mol, which was ?5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O…H and N…H hydrogen bonding and C-H…? non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme. PMID:24312449

Lo, Rabindranath; Chandar, Nellore Bhanu; Kesharwani, Manoj K.; Jain, Aastha; Ganguly, Bishwajit



[The synergistic action of quaternary ammonium derivatives and inhibitors of nitrate reduction in respect to Pseudomonas aeruginosa].  


It was revealed that ability of zink chloride, copper sulphate, aluminium nitrate and sodium chloride to inhibit the nitrate reduction of Pseudomonas correlated with their potentiating influence on the antimicrobial activity of decamethoxin, a quaternary ammonium derivative. So, doses of zink chloride (0.01-0.04%), copper sulphate (0.04%), aluminium nitrate (0.04%), sodium fluoride (0.05-0.1%) able to inhibit effectively the reduction of anions of nitric acid decreased the minimal inhibitory concentration of decamethoxin against Pseudomonas strain ATCC 27853 to 0.15-10 mg/ml and minimal bactericidal concentration to 0.20-10 mg/ml in comparison with 15.6 and 60.4 mg/ml in the control without potentiators. Providing the use of respiration chain's inhibiting doses of sodium fluoride (0.1%) and zink chloride (0.01%), it became possible to decrease the resistance of 54 clinical samples of Pseudomonas aeruginosa to decamethoxin. PMID:9181976

Vievski?, A N



Diet-Induced Changes in AChE Activity after Long-Term Exposure  

Microsoft Academic Search

In the present study we investigated a potential mechanism by which high sugar (HS) and high fat (HF) diets could affect acetylcholinesterase (AChE) activity. The treatment with HS and HF diet was done for six months on male and female rats. The results showed decreased hippocampal AChE activity in male and females receiving HS and HF diets (HS 24% and

Rosilene R. Kaizer; Adriane C. da Silva; Vera M. Morsch; Maisa C. Corrêa; Maria R. C. Schetinger



ACh Receptors Link Two Signaling Pathways to Neuroprotection against Glutamate-Induced Excitotoxicity in Isolated RGCs  

PubMed Central

Previous studies have reported that activation of nicotinic ACh receptors on cultured pig retinal ganglion cells (RGCs) has a neuroprotective effect against glutamate-induced excitotoxicity (Wehrwein et al., 2004; Thompson et al., 2006). However, the mechanism linking nAChRs to neuroprotection is unknown. Here we tested the hypothesis that signaling cascades involving p38 MAP kinase and PI3 kinase ? Akt are involved in linking activation of nAChRs to neuroprotection in isolated pig RGCs. In ELISA studies, regulation of phosphorylated p38 MAP kinase and Akt were analyzed after inducing excitotoxicity or neuroprotection in the presence and absence of specific inhibitors for p38 MAP kinase and PI3 kinase. ELISA results demonstrated that ACh significantly increased phosphorylated Akt and decreased p38 MAP kinase. Glutamate increased phosphorylated p38 MAP kinase but had no significant effect on phosphorylated Akt. Other ELISA studies using p38 MAP kinase and PI3 kinase inhibitors also supported the hypothesis that ACh up-regulated Bcl-2 levels downstream from PI3 kinase and Akt, whereas glutamate down-regulated Bcl-2 levels downstream from p38 MAP kinase. RGC survival was subsequently assessed by culturing RGCs in conditions to induce excitotoxicity or neuroprotection in the presence or absence of specific inhibitors of p38 MAP kinase or PI3 kinase. The p38 MAP kinase inhibitor significantly decreased the number of RGCs that died by glutamate-induced excitotoxicity but had no effect on the number of cells that survived due to ACh-induced neuroprotection. PI3 kinase inhibitors significantly decreased cell survival caused by ACh-induced neuroprotection but had no effect on cell death caused by glutamate-induced excitotoxicity. These results demonstrate that glutamate mediates excitotoxicity through the p38 MAP kinase signaling pathway and that ACh provides neuroprotection by stimulating the PI3 kinase ? Akt ? Bcl-2 signaling pathway and inhibiting the p38 MAP kinase ? Bcl-2 pathway. PMID:19845831

Asomugha, C.O.; Linn, D.M.; Linn, C.L.



Quaternary Studies  

NSDL National Science Digital Library

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


Anticholinesterase inhibitory activity of quaternary alkaloids from Tinospora crispa.  


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

Yusoff, Mashitah; Hamid, Hazrulrizawati; Houghton, Peter



Chemiluminescent high-throughput microassay for evaluation of acetylcholinesterase inhibitors  

Microsoft Academic Search

Current drug therapies for Alzheimer's disease (AD) are mainly based on acetylcholinesterase (AChE) inhibitors. However, such inhibitors may possess non-optimal pharmacological properties or cause adverse effects, therefore research for the development of new drugs is still in progress. In this paper, a rapid and simple chemiluminescent (CL) assay for the in vitro evaluation of AChE inhibitors in which the activity

M. Guardigli; P. Pasini; M. Mirasoli; A. Leoni; A. Andreani; A. Roda



Induction of soluble AChE expression via alternative splicing by chemical stress in Drosophila melanogaster.  


Various molecular forms of acetylcholinesterase (AChE) have been characterized in insects. Post-translational modification is known to be a major mechanism for the molecular diversity of insect AChE. However, multiple forms of Drosophila melanogaster AChE (DmAChE) were recently suggested to be generated via alternative splicing (Kim and Lee, 2013). To confirm alternative splicing as the mechanism for generating the soluble form of DmAChE, we generated a transgenic fly strain carrying the cDNA of DmAChE gene (Dm_ace) that predominantly expressed a single transcript variant encoding the membrane-anchored dimer. 3' RACE (rapid amplification of cDNA ends) and western blotting were performed to compare Dm_ace transcript variants and DmAChE forms between wild-type and transgenic strains. Various Dm_ace transcripts and DmAChE molecular forms were observed in wild-type flies, whereas the transgenic fly predominantly expressed Dm_ace transcript variant encoding the membrane-anchored dimer. This supports alternative splicing as the major determinant in the generation of multiple forms of DmAChE. In addition, treatment with DDVP as a chemical stress induced the expression of the Dm_ace splice variant without the glycosylphosphatidylinositol anchor site in a dose-dependent manner and, accordingly, the soluble form of DmAChE in wild-type flies. In contrast, little soluble DmAChE was expressed in the transgenic fly upon exposure to DDVP. DDVP bioassays revealed that transgenic flies, which were unable to express a sufficient amount of soluble monomeric DmAChE, were more sensitive to DDVP compared to wild-type flies, suggesting that the soluble monomer may exert non-neuronal functions, such as chemical defense against xenobiotics. PMID:24637386

Kim, Young Ho; Kwon, Deok Ho; Ahn, Hyo Min; Koh, Young Ho; Lee, Si Hyeock



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

PubMed Central

Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand-binding domain, to discover a novel ?-conotoxin (?-TxIA) in the venom of Conus textile. ?-TxIA bound with high affinity to AChBPs from different species and selectively targeted the ?3?2 nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20° backbone tilt compared to other AChBP–conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases. PMID:17660751

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



mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells  

PubMed Central

Background Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist. Methods Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses. Results Decreased E-cadherin expression and increased vimentin and ?-SMA expression induced by TGF-?1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-?1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-?1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP. Conclusions Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs. PMID:24678619



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


Decrease in the expression or activity of acetylcholinesterase (AChE) enzymatic activity results in increased cholinergic tonus in the brain and periphery, with concomitant regulations of nicotinic and muscarinic receptors expression. We generated AChE knockout mice and characterized the behavioral phenotype of heterozygous animals, focusing on learning and memory functions. Male and female, AChE+/- and AChE+/+ littermate controls (129 sv strain) were tested at 5-9 weeks of age. AChE activity was significantly decreased in the hippocampus and cortex of AChE+/- mice, but butyrylcholinesterase activity was preserved. AChE+/- mice failed to show any difference in terms of locomotion, exploration and anxiety parameters in the open-field test. Animals were then tested for place learning in the water-maze. They were trained using a 'sustained acquisition' protocol (3 swim trials per day) or a 'mild acquisition' protocol (2 swim trials per day) to locate an invisible platform in fixed position (reference memory procedure). Then, during 3 days, they were trained to locate the platform in a variable position (working memory procedure). Learning profiles and probe test performances were similar for AChE+/- and AChE+/+ mice. Mice were then treated with the muscarinic receptor antagonist scopolamine (0.5, 5 mg/kg) 20 min before each training session. Scopolamine impaired learning at both doses in AChE+/+ mice, but only at the highest dose in AChE+/- mice. Moreover, the intracerebroventricular injection of amyloid-beta25-35 peptide, 9 nmol, 7 days before water-maze acquisition, failed to induce learning deficits in AChE+/- mice, but impaired learning in AChE+/+ controls. The peptide failed to be toxic in forebrain structures of AChE+/- mice, since an increase in lipid peroxidation levels was measured in the hippocampus of AChE+/+ but not AChE+/- mice. We conclude that the increase in cholinergic tonus observed in AChE+/- mice did not result in increased memory functions but allowed a significant prevention of the deleterious effects of muscarinic blockade or amyloid toxicity. PMID:19766675

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



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

PubMed Central

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. Images Figure 5 Figure 6 PMID:8782112

Cuevas, J; Adams, D J



Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis.  


Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer's disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with ?-? interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore -10.801 and MM-GBSA free energy -34.89?kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin-serine adduct has been investigated by the DFT approach at the vacuum MO6/6-311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH. PMID:24805972

Chadha, Nidhi; Tiwari, Anjani K; Kumar, Vikas; Lal, Sangeeta; Milton, Marilyn D; Mishra, Anil K



Current acetylcholinesterase-inhibitors: a neuroinformatics perspective.  


This review presents a concise update on the inhibitors of the neuroenzyme, acetylcholinesterase (AChE; EC 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

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



Irish Quaternary Association (IQUA)  

NSDL National Science Digital Library

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



The Alaska Quaternary Center  

NSDL National Science Digital Library

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



Molecular docking of fisetin with AD associated AChE, ABAD and BACE1 proteins.  


Alzheimer?s disease (AD) is one of the most common dementias showing slow progressive cognitive decline. Progression of intracerebral accumulation of beta amyloid (A?) peptides by the action of amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme and ?-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the degradation of Acetylcholinesterase (AChE) the main pathological characteristics of AD. Therefore, it is of interest to evaluate the importance of fisetin (a flavonol that belongs to the flavonoid group of polyphenols) binding with AChE, ABAD and BACE1 proteins. Docking experiment of fisetin with these proteins using two different tools namely iGEMDOCK and FlexX show significant binding with acceptable binding values. Thus, the potential inhibitory role of fisetin with AD associated proteins is documented. PMID:25352723

Dash, Raju; Emran, Talha Bin; Uddin, Mir Muhammad Nasir; Islam, Ashekul; Junaid, Md



Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection.  


Acetylcholinesterase is a member of the ?/? hydrolase protein super family, with a significant role in acetylcholine-mediated neurotransmission. Research in the modulators of AChEs has moved from a potent poison (Sarin, Soman) in war times to the potent medicine (physostigmine) in peaceful times. Natural anti-AChE includes carbamates, glycoalkaloids, anatoxins derived from green algae; synthetic anti-AChE includes highly poisonous organophosphates used as nerve gases and insecticides. Recently, the role of anti-AChE was reassessed from neurotoxins to neuron-protective in the diseases characterized by impaired acetylcholine-mediated neurotransmission like Alzheimer's disease (AD). So, the AChE has been proven to be the most viable therapeutic target for the symptomatic treatment of AD. This review article gives a spectrum of strategies to design AChE inhibitors used in the Alzheimer therapy. PMID:24148993

Singh, Manjinder; Kaur, Maninder; Kukreja, Hitesh; Chugh, Rajan; Silakari, Om; Singh, Dhandeep



Cholinesterase inhibitors from botanicals  

PubMed Central

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 are also presented and the scope for future research is discussed. PMID:24347920

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



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

Microsoft Academic Search

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

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



Quaternary and Geomorphology.  

ERIC Educational Resources Information Center

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"…

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



Indirect quenching fluororeceptor assay of anti-AChR antibodies.  


A fluororeceptor assay (FRA) has been developed for the determination of antibodies against acetylcholine receptor (AChR), employing an antifluorescein serum and fluorescein-labeled AChR. Antiserum raised against rat muscle AChR in rabbit and the labeled AChR are incubated with antifluorescein serum at room temperature. At high levels of anti-AChR, binding of the labeled AChR prevented subsequent binding of the fluorescein groups by antifluorescein, resulting in little change in the signals of the label. Conversely, at low levels of anti-AChR, the free fraction of the labeled AChR is available to be bound by antifluorescein, which markedly reduced fluorescence intensity of the label. Thus, the fluorescence intensity of the assay mixture directly reflects the amount of anti-AChR antibodies in the serum. It is concluded that the availability of fluorescein-labeled AChR and the antibody directed against it permit measurement of anti-AChR antibodies in human myasthenia. The quality of the assay and its preliminary clinical application have been evaluated. PMID:9271004

Messripour, M; Moein, S



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

PubMed Central

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

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



The characterization of Lucilia cuprina acetylcholinesterase as a drug target, and the identification of novel inhibitors by high throughput screening.  


Acetylcholinesterase (AChE, EC3.1.1.7.) is the molecular target for the carbamate and organophosphate pesticides that are used to combat parasitic arthropods. In this paper we report the functional heterologous expression of AChE from Lucilia cuprina (the sheep blowfly) in HEK293 cells. We show that the expressed enzyme is cell-surface-exposed and possesses a glycosyl-phosphatidylinositol membrane anchor. The substrates acetyl-, propionyl- and butyrylthiocholine (AcTC, PropTC, ButTC), and also 11 further thiocholine and homo-thiocholine derivatives were chemically synthesized to evaluate and compare their substrate properties in L. cuprina AChE and recombinant human AChE. The Michaelis-Menten constants K(M) for AcTC, PropTC and ButTC were found to be 3-7-fold lower for the L. cuprina AChE than for the human AChE. Additionally, 2-methoxyacetyl-thiocholine and isobutyryl-thiocholine were better substrates for the insect enzyme than for the human AChE. The AcTC, PropTC and ButTC specificities and the Michaelis-Menten constants for recombinant L. cuprina AChE were similar to those determined for AChE extracted from L. cuprina heads, which are a particularly rich source of this enzyme. The median inhibition concentrations (IC(50) values) were determined for 21 organophosphates, 23 carbamates and also 9 known non-covalent AChE inhibitors. Interestingly, 11 compounds were 100- to >4000-fold more active on the insect enzyme than on the human enzyme. The substrate and inhibitor selectivity data collectively indicate that there are structural differences between L. cuprina and human AChE in or near the active sites, suggesting that it may be possible to identify novel, specific L. cuprina AChE inhibitors. To this end, a high throughput screen with 107,893 compounds was performed on the L. cuprina head AChE. This led to the identification of 195 non-carbamate, non-organophosphate inhibitors with IC(50) values below 10?M. Analysis of the most potent hit compounds identified 19 previously unknown inhibitors with IC(50) values below 200nM, which were up to 335-fold more potent on the L. cuprina enzyme than on the human AChE. Some of these compounds may serve as leads for lead optimization programs to generate fly-specific pesticides. PMID:21530657

Ilg, Thomas; Cramer, Jörg; Lutz, Jürgen; Noack, Sandra; Schmitt, Harald; Williams, Heike; Newton, Trevor



Pharmacodynamics of cholinesterase inhibitors suggests add-on therapy with a low-dose carbamylating inhibitor in patients on long-term treatment with rapidly reversible inhibitors.  


Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-? peptide (A?) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced A? aggregation, most likely by competing with the A? peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between A? and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders. PMID:24217282

Darreh-Shori, Taher; Hosseini, Sharokh Makvand; Nordberg, Agneta



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

NASA Astrophysics Data System (ADS)

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

Wang, Jing; Gu, Jiande; Leszczynski, Jerzy



Dual binding site acetylcholinesterase inhibitors: potential new disease-modifying agents for AD.  


The therapeutic potential of acetylcholinesterase (AChE) inhibitors has been strengthened recently by evidence showing that besides their role in cognitive function, they might contribute to slow down the neurodegeneration in Alzheimer's disease (AD) patients. It is known that AChE exerts secondary noncholinergic functions, related to its peripheral anionic site, in cell adhesion and differentiation, and recent findings also support its role in mediating the processing and deposition of beta-amyloid (Abeta) peptide. AChE is one of the proteins that colocalizes with Abeta peptide deposits in the brain of AD patients and promotes Abeta fibrillogenesis by forming stable AChEA beta complexes. Additionally, it has also been postulated that AChE binds through its peripheral site to the Abeta nonamyloidogenic form and acts as a pathological chaperone inducing a conformational transition to the amyloidogenic form (Inestrosa et al., 1996; Bartolini et al., 2003). Anew series of dual binding site AChE inhibitors has been designed and synthesized as new potent AChE inhibitors, which might simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting Abeta peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. PMID:17192640

del Monte-Millán, María; García-Palomero, Esther; Valenzuela, Rita; Usán, Paola; de Austria, Celia; Muñoz-Ruiz, Pilar; Rubio, Laura; Dorronsoro, Isabel; Martínez, Ana; Medina, Miguel



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


The magnitude of fluorescence enhancement was found to depend strongly on the distance between fluorophores and metal nanostructures in metal-enhanced fluorescence (MEF). However, the precise placement of the particle in front of the molecule with nanometer accuracy and distance control is a great challenge. We describe a method using acetylcholinesterase (AChE) to modulate the distance between a gold nanoparticle (AuNP) and the fluorophore 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one) (DDAO). We found that DDAO is a reversible mixed type-I AChE inhibitor. DDAO binds to the peripheral anionic site and penetrates into the active gorge site of AChE via inhibition kinetics test and molecular docking study. The affinity ligand DDAO bound to AChE which was immobilized onto AuNPs, and its fluorescence was sharply enhanced due to MEF. The fluorescence was reduced by distance variations between the AuNP and DDAO, which resulted from other inhibitors competitively binding with AChE and partly or completely displacing DDAO. Experimental results show that changes in fluorescence intensity are related to the concentration of inhibitors present in the solution. In addition, the nanobiosensor has high sensitivity, with detection limits as low as 0.4 ?M for paraoxon and 10 nM for tacrine, and also exhibits different reduction efficiencies for the two types of inhibitor. Thus, instead of an inhibition test, a new type of affinity binding-guided fluorescent nanobiosensor was fabricated to detect AChE inhibitors, determine AChE inhibitor binding mode, and screen more potent AChE inhibitors. The proposed strategy may be applied to other proteins or protein domains via changes in the affinity ligand. PMID:22339669

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



Salicylanilide diethyl phosphates as cholinesterases inhibitors.  


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

Krátký, Martin; St?pánková, Sárka; Vor?áková, Katarína; Vinšová, Jarmila



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

E-print Network

(Gauthier, 2010). Neonicotinoids target nAChRs (Matsuda et al., 2001) and thus provide a tool to explore bee neurobiology. In honey bees, the neonicotinoid imidacloprid inhibits receptors for -aminobutyric acid (GABA transmission at cholinergic synapses (Jones et al., 2006). In honey bees, nAChRs are expressed in brain areas

Nieh, James


A novel class of selective acetylcholinesterase inhibitors: synthesis and evaluation of (E)-2-(benzo[d]thiazol-2-yl)-3-heteroarylacrylonitriles.  


(E)-2-(benzo[d]thiazol-2-yl)-3-heteroarylacrylonitriles are described as a new class of selective inhibitors of acetylcholinesterase (AChE). The most potent compound in the series exhibited good AChE inhibitory activity (IC?? = 64 µM). Compound 7f was found to be more selective than galanthamine in inhibiting AChE and it showed a moderate selectivity index. Kinetic studies on AChE indicated that a competitive type of inhibition pattern exist for these acrylonitrile derivates. Molecular docking models of the ligand-AChE complexes suggest that compound 7 g is located on the periphery of the AChE active site. PMID:23085657

de la Torre, Pedro; Saavedra, Luis Astudillo; Caballero, Julio; Quiroga, Jairo; Alzate-Morales, Jans H; Cabrera, Margarita Gutiérrez; Trilleras, Jorge



Quaternary Research Association  

NSDL National Science Digital Library

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


Synthesis and Biological Evaluation of a Phosphonate Analog of the Natural Acetyl Cholinesterase Inhibitor Cyclophostin  

PubMed Central

Two diastereomers of a phosphonate analog 6 of the AChE inhibitor cyclophostin were synthesized. The substitution reaction of phosphono allylic carbonate 10a with methyl acetoacetate gave the vinyl phosphonate 9a. Attempted hydrogenation/debenzylation gave an unexpected enolether lactone. Alternatively, selective hydrogenation, demethylation, cyclization and debenzylation gave the phosphonate analog of cyclophostin as a separable mixture of diastereomers 6. The trans phosphonate isomer was more active than cis isomer against AChE from two sources. PMID:18821801

Bandyopadhyay, Saibal; Dutta, Supratik; Spilling, Christopher D.; Dupureur, Cynthia M.; Rath, Nigam P.



International Union for Quaternary Research  

NSDL National Science Digital Library

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



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


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

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



Lycopodiaceae from Panama: a new source of acetylcholinesterase inhibitors.  


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

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



Novel tacrine analogs as potential cholinesterase inhibitors in Alzheimer's disease.  


Acetylcholinesterase inhibitors (AChEIs) are used for the treatment of Alzheimer's disease (AD). The increase in ACh levels ameliorates the symptoms of the disease. Tacrine is the first clinically approved drug as AChEI used in the treatment of AD. In this paper, we synthesized new tacrine analogs to act on catalytic and peripheral sites of AChE. Their inhibitory activity was evaluated. All novel compounds except 7a showed promising results toward AChE. Two compounds, 10b and 11b, are more potent than tacrine. Furthermore, molecular-modeling studies were performed for these two compounds to rationalize the obtained pharmacological activity. Moreover, various drug-likeness properties of the new compounds were predicted. PMID:24343873

El-Malah, Afaf; Gedawy, Ehab M; Kassab, Asmaa E; Salam, Rania M Abdel



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

Federal Register 2010, 2011, 2012, 2013, 2014

...Proposed Collection of Information: ACH Vendor/Miscellaneous Payment Enrollment Form...comments concerning the SF 3881 ``ACH Vendor/Miscellaneous Payment Enrollment Form...information described below: Title: ACH Vendor/Miscellaneous Payment Enrollment...



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

PubMed Central

Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. Recently, a great attention has been paid to the possible role of vascular changes in the pathogenesis of AD. Reduced microvascular density and degeneration of the endothelium are of structural cerebrovascular changes in AD. Acetylcholinesterase (AChE) inhibitors are widely used for the improvement of AD symptoms. Until now, however, the effects of AChE inhibitors on vascular changes including angiogenesis and endothelial cell apoptosis are not fully understood. In the present work, the effects of three AChE inhibitors (donepezil, rivastigmine, and galantamine) were tested on H2O2-induced apoptosis in human umbilical vein endothelial cells (HUVECs) and on angiogenesis in chicken chorioallantoic membrane model. Incubation of HUVEC with H2O2 led to a significant decrease in cell viability and an increase in the percentage of apoptotic cells. The tested drugs, at concentrations of 1–100??M, significantly inhibited the H2O2-induced toxicity. Also, all donepezil, rivastigmine and galantamine significantly increased the number of vessels in the chorioallantoic membrane when injected into fertilized eggs. In conclusion, AChE inhibitors possess angiogenesis-accelerating properties and have antiapoptotic effects on endothelial cells. These effects of AChE inhibitors may be involved in their beneficial effects on AD. PMID:24159418

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



Acetylcholinesterase inhibitors with photoswitchable inhibition of ?-amyloid aggregation.  


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

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



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


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

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



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


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

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



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

NASA Technical Reports Server (NTRS)

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.

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



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.  


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

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



Synthesis of aminoalkyl-substituted aurone derivatives as acetylcholinesterase inhibitors.  


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

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



Quaternary Faunal Environments  

NSDL National Science Digital Library

Students collect information the environments associated with a list of presently living mammals. Students use FAUNMAP to explore the spatial patterns associated with these living mammals during the late Quaternary. They compare these distributions for living mammals to the distribution patterns for a set of extinct mammals. Students answer a set of questions that provide a basis for a summary report.

Christopher Hill


Gypsogenin derivatives: an unexpected class of inhibitors of cholinesterases.  


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

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



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

ERIC Educational Resources Information Center

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…

Munzel, Mark


Actuation of kagome lattice structures A.C.H. Leung  

E-print Network

Actuation of kagome lattice structures A.C.H. Leung D.D. Symons and S.D. Guest Department shown to have promise as the basis of active structures, whose shape can be changed by linear actuators of the actuation of a single bar in a large two-dimensional kagome lat- tice. Previous work has shown

Guest, Simon



E-print Network

OMB No. 1510-0056 ACH VENDOR/MISCELLANEOUS PAYMENT ENROLLMENT FORM This form is used processed through the Vendor Express Program. Recipients of these payments should bring this information will be used by the Treasury Department to transmit payment data, by electronic means to vendor's financial


Effect of acetylcholinesterase (AChE) point-of-care testing in OP poisoning on knowledge, attitudes and practices of treating physicians in Sri Lanka  

PubMed Central

Background Toxicology and Emergency medicine textbooks recommend measurement of acetylcholinesterase (AChE) in all symptomatic cases of organophosphorus (OP) poisoning but laboratory facilities are limited in rural Asia. The accuracy of point-of-care (POC) acetylcholinesterase testing has been demonstrated but it remains to be shown whether results would be valued by clinicians. This study aims to assess the effect of seeing AChE POC test results on the knowledge, attitudes and practices of doctors who frequently manage OP poisoning. Methods We surveyed 23 clinicians, who had different levels of exposure to seeing AChE levels in OP poisoned patients, on a) knowledge of OP poisoning and biomarker interpretation, b) attitudes towards AChE in guiding poison management, oxime therapy and discharge decisions, and c) practices of ordering AChE in poisoning scenarios. Results An overall high proportion of doctors valued the test (68-89%). However, we paradoxically found that doctors who were more experienced in seeing AChE results valued the test less. Lower proportions valued the test in guidance of acute poisoning management (50%, p = 0.015) and guidance of oxime therapy (25%, p = 0.008), and it was apparent it would not generally be used to facilitate early discharge. The highest proportion of respondents valued it on admission (p < 0.001). A lack of correlation of test results with the clinical picture, and a perception that the test was a waste of money when compared to clinical observation alone were also comments raised by some of the respondents. Greater experience with seeing AChE test results was associated with increased knowledge (p = 0.034). However, a disproportionate lack of knowledge on interpretation of biomarkers and the pharmacology of oxime therapy (12-50%) was noted, when compared with knowledge on the mechanism of OP poisoning and management (78-90%). Conclusions Our findings suggest an AChE POC test may not be valued by rural doctors. The practical use of AChE in OP poisoning management is complex, and a poor understanding of how to interpret test results may have affected its perceived utility. Future research should evaluate the impact of providing both AChE and training in interpretation on clinicians’ attitudes and practice. PMID:24589276



Esterase metabolism of cholinesterase inhibitors using rat liver in vitro.  


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

Moser, V C; Padilla, S



Inhibition of spicule elongation in sea urchin embryos by the acetylcholinesterase inhibitor eserine.  


The activity of acetylcholinesterase (AchE) increases rapidly after the gastrula stage of sea urchin development. In this report, changes in activity and in the molecular differentiation of AchE were investigated. AchE activity increased slightly during gastrulation and rose sharply thereafter, and was dependent on new RNA synthesis. No activity of butyrylcholinesterase was found. Morphogenesis in sea urchin embryos was inhibited by the AchE inhibitor eserine, which specifically inhibited arm rod formation but not body rod formation. Spicule formation and enzyme activity in cultured micromeres were inhibited by eserine in a dose-dependent manner. During gastrulation, two molecular forms of AchE were detected with polyacrylamide gel electrophoresis. The appearance of an additional band on the gel was consistent with the occurrence of a remarkable increase in the enzyme activity. This additional band appeared as a larger molecular form in Anthocidaris crassispina, Hemicentrotus pulcherrimus, Stomopneustes variolaris, and Strongylocentrotus nudus, and as a smaller form in Clypeaster japonicus and Temnopleurus hardwicki. These results suggest that the change in the molecular form of AchE induced a change in enzymatic activity that in turn may play a role in spicule elongation in sea urchin embryos. PMID:19383547

Ohta, Kazumasa; Takahashi, Chifumi; Tosuji, Hiroaki



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

Microsoft Academic Search

The inhibitive action of some quaternary ammonium salts towards the corrosion of aluminium in hydrochloric acid was tested by thermometric, mass loss and polarization measurements. Parallelism between the different methods was established. It is suggested that the tested compounds act as cathodic inhibitors. The inhibitors appear to function through adsorption, following the Temkin adsorption isotherm. The values of free energy

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



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


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

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



Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines.  


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

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



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

PubMed Central

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

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.



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

PubMed Central

There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening towards other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested. PMID:22148173

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



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


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

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



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


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

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



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

PubMed Central

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

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



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


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

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



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

PubMed Central

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



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


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

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



Quaternary Research Association Educational Resources  

NSDL National Science Digital Library

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


Topic in Depth - Quaternary Studies  

NSDL National Science Digital Library

Quaternary Studies examines the geologic period of the Quaternary, the last two million years up to the present day. Glaciers formed and receded; animals evolved and went extinct. Here, visitors can learn all about current research and education initiatives in this field of stratigraphic geology.



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


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

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



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


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

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



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


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

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



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

PubMed Central

Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC50 of 3 ?M. Potency is only preserved when the cyclic enol phosphonate is intact and conjugated to an ester. Kinetic analysis indicates both a binding and a slow inactivation step for all active compounds. Mass spectrometric analysis indicates that the active site Ser is indeed phosphorylated by the bicyclic phosphonate. PMID:20189400

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



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


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

Singh, Digvijay; Singh, Ajay



Marine natural products as acetylcholinesterase inhibitor: comparative quantum mechanics and molecular docking study.  


Alzheimer's disease (AD) is the most common form of dementia which affects the elderly population throughout the world. The inhibition of acetylcholinesterase (AChE) has appeared as one of the most promising strategies for the AD treatment. In this study, the density functional theory and molecular docking studies have been carried out on seven halogenated sesquiterpenes derived from the Persian Gulf sea hare, Aplysia dactylomela, to reveal their electronic, structural and chemical properties. Moreover, influences of these properties on their AChE-inhibition properties have been investigated theoretically. The results indicate that these compounds have several interactions with important residues of AChE active sites. Three of the investigated molecules correlate better to well-known AD drugs such as huperzine A, galanthamine and donepezil which represent possible AChE inhibitors against Alzheimer disease. In conclusion, the information obtained from this theoretical study may aid in the discovery of new potential AChE inhibitors with marine origin. PMID:24712383

Farrokhnia, Maryam; Nabipour, Iraj



Quaternary GIS Laboratory  

NSDL National Science Digital Library

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


The ?7 nAChR Selective Agonists as Drug Candidates for Alzheimer's Disease.  


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

Fan, Huaimeng; Gu, Ruoxu; Wei, Dongqing



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


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

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



Synthesis of Quaternary Heterocyclic Salts  

PubMed Central

The microwave synthesis of twenty quaternary ammonium salts is described. The syntheses feature comparable yields to conventional synthetic methods reported in the current literature with reduced reaction times and the absence of solvent or minimal solvent. PMID:24256924

Winstead, Angela J.; Nyambura, Grace; Matthews, Rachael; Toney, Deveine; Oyaghire, Stanley



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

NASA Astrophysics Data System (ADS)

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

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



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


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

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



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

PubMed Central

We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (kinact/KI) of 3,604–458,597?M?1sec?1 but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with kinact/KI values of 1,915 and 1,507?M?1sec?1, respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases. PMID:23323211

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



bis-Azaaromatic quaternary ammonium analogues: ligands for alpha4beta2* and alpha7* subtypes of neuronal nicotinic receptors.  


A series of bis-nicotinium, bis-pyridinium, bis-picolinium, bis-quinolinium and bis-isoquinolinium compounds was evaluated for their binding affinity at nicotinic acetylcholine receptors (nAChRs) using rat brain membranes. N,N'-Decane-1,12-diyl-bis-nicotinium diiodide (bNDI) exhibited the highest affinity for [(3)H]nicotine binding sites (K(i)=330 nM), but did not inhibit [(3)H]methyllycaconitine binding (K(i) >100 microM), indicative of an interaction with alpha4beta2*, but not alpha7* receptor subtypes, respectively. Also, bNDI inhibited (IC(50)=3.76 microM) nicotine-evoked (86)Rb(+) efflux from rat thalamic synaptosomes, indicating antagonist activity at alpha4beta2* nAChRs. N,N'-Dodecane-1,12-diyl-bis-quinolinium dibromide (bQDDB) exhibited highest affinity for [(3)H]methyllycaconitine binding sites (K(i)=1.61 microM), but did not inhibit [(3)H]nicotine binding (K(i)>100 microM), demonstrating an interaction with alpha7*, but not alpha4beta2* nAChRs. Thus, variation of N-n-alkyl chain length together with structural modification of the azaaromatic quaternary ammonium moiety afforded selective antagonists for the alpha4beta2* nAChR subtype, as well as ligands with selectivity at alpha7* nAChRs. PMID:12372503

Ayers, Joshua T; Dwoskin, Linda P; Deaciuc, A Gabriela; Grinevich, Vladimir P; Zhu, Jun; Crooks, Peter A



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


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

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



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...


3-Fluoro-2,4-dioxa-3-phosphadecalins as Inhibitors of Acetylcholinesterase. A Reappraisal of Kinetic Mechanisms and Diagnostic Methods  

E-print Network

that many of the prepared organophosphates of type I­IV (Fig. 1) are inhibitors of AChE [8­12] (Scheme 2 synthesized all the optically active (ee>99%) organophosphates of type I­IV (L¼F; Scheme 1), and the mentioned

Rüedi, Peter


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


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

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



Histamine innervation and activation of septohippocampal GABAergic neurones: involvement of local ACh release  

PubMed Central

Recent studies indicate that the histaminergic system, which is critical for wakefulness, also influences learning and memory by interacting with cholinergic systems in the brain. Histamine-containing neurones of the tuberomammillary nucleus densely innervate the cholinergic and GABAergic nucleus of the medial septum/diagonal band of Broca (MSDB) which projects to the hippocampus and sustains hippocampal theta rhythm and associated learning and memory functions. Here we demonstrate that histamine, acting via H1 and/or H2 receptor subtypes, utilizes direct and indirect mechanisms to excite septohippocampal GABA-type neurones in a reversible, reproducible and concentration-dependent manner. The indirect mechanism involves local ACh release, is potentiated by acetylcholinesterase inhibitors and blocked by atropine methylbromide and 4-DAMP mustard, an M3 muscarinic receptor selective antagonist. This indirect effect, presumably, results from a direct histamine-induced activation of septohippocampal cholinergic neurones and a subsequent indirect activation of the septohippocampal GABAergic neurones. In double-immunolabelling studies, histamine fibres were found in the vicinity of both septohippocampal cholinergic and GABAergic cell types. These findings have significance for Alzheimer's disease and other neurodegenerative disorders involving a loss of septohippocampal cholinergic neurones as such a loss would also obtund histamine effects on septohippocampal cholinergic and GABAergic functions and further compromise hippocampal arousal and associated cognitive functions. PMID:15486020

Xu, Changqing; Michelsen, Kimmo A; Wu, Min; Morozova, Elena; Panula, Pertti; Alreja, Meenakshi



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

PubMed Central

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

Gupta, Shikhar; Mohan, C. Gopi



Impact of quinalphos on blood glucose and acetylcholinesterase (AChE) activity in brain and pancreas in a roseringed parakeet ( Psittacula krameri borealis: Newmann)  

Microsoft Academic Search

Quinalphos (O,O-diethyl O-2-quinoxalinyl phosphorothioate), an organophosphate pesticide, was orally administered in graded sublethal doses (5 µg-, 10 µg- and 20 µg\\/ 100 g body mass\\/day) for 10 consecutive days to study the effects on the levels of blood glucose, liver- and muscle-glycogen, and acetylcholinesterase (AChE) activity in the brain and pancreas of adult male Roseringed parakeets (Psittacula krameri borealis). Orally

K. K. Anam; S. K. Maitra



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


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

Shinagawa, Shunichiro; Shigeta, Masahiro



Lithium Inhibits a Late Step in Agrin-Induced AChR Aggregation  

E-print Network

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

Sharma, Shiv K.


Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors  

PubMed Central

Aim: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). Methods: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BuChE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT. Results: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. Conclusion: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies. PMID:19578388

Shi, Yu-fang; Zhang, Hai-yan; Wang, Wei; Fu, Yan; Xia, Yu; Tang, Xi-can; Bai, Dong-lu; He, Xu-chang



Porphyrin derivatives as inhibitors for acetylcholinesterase from Drosophila melanogaster.  


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

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



Comparative functional expression of nAChR subtypes in rodent DRG neurons  

PubMed Central

We investigated the functional expression of nicotinic acetylcholine receptors (nAChRs) in heterogeneous populations of dissociated rat and mouse lumbar dorsal root ganglion (DRG) neurons by calcium imaging. By this experimental approach, it is possible to investigate the functional expression of multiple receptor and ion-channel subtypes across more than 100 neuronal and glial cells simultaneously. Based on nAChR expression, DRG neurons could be divided into four subclasses: (1) neurons that express predominantly ?3?4 and ?6?4 nAChRs; (2) neurons that express predominantly ?7 nAChRs; (3) neurons that express a combination of ?3?4/?6?4 and ?7 nAChRs; and (4) neurons that do not express nAChRs. In this comparative study, the same four neuronal subclasses were observed in mouse and rat DRG. However, the expression frequency differed between species: substantially more rat DRG neurons were in the first three subclasses than mouse DRG neurons, at all developmental time points tested in our study. Approximately 70–80% of rat DRG neurons expressed functional nAChRs, in contrast to only ~15–30% of mouse DRG neurons. Our study also demonstrated functional coupling between nAChRs, voltage-gated calcium channels, and mitochondrial Ca2+ transport in discrete subsets of DRG neurons. In contrast to the expression of nAChRs in DRG neurons, we demonstrated that a subset of non-neuronal DRG cells expressed muscarinic acetylcholine receptors and not nAChRs. The general approach to comparative cellular neurobiology outlined in this paper has the potential to better integrate molecular and systems neuroscience by uncovering the spectrum of neuronal subclasses present in a given cell population and the functionally integrated signaling components expressed in each subclass. PMID:24348328

Smith, Nathan J.; Hone, Arik J.; Memon, Tosifa; Bossi, Simon; Smith, Thomas E.; McIntosh, J. Michael; Olivera, Baldomero M.; Teichert, Russell W.



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

NASA Astrophysics Data System (ADS)

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

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



Most acetylcholinesterase activity of non-nervous tissues and cells arises from the AChE-H transcript.  


While the functional implications of AChE-T, PRiMA and ColQ have been firmly established, those of glypiated AChE remain uncertain. Insights into the physiological meaning of glycosylphosphatidylinositol (GPI)-linked AChE-H were gained by comparing nervous and non-nervous tissues for the amount of AChE mRNA variants they contained. PCR showed that AChE-T mRNA prevailed in the mouse brain, spinal cord, sciatic nerve and muscle, and AChE-H mRNA in the bone marrow and thymus, as well as in the human gut. The similar levels of AChE-T and AChE-H mRNAs in mouse liver and human kidney contrasted with the almost exclusive presence of catalytically active AChE-H in both organs. The absence of PRiMA mRNA in liver suggested that the tetramers made of AChE-T fail to bind to the cell membrane and are secreted due to the lack of PRiMA in non-nervous organs. In contrast, glypiated AChE-H is largely and lastingly bound to the cell membrane. Thus, non-synaptic glypiated AChE-H seems to be the counterpart of synaptic PRiMA-linked AChE-T, the former designed for clearing ACh waves, the latter for confronting ACh bursts, and both for helping to protect cells against the harmful effects of durable nicotinic and muscarinic activation. PMID:24242952

Montenegro, María Fernanda; Nieto-Cerón, Susana; Cabezas-Herrera, Juan; Muñoz-Delgado, Encarnación; Campoy, Francisco Javier; Vidal, Cecilio J



Quaternary uplift of southern Italy  

Microsoft Academic Search

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

Rob Westaway



Quaternary faults of west Texas  

Microsoft Academic Search

North- and northwest-striking intermontane basins and associated normal faults in West Texas and adjacent Chihuahua, Mexico, formed in response to Basin and Range tectonism that began about 24 Ma ago. Data on the precise ages of faulted and unfaulted Quaternary deposits are sparse. However, age estimates made on the basis of field stratigraphic relationships and the degree of calcic soil

E. W. Collins; J. A. Raney



Quaternary Studies: An Interdisciplinary Program  

NSDL National Science Digital Library

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



Inhibition of putrescine uptake by polypyridinium quaternary salts in B16 melanoma cells treated with difluoromethylornithine.  

PubMed Central

Several bipyridinium, tetrapyridinium and hexapyridinium quaternary salts have been found to be potent inhibitors of putrescine uptake into B16 melanoma cells which had previously been treated with difluoromethylornithine. In general, the potency of inhibitors increased as the number of quaternary centres increased. A relationship between the distance apart of the positively charged nitrogen atoms and the potency of the salts as inhibitors of uptake has been established by comparison with a number of diaminoalkanes. It was found that an inter-nitrogen distance of 0.6-0.7 nm or 1.0-1.1 nm was optimal for high activity. This finding is significant in determining structural features of the polyamine transport system. PMID:2508626

Minchin, R F; Martin, R L; Summers, L A; Ilett, K F



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

NASA Astrophysics Data System (ADS)

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

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



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

E-print Network

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

Fearing, Ron


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

E-print Network

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


[The action of quaternary ammonium derivatives on respiration and nitrate reduction in Pseudomonas aeruginosa].  


It was revealed that the same dosages of quaternary ammonium derivatives, such as decamethoxin and cetyltrimethylammonium bromide, inhibited the respiratory chains and caused destruction of Pseudomonas aeruginosa under aerobic conditions more effectively than under anaerobic ones when anions of nitric acid were the terminal acceptors of electrons. It was also registered that Pseudomonas were able to dissimilatory nitrate reduction in the media under the polysaccharide layer that was produced by these bacteria: this fact possibly proves the possibility of survival of denitrifying bacteria in solutions with high concentrations of quaternary ammonium salts. The data obtained permit supposing that inhibitors of respiratory chains and oxidizers may be used as potentiators of the antimicrobial action of quaternary ammonium derivatives. PMID:7952225

Bievski?, A N



Quaternary ecology: A paleoecological perspective  

SciTech Connect

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

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



40 CFR 721.4095 - Quaternary ammonium alkyltherpropyl trialkylamine halides.  

Code of Federal Regulations, 2010 CFR

... 2010-07-01 false Quaternary ammonium alkyltherpropyl trialkylamine halides...Substances § 721.4095 Quaternary ammonium alkyltherpropyl trialkylamine halides...substances identified generically as quaternary ammonium alkyltherpropyl trialkylamine...



21 CFR 172.165 - Quaternary ammonium chloride combination.  

Code of Federal Regulations, 2010 CFR

... 2009-04-01 true Quaternary ammonium chloride combination. 172.165 ...Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be...



40 CFR 721.4467 - Quaternary ammonium hydroxide.  

Code of Federal Regulations, 2010 CFR

... 2010-07-01 false Quaternary ammonium hydroxide. 721.4467 Section 721...Substances § 721.4467 Quaternary ammonium hydroxide. (a) Chemical substance...identified generically as a quaternary ammonium hydroxide (PMN P-95-1806)...



40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.  

Code of Federal Regulations, 2010 CFR

... false Ethoxylated alkyl quaternary ammonium compound. 721.655 Section 721...655 Ethoxylated alkyl quaternary ammonium compound. (a) Chemical substance...generically as an ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is...



40 CFR 721.10511 - Quaternary ammonium salts (generic).  

Code of Federal Regulations, 2014 CFR

...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,...



40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.  

Code of Federal Regulations, 2011 CFR

...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...



Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.  


A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates. PMID:18517184

Camps, Pelayo; Formosa, Xavier; Galdeano, Carles; Gómez, Tània; Muñoz-Torrero, Diego; Scarpellini, Michele; Viayna, Elisabet; Badia, Albert; Clos, M Victòria; Camins, Antoni; Pallàs, Mercè; Bartolini, Manuela; Mancini, Francesca; Andrisano, Vincenza; Estelrich, Joan; Lizondo, Mònica; Bidon-Chanal, Axel; Luque, F Javier



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


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. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25186309

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



Selection of corrosion inhibitors to control microbiologically influenced corrosion  

SciTech Connect

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

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



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


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

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



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


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

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



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

PubMed Central

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

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



Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.  


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

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



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

SciTech Connect

A plasma beam scanning treatment has been developed to modify the surface of the hydrogenated amorphous carbon (a-C:H) film on the indium tin oxide glass. The plasma beam scanning treatment makes the a-C:H film an excellent layer for liquid-crystal alignment. The qualities of a-C:H films were characterized by using atomic force microscope, micro-Raman spectroscopy, and field-emission scanning electron microscope. The ultrathin a-C:H films were deposited at 50% CH{sub 4}/(H{sub 2}+CH{sub 4}) gas ratio, 100 W radio-frequency power, and a gas pressure of 10 mtorr for 15 min by capacitive-coupled plasma chemical-vapor deposition method. The twist nematic cells were filled with liquid crystal (ZLI-2293) on the a-C:H film treated with different nitrogen plasma beam scanning time. The grooving mechanism is considered not responsible for the liquid-crystal (LC) alignment. Raman spectra suggest that a bond-breaking process of aromatic rings occurs in the a-C:H film. The O{sub 1s}, C{sub 1s}, and N{sub 1s} core-level spectra support that the nitrogen plasma beam scanning treatment induces a bond-breaking process of aromatic rings to create available carbon dangling bonds for the formation of C-O bonds. The newly formed C-O bonds are 'directional', which favor the LC alignment on the a-C:H film.

Wu, K.Y.; Chen, C.-H.; Yeh, C.-M.; Hwang, J.; Liu, P.-C.; Lee, C.-Y.; Chen, C.-W.; Wei, H.K.; Kou, C.S.; Lee, C.-D. [Department of Materials Science and Engineering, National Tsing Hua University, Hsin-Chu City, Taiwan (China); Mechanical Industry Research Laboratories, ITRI, Hsin-Chu City, Taiwan (China); Department of Physics, National Tsing Hua University, Hsin-Chu City, Taiwan (China); Materials Research Laboratories, ITRI, Hsin-Chu City, Taiwan (China)



?–RgIA, a Novel Conotoxin that Blocks the ?9?10 nAChR: Structure and Identification of Key Receptor Binding Residues  

PubMed Central

?-Conotoxins are small disulfide-constrained peptides from cone snails which act as antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). The 13-residue peptide ?-RgIA is a member of the ?-4,3 family of ?-conotoxins and selectively blocks the ?9?10 nAChR subtype, in contrast to another well characterized member of this family, ?-ImI, which is a potent inhibitor of the ?7 and ?3?2 nAChR subtypes. In this study, we have altered side chains in both the 4-residue and 3-residue loops of ?-RgIA, and have modified its C-terminus. The effects of these changes on activity against ?9?10 and ?7 nAChRs were measured, the solution structures of ?-RgIA and its Y10W, D5E and P6V analogues were determined from NMR data, and resonance assignments made for ?-RgIA[R9A]. The structures for ?-RgIA and its three analogues were well-defined except at the chain termini. Comparison of these structures with reported structures of ?-ImI reveals a common two-loop backbone architecture within the ?-4,3 family, but with variations in side chain solvent accessibility and orientation. Asp5, Pro6 and Arg7 in loop 1 are critical for blockade of both the ?9?10 and ?7 subtypes. In loop 2, ?-RgIA[Y10W] had activity near that of wild-type ?-RgIA, with high potency for ?9?10 and low potency for ?7, and had a similar structure to wild-type. By contrast, Arg9, in loop 2, is critical for specific binding to the ?9?10 subtype, probably because it is larger and more solvent accessible than Ala9 in ?-ImI. Our findings contribute to a better understanding of the molecular basis for antagonism of the ?9?10 nAChR subtype, which is a target for the development of analgesics for treatment of chronic neuropathic pain. PMID:18295795

Ellison, Michael; Feng, Zhi-Ping; Park, Anthony J.; Zhang, Xuecheng; Olivera, Baldomero M.; McIntosh, J. Michael; Norton, Raymond S.



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


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

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



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

Vuille, Mathias


Determinants of quaternary association in legume lectins  

Microsoft Academic Search

It is well known that the sequence of amino acids in proteins code for its tertiary structure. It is also known that there exists a relationship between sequence and the quaternary structure of proteins. The question addressed here is whether the nature of quaternary association can be predicted from the sequence, similar to the three-dimensional structure prediction from the sequence.

K. V. Brinda; Nivedita Mitra; Avadhesha Surolia; Saraswathi Vishveshwara



Stereoselective Synthesis of Quaternary Proline Analogues  

PubMed Central

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

Calaza, M. Isabel



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

SciTech Connect

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.

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



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


The aim of this study was to investigate the pathological changes in a rat model of Alzheimer's disease (AD) and the effect of donepezil hydrochloride (HCl) treatment. The rat model of AD was established by the bilateral injection of amyloid ????? (A?????) into the hippocampus. Changes in spatial learning and memory functions were examined using the Morris water maze test and changes in catalase (CAT) and glutathione peroxidase (GSH-Px) activities were determined using chemical colorimetry. Moreover, the changes in acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) expression were analyzed using immunohistochemical staining. The mRNA expression levels of the amyloid precursor protein (APP) and ?-secreted enzyme 1 (BACE1) were evaluated using RT-PCR. The effects of donepezil HCl on the aforementioned indices were also observed. The rat memories of the platform quadrants in the blank, sham and donepezil HCl groups were improved compared with those of the rats in the model group. The ratio of swim distance in the fourth platform quadrant (l?) to the total swim distance (l total) for the model group rats (l?/l total) was significantly decreased compared with that for the blank and sham group rats. Following donepezil HCl treatment, the ratio of l?/l total significantly increased. AD modeling caused a significant decrease in the CAT and GSH-Px activities in the brain tissues of the rats. The CAT and GSH-Px activities in the AD model rats significantly increased following donepezil HCl treatment. Moreover, donepezil HCl treatment significantly decreased the AChE, APP and BACE1 mRNA expression levels and increased the ChAT expression levels. Therefore, donepezil HCl was able to significantly decrease learning and memory damage in a rat model of AD. PMID:23023803

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



Treatment-responsive pandysautonomia in an adolescent with ganglionic ?3-AChR antibodies.  


Autoimmune autonomic ganglionopathy (AAG) is a rare disorder that presents with pandysautonomia typically in middle age and elderly patients. AAG is typically associated with serum autoantibodies that bind to the alpha-3 subunit of the ganglionic acetylcholine receptor (?3-AChR Ab). We report a 13 year old girl who presented with gut pseudo-obstruction, bladder dysfunction and dilated pupils unresponsive to pilocarpine. She had positive ?3-AChR Ab plus other autoantibodies suggesting an autoimmune diathesis. Our patient was initially resistant to steroid therapy but responded to the addition of azathioprine resulting in a near complete clinical remission. We conclude that pandysautonomia associated with ?3-AChR Ab can occur in children and has multi-organ involvement. PMID:22130491

Dale, Russell C; Lang, Bethan; Brilot, Fabienne; Polfrit, Yann; Smith, Grahame H H; Wong, Melanie



Neurochemical mechanism of the gastrointestinal interdigestive migrating motor complex in rats with acute inflammatory stomach ache  

PubMed Central

The normal gastrointestinal interdigestive migrating motor complex cycle was interrupted, and paroxysmal contraction appeared after formaldehyde-induced stomach ache. Activities of nitric oxide synthase, acetylcholinesterase and vasoactive intestinal peptide neurons were significantly reduced, whereas activities of calcitonin gene-related peptide neurons were significantly increased in the pyloric sphincter muscular layer, myenteric nerve plexus and submucous nerve plexus. Electroacupuncture at Zusanli (ST36) suppressed paroxysmal contraction in rats with formaldehyde-induced stomach ache, and neurons in the enteric nervous system were normal. These results indicated that nitrergic neurons, cholinergic neurons, vasoactive intestinal peptide neurons and calcitonin gene-related peptide neurons in the enteric nervous system may be involved in changes to the gastrointestinal interdigestive migrating motor complex following stomach ache, and that electroacupuncture can regulate this process.

Xu, Xiaoli; Li, Qin; Zhou, Lv; Ru, Liqiang



Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates.  


Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression. PMID:20167211

Camps, Pelayo; Formosa, Xavier; Galdeano, Carles; Gómez, Tània; Muñoz-Torrero, Diego; Ramírez, Lorena; Viayna, Elisabet; Gómez, Elena; Isambert, Nicolás; Lavilla, Rodolfo; Badia, Albert; Clos, M Victòria; Bartolini, Manuela; Mancini, Francesca; Andrisano, Vincenza; Bidon-Chanal, Axel; Huertas, Oscar; Dafni, Thomai; Luque, F Javier



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


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

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



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

PubMed Central

Second-long increases in prefrontal cholinergic activity (“transients”) were previously demonstrated to be necessary for the incorporation of cues into ongoing cognitive processes ("cue detection"). Nicotine and, more robustly, selective agonists at ?4?2* nicotinic acetylcholine receptors (nAChRs), enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of ?2-containing and ?7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the ?4?2* nAChR agonist ABT-089 or the ?7 nAChR agonist A-582941. Transients were recorded in mice lacking ?2 or ?7 nAChRs and in rats following removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of ?4?2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking ?2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by ?2* knockout. Conversely, in mice lacking the ?7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of ?7 nAChR in controlling the duration of release events, stimulation of ?7 nAChR produced cholinergic transients that lasted 10–15 fold longer than those evoked by nicotine. ?7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal ?4?2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance. PMID:20203212

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



Micromechanical measurement of AChBP binding for label-free drug discovery.  


A potential binding assay based on binding-driven micromechanical motion is described. Acetylcholine binding protein (AChBP) was used to modify a microcantilever. The modified microcantilever was found to bend on application of the naturally occurring agonist (acetylcholine) or the antagonist (nicotine and d-tubocurarine). Control experiments show that microcantilevers modified without AChBP do not respond to acetylcholine, nicotine, and d-tubocurarine. K(d) values obtained for acetylcholine, nicotine, and d-tubocurarine are similar to those obtained from radio-ligand binding assays. These results suggest that the microcantilever system has potential for use in label free, drug screening applications. PMID:22046583

Buchapudi, Koutilya; Xu, Xiaohe; Ataian, Yeganeh; Ji, Hai-Feng; Schulte, Marvin



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

PubMed Central

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



Xanthenedione derivatives, new promising antioxidant and acetylcholinesterase inhibitor agents.  


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

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



A fluorometric assay for acetylcholinesterase activity and inhibitor detection based on DNA-templated copper/silver nanoclusters.  


A novel label-free, rapid, cost-effective, and highly sensitive fluorometric sensor has been constructed for the detection of acetylcholinesterase (AChE) activity and its inhibitor based on the fluorescence quenching of DNA-templated copper/silver nanoclusters (DNA-Cu/AgNCs). In this assay, AChE catalyzes the hydrolysis of acetylthiocholine (ATCh) to form thiocholine which induces fluorescence quenching of DNA-Cu/AgNCs. The AChE activity could be detected as low as 0.05mU/mL and with a linear range from 0.05 to 2.0mU/mL. This assay offers a very convenient "mix and detect" approach for AChE activity. On the other hand, tacrine and organophosphorus pesticides (OPPs) were employed to inhibit the hydrolysis of ATCh, which could eliminate the fluorescence quenching of DNA-Cu/AgNCs. The IC50 of tacrine and methamidophos were estimated to be 16.9nM and 0.075mg/L, respectively. This method was also used to detect spiked OPPs in agricultural products successfully. The present work may expand the use of DNA-Cu/AgNCs to the field of enzyme sensors. PMID:23603132

Li, Wenhua; Li, Wang; Hu, Yufang; Xia, Yalin; Shen, Qinpeng; Nie, Zhou; Huang, Yan; Yao, Shouzhuo



Natural indole butyrylcholinesterase inhibitors from Nauclea officinalis.  


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

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



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

NASA Astrophysics Data System (ADS)

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

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



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


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

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



Usefulness of administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using paraoxon.  


Reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of irreversible organophosphorus AChE inhibitors (OPCs), when administered before OPC exposure. We have assessed in vivo the mortality-reducing efficacy of a group of known AChE inhibitors, when given in equitoxic dosage before exposure to the OPC paraoxon. Protection was quantified in rats by determining the relative risk (RR) of death. Best in vivo protection from paraoxon-induced mortality was observed after prophylactic administration of physostigmine (RR?=?0.30) or the oxime K-27 (RR?=?0.34); both treatments were significantly superior to the pre-treatment with all other tested compounds, including the established substance pyridostigmine. Tacrine (RR?=?0.67), ranitidine (RR?=?0.72), pyridostigmine (RR?=?0.76), tiapride (RR?=?0.80) and 7-MEOTA (RR?=?0.86) also significantly reduced the relative risk of paraoxon-induced death, but to a lesser degree. Methylene blue, amiloride and metoclopramide had an unfavorable effect (RR???1), significantly increasing mortality. When CNS penetration by prophylactic is undesirable K-27 is a promising alternative to pyridostigmine. PMID:22611016

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



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


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

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



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

PubMed Central

The identification and characterization of drugs for the treatment of cognitive disorders has been hampered by the absence of comprehensive hypotheses. Such hypotheses consist of (a) a precisely defined cognitive operation that fundamentally underlies a range of cognitive abilities and capacities and, if impaired, contributes to the manifestation of diverse cognitive symptoms; (b) defined neuronal mechanisms proposed to mediate the cognitive operation of interest; (c) evidence indicating that the putative cognition enhancer facilitates these neuronal mechanisms; (d) and evidence indicating that the cognition enhancer facilitates cognitive performance by modulating these underlying neuronal mechanisms. The evidence on the neuronal and attentional effects of nAChR agonists, specifically agonists selective for ?4?2* nAChRs, has begun to support such a hypothesis. nAChR agonists facilitate the detection of signals by augmenting the transient increases in prefrontal cholinergic activity that are necessary for a signal to gain control over behavior in attentional contexts. The prefrontal microcircuitry mediating these effects include ?4?2* nAChRs situated on the terminals of thalamic inputs and the glutamatergic stimulation of cholinergic terminals via ionotropic glutamate receptors. Collectively, this evidence forms the basis for hypothesis-guided development and characterization of cognition enhancers. PMID:19406107

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



Attention as Sigma-Pi Controlled ACh-Based John Taylor  

E-print Network

Attention as Sigma-Pi Controlled ACh-Based Feedback John Taylor Department of Mathematics King that any attention feedback control signals to lower order cortical sites will lead to a quadratic sigma the action of diffuse acetylcholine signals from the NBM, especially involving nicotinic receptors. We deduce

Heinke, Dietmar


Helium permeation through a-C:H films deposited on polymeric substrates  

NASA Astrophysics Data System (ADS)

The influence of amorphous hydrogenated carbon a-C:H coatings on gas permeation through polymer films was investigated. Hydrogenated amorphous carbon (a-C:H) films were deposited, at room temperature, from a CH4/Ar plasma produced by a radio frequency glow discharge system at 13.56 MHz. Polyether-etherketone (PEEK) and polyetherimide foils with different thicknesses were used as substrates. The permeation of He was measured and the reduction of the permeability coefficient is correlated here to the composition and density of the a-C:H films. The density and film structure of the layers were analyzed using x-ray reflectivity and Raman spectroscopy of films deposited onto silicon reference samples. A less pronounced reduction of the permeability coefficients for hard, dense diamond-like layers is reported with respect to those obtained for soft, polymer-like layers on PEEK substrates. Surprisingly, the barrier efficacy of the coating decreases with an increase in a-C:H film density. This unexpected result is attributed to intrinsic stress and the corresponding formation of microcracks. The effect of nitrogen incorporation, which reduces film permeability, is investigated in terms of the stress relaxation mechanism promoted. copyright 2002 American Vacuum Society.

Valentini, L.; Bellachioma, M. C.; Lozzi, L.; Santucci, S.; Kenny, J. M.



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

Microsoft Academic Search

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

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



Telithromycin blocks neuromuscular transmission and inhibits nAChR currents in vitro.  


Telithromycin, a ketolide antibiotic, is reported to exacerbate myasthenia gravis, potentially leading to respiratory failure and death. However, telithromycin is not associated with neuromuscular effects in animal toxicity studies. The objective of this study was to examine the effect of telithromycin on the neuromuscular junction in the isolated rat phrenic nerve-diaphragm preparation and to investigate its postsynaptic effects on the muscle-like nicotinic acetylcholine (ACh) receptors expressed on human TE671 cells. Telithromycin decreased the twitch contraction force of the rat diaphragm muscle in response to phrenic nerve stimulation in a concentration-dependent manner with an IC(50) of 22.3 microM and a maximal inhibition of approximately 70%. The trans-membrane current from the ACh receptors expressed in the TE671 neuromedulloblastoma cells was recorded in the whole-cell patch-clamp configuration. When applied to the TE671 cells, telithromycin caused a dose-dependent inhibition of the nicotinic ACh current with an IC(50) of 3.5 microM and maximal inhibition of nearly 100%. These results indicate that telithromycin inhibits postsynaptic nicotinic ACh receptors in vitro and partially blocks neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Based on these findings, we propose that exacerbation of myasthenia gravis reported in some patients taking telithromycin results in part from postsynaptic neuromuscular transmission block. PMID:20153815

Liu, Chang-Ning; Somps, Chris J



Actuation-softening in kagome lattice structures A.C.H. Leung  

E-print Network

Actuation-softening in kagome lattice structures A.C.H. Leung and S.D. Guest Department actuation resistance and high passive stiffness. Linear actuators replace some members of the truss: activation of the actuators results in a global macroscopic shape change. The linear behaviour

Guest, Simon


Ion-beam-induced hydrogen release from a-C:H: A bulk molecular recombination model  

NASA Astrophysics Data System (ADS)

Data on the hydrogen release from a-C:H induced by ion irradiation have been analyzed using a statistical model based on bulk molecular recombination. Good fits were obtained for all available data by adjusting a single parameter which is correlated to the stopping power of the projectile in the material.

Adel, M. E.; Amir, O.; Kalish, R.; Feldman, L. C.



trftEKirAch .anr 311{ffirw 3 .TTfiM' COUNCIL OF SCIENTIFIC & INDUSTRIAL  

E-print Network

· trftEKirAch .anr 311{ffirw 3 .TTfiM' COUNCIL OF SCIENTIFIC & INDUSTRIAL 3,101.ila arda, 2 Vif't J of the Moon. It has now been decided that for offims in Delhi / New Delhi, the Holiday on the occasion

Jayaram, Bhyravabotla


Authorization For Direct Deposit Of Vendor Payments (ACH) Click here for online help.  

E-print Network

Authorization For Direct Deposit Of Vendor Payments (ACH) Click here for online help. Instructions) CANCELLATION of a prior request Vendor is responsible for notifying The University of Memphis of any changes. Vendor Name: Federal Tax ID/U Number: Remit-to-Address: City: State: Zip Code: E-mail Address (REQUIRED

Dasgupta, Dipankar


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

PubMed Central

Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg) or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2%) for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE), choline acetylase (ChAT) and ?7 nicotinic receptor (?7-nAChR) were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or ?7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane. PMID:22114680

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



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

PubMed Central

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



GABA-to-ACh Ratio in Basal Forebrain and Cerebral Cortex Varies Significantly During Sleep  

PubMed Central

Study Objectives: GABAergic and cholinergic transmission within the basal forebrain and cerebral cortex contribute to the regulation of sleep and wakefulness. In contrast to levels of acetylcholine (ACh), levels of endogenous GABA in basal forebrain and cortex during sleep and wakefulness have not previously been quantified. This study (1) tested the hypothesis that there are differential, state-specific changes in GABA levels within the substantia innominata (SI) region of the basal forebrain and somatosensory cortex; and (2) quantified the ratio of GABAergic to cholinergic transmission in the SI, cortex, and pontine reticular formation during rapid eye movement sleep (REM), non-REM sleep (NREM), and wakefulness. Design: Within/between subjects. Setting: University of Michigan. Patients or Participants: Adult, male, purpose bred cats (n = 5). Interventions: In vivo microdialysis, high performance liquid chromatography, electrophysiological recordings. Measurements and Results: In the SI, GABA levels were significantly greater during NREM (17%) than during REM. In the cortex, GABA levels were significantly greater during NREM than during wakefulness (39%) and REM (63%). During prolonged wakefulness, there was a linear increase in cortical GABA levels, and the amount of time spent awake accounted for 87% of the variance in GABA. The GABA-to-ACh ratio was largest during NREM for all brain regions. REM was characterized by a 68% decrease in the GABA-to-ACh ratio across brain regions, always due to a decrease in GABA levels. Conclusion: Three of the brain regions that comprise the anatomically distributed, sleep-generating network have in common a GABA-mediated, sleep-dependent decrease in the GABA-to-ACh ratio. Citation: Vanini G; Lydic R; Baghdoyan HA. GABA-to-ACh ratio in basal forebrain and cerebral cortex varies significantly during sleep. SLEEP 2012;35(10):1325-1334. PMID:23024430

Vanini, Giancarlo; Lydic, Ralph; Baghdoyan, Helen A.



tetrakis-Azaaromatic quaternary ammonium salts: Novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release  

PubMed Central

A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized in order to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogues that inhibit these nAChRs. Three tetrakis analogues, 11j, 11f and 11g, were identified as potent (IC50 = 3, 28 and 56 nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists. PMID:18851914

Zhang, Zhenfa; Zheng, Guangrong; Pivavarchyk, Marharyta; Deaciuc, A. Gabriela; Dwoskin, Linda P.; Crooks, Peter A.



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


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

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



Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gating  

PubMed Central

We describe a highly disabling congenital myasthenic syndrome (CMS) associated with rapidly decaying, low-amplitude synaptic currents, and trace its cause to a valine to leucine mutation in the signature cystine loop (cys-loop) of the AChR ? subunit. The recently solved crystal structure of an ACh-binding protein places the cys-loop at the junction between the extracellular ligand-binding and transmembrane domains where it may couple agonist binding to channel gating. We therefore analyzed the kinetics of ACh-induced single-channel currents to identify elementary steps in the receptor activation mechanism altered by the ?V132L mutation. The analysis reveals that ?V132L markedly impairs ACh binding to receptors in the resting closed state, decreasing binding affinity for the second binding step 30-fold, but attenuates gating efficiency only about twofold. By contrast, mutation of the equivalent valine residue in the ? subunit impairs channel gating approximately fourfold with little effect on ACh binding, while corresponding mutations in the ? and ? subunits are without effect. The unique functional contribution of the ? subunit cys-loop likely owes to its direct connection via a ? strand to ?W149 at the center of the ligand-binding domain. The overall findings reveal functional asymmetry between cys-loops of the different AChR subunits in contributing to ACh binding and channel gating. PMID:12588888

Shen, Xin-Ming; Ohno, Kinji; Tsujino, Akira; Brengman, Joan M.; Gingold, Monique; Sine, Steven M.; Engel, Andrew G.



Genome Sequence of the Octopine-Type Agrobacterium tumefaciens Strain Ach5  

PubMed Central

We have sequenced the complete genome of the plant pathogen Agrobacterium tumefaciens strain LBA4213, a derivative of the wild-type strain A. tumefaciens Ach5 and the ancestor of A. tumefaciens strain LBA4404 used in genetic engineering. The genome consists of a circular chromosome and a linear chromosome, as well as a megaplasmid and a tumor-inducing plasmid. PMID:24675863

Henkel, Christiaan V.; den Dulk-Ras, Amke; Zhang, Xiaorong



Genome Sequence of the Octopine-Type Agrobacterium tumefaciens Strain Ach5.  


We have sequenced the complete genome of the plant pathogen Agrobacterium tumefaciens strain LBA4213, a derivative of the wild-type strain A. tumefaciens Ach5 and the ancestor of A. tumefaciens strain LBA4404 used in genetic engineering. The genome consists of a circular chromosome and a linear chromosome, as well as a megaplasmid and a tumor-inducing plasmid. PMID:24675863

Henkel, Christiaan V; den Dulk-Ras, Amke; Zhang, Xiaorong; Hooykaas, Paul J J



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

Microsoft Academic Search

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

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



In vitro and in vivo characterization of a novel negative allosteric modulator of neuronal nAChRs  

PubMed Central

In this study, we compared the in vitro and in vivo neuronal nicotinic acetylcholine receptor (nAChR) properties of 1,2,3,3a,4,8b-hexahydro-2-benzyl-6-N,N-dimethylamino-1-methylindeno[1,2,-b]pyrrole (HDMP, 4) to that of negative allosteric modulator (NAM), PCP. Patch-clamp experiments showed that HDMP exhibited an inhibitory functional activity at ?7 nAChRs with an IC50 of 0.07 ?M, and was 357- and 414-fold less potent at ?4?2 and ?3?4 nAChRs, with IC50s of 25.1 and 29.0 ?M, respectively. Control patch-clamp experiments showed that PCP inhibited ?7, ?4?2 and ?3?4 nAChRs with IC50s of to 1.3, 29.0 and 6.4 ?M, respectively. Further, HDMP did not exhibit any appreciable binding affinity to either ?7 or ?4?2 nAChRs, suggesting its action via a non-competitive mechanism at these neuronal nAChR subtypes. The in vivo study showed that HDMP was a potent antagonist of nicotine-induced analgesia in the tail-flick (AD50 = 0.008 mg/kg), but not in the hot-plate test. All together, our in vitro and in vivo data suggest that HDMP is a novel NAM of neuronal nAChRs with potent inhibitory activity at ?7 nAChR subtype at concentrations ? 1 ?M that are not effective for ?4?2 and ?3?4 nAChRs. PMID:20633568

Abdrakhmanova, Galya R.; Blough, Bruce E.; Nesloney, Carey; Navarro, Hernán A.; Damaj, M. Imad; Carroll, F. Ivy



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


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

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



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

PubMed Central

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

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



Pharmacodynamic study of FS-0311: a novel highly potent, selective acetylcholinesterase inhibitor.  


(1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311, a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance. PC12 cell injury was induced by beta-amyloid 25-35 (Abeta(25-35)), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase (AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against Abeta(25-35) peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising candidate in neurodegenerative diseases, such as Alzheimer's disease and Vascular dementia. PMID:17786550

Wang, Zhi Fei; Yan, Jin; Fu, Yan; Tang, Xi Can; Feng, Song; He, Xu Chang; Bai, Dong Lu



Cholinesterase enzymes inhibitors from the leaves of Rauvolfia reflexa and their molecular docking study.  


Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1), (E)-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl) acrylate (2), 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3) and 1,2,3,4-tetrahydro-1-oxo-?-carboline (4). The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM) and BChE (IC50 = 61.72 µM), respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes. PMID:23529036

Fadaeinasab, Mehran; Hadi, A Hamid A; Kia, Yalda; Basiri, Alireza; Murugaiyah, Vikneswaran



Corrosion inhibitor  

SciTech Connect

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

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



Anionic Lipid and Cholesterol Interactions with ?4?2 nAChR  

PubMed Central

Anionic lipids and cholesterols (CHOL) are critical to the function of nicotinic acetylcholine receptors (nAChR). We investigated their interactions with an open- and closed-channel ?4?2 nAChR by over 10-ns molecular dynamics simulations in a ternary lipid mixture of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidic acid (POPA), and CHOL with a ratio of 3:1:1. On average there were 65 and 74 interfacial lipids around the closed- and open-channel ?4?2 nAChR, respectively, in the equilibrated simulation systems. 42% of the interfacial POPA in the open-channel system had acyl chains partially inserted into intra- or inter-subunit cavities, as compared to only 7% in the closed-channel ?4?2. No CHOL was found in cavities within single subunits, though some CHOL infiltrated into the gaps between subunits. Because of its smaller head group, POPA could access some non-annular sites where POPC could not easily reach due to steric exclusion. Furthermore, POPA not only acted as an acceptor for hydrogen bonding (H-bonding) as POPC did, but also as a donor through its hydroxyl group for H-bonding with the backbone of the protein. The charged head group of POPA allowed the lipid to form stable salt bridges with conserved Arg and Lys residues at the interfaces of the transmembrane (TM) and extracellular (EC) or intracellular (IC) domains of the ?4?2. A higher number of salt bridges and hydrogen bonds (H-bonds) between POPA and the ?4?2 nAChR were found in the open system than in the closed system, suggesting a potential role of POPA in the equilibrium between different channel states. Most interfacial POPA molecules showed lower order parameters than the bulk POPA due to the mixed effect of gauche defects, hydrophobic mismatch, and the lipid orientations near the magic angle. These unique properties enable the interfacial POPA to achieve what POPC cannot with regard to specific interactions with the protein, thereby making POPA essential for the function of nAChR. PMID:19419220

Cheng, Mary H.; Xu, Yan; Tang, Pei



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

Code of Federal Regulations, 2013 CFR

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



Synthesis of Brominated 2-Phenitidine Derivatives as Valuable Inhibitors of Cholinesterases for the Treatment of Alzheimer’s Disease  

PubMed Central

The present study reports the synthesis of a series N-substituted derivatives of brominated 2-phenitidine. First, the reaction of 2-phenitidine (1) with benzenesulfonyl chloride (2) in aqueous media yielded N-(2-ethoxyphenyl) benzenesulfonamide (3), which was then subjected to bromination with bromine in the presence of glacial acetic acid to give N-(4,5-dibromo-2-ethoxyphenyl) benzenesulfonamide (4). Secondly, the product (4) on further treatment with alkyl/aryl halides (5a-l) in the presence of lithium hydride (LiH) produced twelve new derivatives of N-substituted sulfonamides (6a-l). These were characterized by 1H-NMR spectrum and screened against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX) and were found to be valuable inhibitors of butyrylcholinesterase (BChE) and acetylcholinesterase (AChE). Few of them were also active against LOX. PMID:24734059

Abbasi, Muhammad Athar; Saeed, Amna; Aziz-ur-Rehman; Mohmmed Khan, Khalid; Ashraf, Muhammad; Ejaz, Syeda Abida



Catalytic enantioselective synthesis of quaternary carbon stereocentres  

NASA Astrophysics Data System (ADS)

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.

Quasdorf, Kyle W.; Overman, Larry E.



Catalytic enantioselective synthesis of quaternary carbon stereocentres.  


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. PMID:25503231

Quasdorf, Kyle W; Overman, Larry E



The vascular effects of different arginase inhibitors in rat isolated aorta and mesenteric arteries  

PubMed Central

Background and purpose Arginase and nitric oxide (NO) synthase share the common substrate L-arginine, and arginase inhibition is proposed to increase NO production by increasing intracellular levels of L-arginine. Many different inhibitors are used, and here we have examined the effects of these inhibitors on vascular tissue. Experimental approach Each arginase inhibitor was assessed by its effects on isolated rings of aorta and mesenteric arteries from rats by: (i) their ability to preserve the tolerance to repeated applications of the endothelium-dependent agonist acetylcholine (ACh); and (ii) their direct vasorelaxant effect. Key results In both vessel types, tolerance (defined as a reduced response upon second application) to ACh was reversed with addition of L-arginine, (S)-(2-boronethyl)-L-cysteine HCl (BEC) or NG-Hydroxy-L-arginine (L-NOHA). On the other hand, N?-hydroxy-nor-L-arginine (nor-NOHA) significantly augmented the response to ACh, an effect that was partially reversed with L-arginine. No effect on tolerance to ACh was observed with L-valine, nor-valine or D,L, ?-difluoromethylornithine (DFMO). BEC, L-NOHA and nor-NOHA elicited endothelium-independent vasorelaxation in both endothelium intact and denuded aorta while L-valine, DFMO and nor-valine did not. Conclusions and implications BEC and L-NOHA, but not nor-NOHA, L-valine, DFMO or nor-valine, significantly reversed tolerance to ACh possibly conserving L-arginine levels and therefore increasing NO bioavailability. However, both BEC and L-NOHA caused endothelium-independent vasorelaxation in rat aorta, suggesting that these inhibitors have a role beyond arginase inhibition alone. Our data thus questions the interpretation of many studies using these antagonists as specific arginase inhibitors in the vasculature, without verification with other methods. PMID:19133993

Huynh, NN; Harris, EE; Chin-Dusting, JFP; Andrews, KL



Inhibitory mechanisms and binding site location for serotonin selective reuptake inhibitors on nicotinic acetylcholine receptors.  


Functional and structural approaches were used to examine the inhibitory mechanisms and binding site location for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholine receptors (AChRs) in different conformational states. The results establish that: (a) fluoxetine and paroxetine inhibit h alpha1beta1 gammadelta AChR-induced Ca(2+) influx with higher potencies than dizocilpine. The potency of fluoxetine is increased approximately 10-fold after longer pre-incubation periods, which is in agreement with the enhancement of [(3)H]cytisine binding to resting but activatable Torpedo AChRs elicited by these antidepressants, (b) fluoxetine and paroxetine inhibit the binding of the phencyclidine analog piperidyl-3,4-(3)H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3,4-piperidine to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits [(3)H]dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with the highest LUDI score interact with the domain between the valine (position 13') and leucine (position 9') rings. Molecular mechanics calculations also evidence electrostatic interactions of protonated fluoxetine at positions 20', 21', and 24'. Protonated dizocilpine bridges these two binding domains by interacting with the valine and outer (position 20') rings. The high proportion of protonated fluoxetine and dizocilpine calculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel between the leucine and valine rings, a domain shared with phencyclidine, finally blocking ion flux and inducing AChR desensitization. PMID:20079457

Arias, Hugo R; Feuerbach, Dominik; Bhumireddy, Pankaj; Ortells, Marcelo O



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


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

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



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


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

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



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

Microsoft Academic Search

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

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



BEETLE RECORDS Late Tertiary and Early Quaternary  

E-print Network

B BEETLE RECORDS Contents Overview Late Tertiary and Early Quaternary Middle Pleistocene of Europe of London, Surrey, UK ª 2007 Elsevier B.V. All rights reserved. The study of fossil beetles (Coleoptera of the world, most recently to Australia, New Zealand, and Japan. Fossil beetle research has led to many

Sheldon, Nathan D.


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

E-print Network

Enantioselective Construction of Cyclic Quaternary Centers: (-)-Mesembrine Douglass F. Taber next needed a dehydration method that would give predominantly the (E)-R, -unsaturated ester from) Gericke, N. P.; Van Wyk, B. E. World Patent 9746234, 1997. (2) For leading references to previous

Taber, Douglass


Antibacterial and Hemolytic Activities of Quaternary Pyridinium  

E-print Network

bacteria but not mammalian cells.[2­4] Polymers have been used as antimicrobial agents due commonly used as biocidal agents.[6­15] A number of polymeric disinfectants based on quaternary pyridinium bacteria. Recently, Gao and coworkers synthesized random copolymers of acrylamide and vinyl pyridine


Quaternary Ammonium Compounds as Water Channel Blockers  

E-print Network

, West Mains Road, EH9 3JJ Scotland, United Kingdom Excessive water uptake through Aquaporins (AQP) canQuaternary Ammonium Compounds as Water Channel Blockers SPECIFICITY, POTENCY, AND SITE OF ACTION, potency, and binding site of tetraethyl- ammonium (TEA) to block Aquaporin water permeability. Using

de Groot, Bert


Aromatase Inhibitors  


... used to reduce the risk of breast cancer? Tamoxifen and raloxifene Aromatase inhibitors Who should consider taking ... cancer risk To learn more References Previous Topic Tamoxifen and raloxifene Next Topic Who should consider taking ...


Novel coumarin derivatives bearing N-benzyl pyridinium moiety: potent and dual binding site acetylcholinesterase inhibitors.  


A novel series of coumarin derivatives linked to benzyl pyridinium group were synthesized and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The enzyme inhibitory activity of synthesized compounds was measured using colorimetric Ellman's method. It was revealed that compounds 3e, 3h, 3l, 3r and 3s have shown higher activity compared with donepezil hydrochloride as standard drug. Most of the compounds in these series had nanomolar range IC(50) in which compound 3r (IC(50) = 0.11 nM) was the most active compound against acetylcholinesterase enzyme. PMID:23140986

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



Comparative pharmacology of rat and human ?7 nAChR conducted with net charge analysis  

PubMed Central

Pharmacological studies of ?7 nicotinic acetylcholine receptors are confounded by the fact that rapid desensitization to high agonist concentration causes ?7 peak responses to occur well in advance of complete solution exchange. For this reason, peak currents are an invalid measure of response to applied agonist concentrations. We show that results comparable to those that have been corrected for instantaneous concentration are obtained if net charge is used as the measure of receptor response. Dose response curves obtained with these methods indicate that ?7 receptors are approximately 10 fold more sensitive to agonist than previously reported. The agonists, ACh, choline, cytisine, GTS-21, 4OH-GTS-21 and 4-MeO-CA have the same rank order potency for both human and rat receptors: 4-MeO-CA > 4OH-GTS-21 > GTS-21 > cytisine > ACh > choline. However, differences in efficacy exist between rat and human receptors. GTS-21 is more efficacious for rat than human ?7 receptors and cytisine more efficacious for human than rat ?7 receptors. Choline is the least potent agonist for both human and rat ?7, with a potency approximately 10 fold lower than that of ACh. While the EC50 for the activation of ?7 receptors by choline (400–500 ?M) is outside the normal physiological range (10–100 ?M), choline can nonetheless produce detectable levels of channel activation in the physiological concentration range. Since these concentrations are relatively non-desensitizing, the contribution of choline-activated ?7 receptor current may play a significant role in the regulation of calcium homeostasis in ?7-expressing neurons. PMID:12183330

Papke, Roger L; Porter Papke, Julia K



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

PubMed Central

ACH-702, a novel isothiazoloquinolone (ITQ), was assessed for antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and a Neisseria sp. but was less active against members of the Enterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well as Legionella pneumophila and Mycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10× MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple. In vivo efficacy was demonstrated against S. aureus with murine sepsis and thigh infection models, with decreases in the number of CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci, and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism of action include the following: low MIC values (?0.25 ?g/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of ?0.5 ?g/ml) against staphylococcal strains with two mutations in both gyrA and grlA, and low frequencies for the selection of higher-level resistance (<10?10). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates. PMID:21464250

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



[Throat ache ans swelling of the neck: first symptoms of Lemierre's syndrome].  


Lemierre's syndrome, a thrombophlebitis of the internal jugular vein, is a rare disorder, usually caused by the microorganism Fusobacterium necrophorum. Throat ache and swelling of the neck are often the first symptoms. Without adequate treatment, Lemierre's syndrome may result in thrombosis of the internal jugular vein and metastatic lung abscesses, with a mortality rate of 18%. On the basis of 2 cases, Lemierre's syndrome is described here. In cases where Lemierre's syndrome is suspected, hospitalization often follows, with the administration of intravenous antibiotics and drainage of the abscesses. One should be on the alert for Lemierre's syndrome when a patient is presented with swelling in the neck following an oropharyngeal infection. PMID:24684132

Ybema, A; de Lange, J; Baas, E M



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

PubMed Central

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



Mechanisms underlying ACh induced modulation of neurogenic and applied ATP constrictions in the submucosal arterioles of the guinea-pig small intestine  

PubMed Central

Role of the vascular endothelium in acetylcholine (ACh) induced modulation of neurogenic and applied ATP (adenosine 5?-triphosphate) constrictions of intestinal submucosal arterioles was investigated. Arteriole constrictions, induced either by exogenous ATP or evoked by perivascular nerve stimulation, were attenuated in the presence of ACh. 100?nM ACh almost completely abolished neurogenic constrictions whereas up to 10??M ACh reduced constrictions to exogenous ATP by only about 60%. Treatment of the arterioles with 100??M N?-nitro-L-arginine (NOLA) and 5??M indomethacin, to block respectively nitric oxide (NO) and prostanoid release from the endothelium, had no effect on the ACh induced inhibition of neurogenic constrictions but significantly attenuated the inhibitory effects of ACh on constrictions to exogenous ATP. Disruption of the vascular endothelium had no effect on the ACh induced inhibition of neurogenic constrictions but attenuated the inhibitory effects of ACh on applied ATP constrictions to the same extent as after treatment with NOLA and indomethacin. In comparison, endothelial disruption completely abolished the inhibitory effect of substance P (SP) on exogenously applied ATP constrictions. 50?nM ACh significantly attenuated the amplitude of neurally evoked excitatory junction potentials (ejps) recorded from the vascular smooth muscle without altering the time constant of decay (?decay) of the ejps. It is concluded that ACh inhibits neurogenic constrictions by prejunctional modulation of transmitter release from the perivascular sympathetic nerves with no major role for endothelial paracrine factors. Endothelial NO and/or prostanoids mediate some of the ACh induced inhibition of constrictions to exogenous ATP whereas the endothelium independent inhibitory effects of ACh are attributed to a direct action of ACh on the vascular smooth muscle. However, an indirect effect resulting from activation of vasodilator nerves cannot be ruled out. PMID:10323595

Kotecha, N



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


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

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



Antimitotic inhibitors.  


Of the agents available in the treatment of both solid and hematologic cancers, microtubule-targeted agents are among the most widely used and exploiting other mechanisms involving the microtubule and its role in mitosis is an area of continued interest. This review will focus on novel microtubule-targeted agents, both recently approved (eg, ixabepilone and eribulin) and in later-stage clinical trials, and kinase inhibitors that aim to directly inhibit the mitotic spindle, such as the aurora kinase, pololike kinase, and kinsein-spindle protein inhibitors. PMID:22520982

Campos, Susana M; Dizon, Don S



Quantifying ligand-receptor interactions for gorge-spanning acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.  


There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-à-vis the standard 3D-QSAR methods, CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE. These interactions were quantified to gauge the magnitude of their contribution to the biological activity. In order to validate the CoRIA model, a pharmacophore map was first constructed and then used to virtually screen public databases, from which novel scaffolds were cherry picked that were not present in the training set. The biological activities of these novel molecules were then predicted by the CoRIA, CoMFA, and CoMSIA models. The hits identified were purchased and their biological activities were measured by the Ellman's method for AChE inhibition. The predicted activities are in unison with the experimentally measured biological activities. PMID:24905476

Martis, Elvis A F; Chandarana, Rakesh C; Shaikh, Mushtaque S; Ambre, Premlata K; D'Souza, Jacinta S; Iyer, Krishna R; Coutinho, Evans C; Nandan, Santosh R; Pissurlenkar, Raghuvir R S



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


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

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



Quaternary phylogeography: the roots of hybrid zones  

Microsoft Academic Search

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

Godfrey M. Hewitt



Comparison of HDAC inhibitors in clinical development  

PubMed Central

Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. Design: In vitro study Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model. Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ?belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8–31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection. PMID:23370291

Rasmussen, Thomas Aagaard; Søgaard, Ole Schmeltz; Brinkmann, Christel; Wightman, Fiona; Lewin, Sharon R.; Melchjorsen, Jesper; Dinarello, Charles; Østergaard, Lars; Tolstrup, Martin



Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease.  


A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC?? values of 0.76 and 0.46 ?M, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD. PMID:24461494

Luo, Zonghua; Liang, Liang; Sheng, Jianfei; Pang, Yanqing; Li, Jianheng; Huang, Ling; Li, Xingshu



40 CFR 721.10154 - Quaternary ammonium compounds, dicoco alkyldimethyl, chlorides, reaction products with silica.  

Code of Federal Regulations, 2010 CFR

... 2010-07-01 false Quaternary ammonium compounds, dicoco alkyldimethyl, chlorides...Substances § 721.10154 Quaternary ammonium compounds, dicoco alkyldimethyl, chlorides...chemical substance identified as quaternary ammonium compounds, dicoco...



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

Code of Federal Regulations, 2010 CFR

...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...



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

Code of Federal Regulations, 2011 CFR

...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...



40 CFR 721.10154 - Quaternary ammonium compounds, dicoco alkyldimethyl, chlorides, reaction products with silica.  

Code of Federal Regulations, 2011 CFR

...2011-07-01 false Quaternary ammonium compounds, dicoco alkyldimethyl, chlorides... § 721.10154 Quaternary ammonium compounds, dicoco alkyldimethyl, chlorides...substance identified as quaternary ammonium compounds, dicoco alkyldimethyl,...



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

NASA Technical Reports Server (NTRS)

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

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



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


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

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



Effects of cholinesterase inhibitors on rat nicotinic receptor levels in vivo and in vitro  

PubMed Central

Cholinesterase inhibitors (ChEIs) are the mainstay of treatment for AD but differ by secondary mechanisms of action. We determine the effects of sub-chronic dosing of ChEIs on ?7 and non-?7 nAChRs and determine if differences can be observed between them. Sprague–Dawley rats were administered donepezil, galantamine; rivastigmine at two doses each, in saline SQ twice daily or with nicotine (0.4 mg/kg) as a positive control. After 14 days the animals were sacrificed, and the levels of nAChRs were measured using [3H]-EPI to measure non-?7 nAChRs and [3H]-MLA to measure ?7 nAChRs. In the cortex, all compounds tested at the higher doses significantly increased the levels of both [3H]-EPI and [3H]-MLA. In the hippocampus all compounds significantly increased [3H]-EPI but had no effect on [3H]-MLA binding. No effects were observed in the striatum with treatment. There were no differences observed among the ChEIs. In cell cultures, none of the ChEIs increased non-?7 or ?7 receptor binding. Treatment with ChEIs result in similar increases in receptor levels which suggest that the increases in nAChRs may be due simply to the increases in synaptic levels of acetylcholine. PMID:18726544

Sabbagh, Marwan N.



Quaternary Geologic Map of Connecticut and Long Island Sound Basin  

USGS Publications Warehouse

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.

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



MusÃ?©e AchÃ?©mÃ?©nide  

NSDL National Science Digital Library

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


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

NASA Technical Reports Server (NTRS)

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

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



Differential regulation of AChR clustering in the polar and equatorial region of murine muscle spindles.  


Intrafusal fibers of muscle spindles are innervated in the central region by afferent sensory axons and at both polar regions by efferent ?-motoneurons. We previously demonstrated that both neuron-muscle contact sites contain cholinergic synapse-like specialisation, including aggregates of the nicotinic acetylcholine receptor (AChR). In this study we tested the hypothesis that agrin and its receptor complex (consisting of LRP4 and the tyrosine kinase MuSK) are involved in the aggregation of AChRs in muscle spindles, similar to their role at the neuromuscular junction. We show that agrin, MuSK and LRP4 are concentrated at the contact site between the intrafusal fibers and the sensory- and ?-motoneuron, respectively, and that they are expressed in the cell bodies of proprioceptive neurons in dorsal root ganglia. Moreover, agrin and LRP4, but not MuSK, are expressed in ?-motoneuron cell bodies in the ventral horn of the spinal cord. In agrin- and in MuSK-deficient mice, AChR aggregates are absent from the polar regions. In contrast, the subcellular concentration of AChRs in the central region where the sensory neuron contacts the intrafusal muscle fiber is apparently unaffected. Skeletal muscle-specific expression of miniagrin in agrin(-/-) mice in vivo is sufficient to restore the formation of ?-motoneuron endplates. These results show that agrin and MuSK are major determinants during the formation of ?-motoneuron endplates but appear dispensable for the aggregation of AChRs at the central region. Our results therefore suggest different molecular mechanisms for AChR clustering within two domains of intrafusal fibers. PMID:25377642

Zhang, Yina; Lin, Shuo; Karakatsani, Andromachi; Rüegg, Markus A; Kröger, Stephan



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


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

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



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

PubMed Central

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

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



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


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

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



Paleopedology and soil stratigraphy in the New Zealand Quaternary succession  

Microsoft Academic Search

Information, presented in other papers on the pedological implications of the Quaternary succession is summarised, correlated and interpreted. Such paleo-pedological evidence may be employed to confirm and extend the chronology of the later part of the New Zealand Quaternary. A soil stratigraphic terminology is proposed for New Zealand conditions, and it is applied to paleosols in some North and South

M. L. Leamy; J. D. G. Milne; W. A. Pullar; J. G. Bruce



Uplift of quaternary shorelines in eastern Patagonia: Darwin revisited  

Microsoft Academic Search

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

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



Quaternary Stratigraphy and Paleogeography of the Galilee Coastal Plain, Israel  

Microsoft Academic Search

The Quaternary deposits in the Galilee coastal plain comprise alternating calcareous sandstone, red loam, dark clay, and uncemented sand. The calcareous sandstone in the lower part of the sequence represents a Pliocene to early Pleistocene marine transgression, and is covered unconformably by the late Quaternary sequence. The base of this sequence has an estimated age of ?500,000 yr. It is

Dorit Sivan; Gedaliahu Gvirtzman; Eytan Sass



The newsletter of the CAMBRIDGE QUATERNARY ISSUE 36 LENT 2007  

E-print Network

but also provides easily accessible, expert information for active researchers. Prof Phil Gibbard and clast fabric analyses, and will be using ground penetrating radar methods. When he is not working, he QUATERNARY ENVIRONMENTS AND THE HUMAN PAST There is a one day discussion meeting hosted by the Quaternary

de Gispert, Adrià


Surface Micellization Patterns of Quaternary Ammonium Surfactants on Mica  

E-print Network

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

Aksay, Ilhan A.


Nicotine-induced upregulation of VCAM-1, MMP-2, and MMP-9 through the ?7-nAChR-JNK pathway in RAW264.7 and MOVAS cells.  


The ability of nicotine to induce aortic aneurysms has been shown in animal models; however, its underlying mechanisms remain elusive. In the present experiment, both the RAW264.7 and MOVAS cell lines were employed to examine the nicotine-induced modulation of VCAM-1, MMP-2, and MMP-9 expressions in macrophages and vascular smooth muscle cells. Our results showed that nicotine concentrations of both 0.5 and 5 ng/ml induced VCAM-1, MMP-2, and MMP-9 upregulation, while a concentration of 50 ng/ml had a slight inhibitory effect and a concentration of 500 ng/ml showed a significant inhibitory effect. When cells were pretreated with either SP600125 (JNK inhibitor) or PNU-282987 (?7-nAChR agonist) prior to nicotine exposure, the nicotine-induced upregulation of VCAM-1, MMP-2, MMP-9, and p-JNK was suppressed, with a joint treatment producing a more significant inhibitory effect. Moreover, PNU-282987 had a comparable inhibitory effect on VCAM-1, MMP-2, and MMP-9 expressions and JNK activation via phosphorylation as did SP600125. In conclusion, nicotine-induced VCAM-1, MMP-2, and MMP-9 expressions occur in a dose-dependent fashion in both of the cell lines tested. Furthermore, the nicotine exposure equivalent to plasma levels found in regular smokers can augment VCAM-1, MMP-2, and MMP-9 expressions through the ?7-nAChR-JNK pathway. PMID:25381636

Li, Zong-Zhuang; Guo, Zhen-Zhen; Zhang, Zhi; Cao, Qun-An; Zhu, Ya-Juan; Yao, Hua-Li; Wu, Li-Li; Dai, Qiu-Yan



Late Quaternary history of southern Chesapeake Bay  

SciTech Connect

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

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



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...



E-print Network

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Torgersen, Christian


Quaternary vertebrates from Greenland: A review  

NASA Astrophysics Data System (ADS)

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.

Bennike, Ole


New ternary and quaternary group IV tellurides  

SciTech Connect

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

Keane, P.M.



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

SciTech Connect

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.

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



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

E-print Network

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

Caughman, John


PARP inhibitors.  


Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b) .The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD). PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities of breast, uterine, colorectal and ovarian cancer. This review summarizes current insights into the mechanism of action of PARP inhibitors, its recent clinical trials, and potential next steps in the evaluation of this promising class of anti-cancer drugs. PMID:25606064

Anwar, Maheen; Aslam, Hafiz Muhammad; Anwar, Shahzad



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


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

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



The novel Na+/Ca2+ exchange inhibitor KB-R7943 also blocks native and expressed neuronal nicotinic receptors  

PubMed Central

We studied the effects of the novel Na+/Ca2+ exchange inhibitor KB-R7943, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulphonate, on the native nicotinic receptors present at the bovine adrenal chromaffin cells, as well as on rat brain ?3?4 and ?7 nicotinic acetylcholine receptors (AChRs) expressed in Xenopus oocytes.As expected, KB-R7943 blocked the Na+-gradient dependent 45Ca2+ uptake into chromaffin cells (IC50 of 5.5??M); but in addition, the compound also inhibited the 45Ca2+ entry and the increase of cytosolic Ca2+ concentration, [Ca2+]c, stimulated by 5?s pulses of ACh (IC50 of 6.5 and 1.7??M, respectively).In oocytes expressing ?3?4 and ?7 nicotinic AChRs, voltage-clamped at ?60?mV, inward currents elicited by 1?s pulses of 100??M ACh (IACh) were blocked by KB-R7943 with an IC50 of 0.4??M and a Hill coefficient of 0.9.Blockade of ?3?4 currents by KB-R7943 was noncompetitive; moreover, the blocker (0.3??M) became more active as the ACh concentration increased (34 versus 66% blockade at 30??M and 1?mM ACh, respectively).Inhibition of ?3?4 currents by 0.3??M KB-R7943 was more pronounced at hyperpolarized potentials. If given within the ACh pulse (10??M), the inhibition amounted to 33, 64 and 80% in oocytes voltage-clamped at ?40, ?60 and ?100?mV, respectively. The onset of blockade was faster and the recovery slower at ?100?mV; the reverse was true at ?40?mV.In conclusion, KB-R7943 is a potent blocker of nicotinic AChRs; moreover, it displays many features of an open-channel blocker at the rat brain ?3?4 AChR. These results should be considered when KB-R7943 is to be used to study Ca2+ homeostasis in cells expressing nicotinic AChRs and the Na+/Ca2+ exchanger. PMID:10952680

Pintado, Antonio J; Herrero, Carlos J; García, Antonio G; Montiel, Carmen



Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme.  


An in vitro evaluation of the Johns Hopkins Clinical Compound Library demonstrates that certain drugs can alter the quaternary structure of an essential human protein. Human porphobilinogen synthase (HsPBGS) is an essential enzyme involved in heme biosynthesis; it exists as an equilibrium of high-activity octamers, low-activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. Decreased HsPBGS activity is implicated in toxicities associated with lead poisoning and 5-aminolevulinate dehydratase (ALAD) porphyria, the latter of which involves hexamer-favoring HsPBGS variants. A medium-throughput native PAGE mobility-shift screen coupled with evaluation of hits as HsPBGS inhibitors revealed 12 drugs that stabilize the HsPBGS hexamer and inhibit HsPBGS activity in vitro. A detailed characterization of these effects is presented. Drug inhibition of HsPBGS in vivo by inducing hexamer formation would constitute an unprecedented mechanism for side effects. We suggest that small-molecule perturbation of quaternary structure equilibria be considered as a general mechanism for drug action and side effects. PMID:21506274

Lawrence, Sarah H; Selwood, Trevor; Jaffe, Eileen K



A quaternary temperament model and defense cluster preferences.  


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

Kelly, Kathryn E; Tobacyk, Jerome J



Hepatitis C virus NS5A inhibitors and drug resistance mutations.  


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

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



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

PubMed Central

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

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



Photoluminescence properties and local structure of polymer-like a-C:H films  

SciTech Connect

In order to understand better the electronic properties of {pi}-bonded materials, some optical and photoluminescence properties of amorphous carbon films have been investigated as a function of film density (0.9 to 1.7{sup {minus}3}). This study gives an overview of the radiative recombination properties in relation with local structure characterizations (in situ infrared ellipsometry and Raman spectroscopies) for a series of dual-plasma deposited polymer-like a-C:H films. Medium range topology has consequences in the hyperconjugation effects seen on infrared bands, as well as in optical and resonant Raman characteristics. Photoluminescence (PL) excitation spectroscopy reveals resonance features which are attributed to exciton-like electron-hole pairs in close Coulomb interaction. The PL efficiency shows a sharp quenching for densities above 1.3{sup {minus}3} where a clear transition also occurs in the Raman fingerprint. In addition, quantitative analysis of IR ellipsometry and Elastic Recoil Detection give evidence of a strong decrease of both the effective dynamical charge e*(C-H) and the bandwidth of sp{sup 3} C-H vibrations; this is interpreted as being a result of the increase of local strains in the carbon skeleton, meaning that matrix distortions already appear at H content values as high as 46 H at.% due to film densification. An expected consequence is the mixing between {pi} and {sigma} molecular orbitals and the enhancement of the dissociation rate of confined electron-hole pairs. PL quenching would thus result from both a decrease of exciton confinement and an increase of the density of accessible nonradiative centers.

Godet, C.; Heitz, T.; Bouree, J.E.



Photoluminescence Properties and Local Structure of Polymer-Like a-C:H Films  

NASA Astrophysics Data System (ADS)

In order to understand better the electronic properties of ?-bonded materials, some optical and photoluminescence properties of amorphous carbon films have been investigated as a function of film density (0.9 to 1.7 This study gives an overview of the radiative recombination properties in relation with local structure characterizations (in situ infrared ellipsometry and Raman spectroscopies) for a series of dual-plasma deposited polymer-like a-C:H films. Medium range topology has consequences in the hyperconjugation effects seen on infrared bands, as well as in optical and resonant Raman characteristics. Photoluminescence (PL) excitation spectroscopy reveals resonance features which are attributed to exciton-like electron-hole pairs in close Coulomb interaction. The PL efficiency shows a sharp quenching for densities above 1.3 where a clear transition also occurs in the Raman ``fingerprint''. In addition, quantitative analysis of IR ellipsometry and Elastic Recoil Detection give evidence of a strong decrease of both the effective dynamical charge e*(C-H) and the bandwidth of sp3 C-H vibrations; this is interpreted as being a result of the increase of local strains in the carbon skeleton, meaning that matrix distortions already appear at H content values as high as 46 H at.% due to film densification. An expected consequence is the mixing between ? and ? molecular orbitals and the enhancement of the dissociation rate of confined electron-hole pairs. PL quenching would thus result from both a decrease of exciton confinement and an increase of the density of accessible nonradiative centers.

Godet, C.; Heitz, T.; Dravillon, B.; Bourée, J. E.


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.  


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

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



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

PubMed Central

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



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


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., [32]). 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

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



Docking of 6-chloropyridazin-3-yl derivatives active on nicotinic acetylcholine receptors into molluscan acetylcholine binding protein (AChBP).  


The crystal structure of Acetylcholine Binding Protein (AChBP), homolog of the ligand binding domain of nAChR, has been used as model for computational investigations on the ligand-receptor interactions of derivatives of 6-chloropyridazine substituted at C3 with 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane and with piperazine and homopiperazine, substituted or not at N4. The ligand-receptor complexes have been analyzed by docking techniques using the binding site of HEPES complexed with AChBP as template. The good relationship between the observed binding affinity and the calculated docking energy confirms that this model provides a good starting point for understanding the binding domain of neuronal nicotinic receptors. An analysis of the possible factors significant for the ligand recognition has evidenced, besides the cation-pi interaction, the distance between the chlorine atom of the pyridazinyl group and the carbonylic oxygen of Leu B112 as an important parameter in the modulation of the binding energy. PMID:15848206

Artali, Roberto; Bombieri, Gabriella; Meneghetti, Fiorella



Is ?7-nAChR a possible target for lung cancer and malignant pleural mesothelioma treatment?  


This paper discusses the potential therapeutic effect of ?7-nAChR antagonists for NSCLC (non small cell lung cancer) and MPM (malignant pleural mesothelioma). This therapeutic approach is based on the experimental observations that: (a) functional ?7-nAChR are expressed in NSCLC and MPM cells, (b) the activation of these receptors by agonists, namely nicotine, induces cell proliferation and inhibits apoptosis, whereas antagonists have a pro-apoptotic effect. Among competitive ?7-nAChR antagonists, d-tubocurarine and -cobratoxin (?-CbT), from the snake venom of Naja, emerged as possible drug candidates. However, some aspects of the samples must be particularly taken into account, such as the particular nature of the sample. Thus, when using natural compounds purified from snake venom, it is important to take into account the factors such as whether the venom sample was derived from different animals, purified by different methods, or contained contaminants of the same molecular weight. Finally, biological activity may be different for different batches, which could also have been stored under different conditions (e.g. temperature, dilution, suspension medium etc.). These factors, affecting the experimental results, are also discussed. PMID:22300036

Cesario, Alfredo; Russo, Patrizia; Nastrucci, Candida; Granone, Pierluigi



Single Particle Tracking of ?7 Nicotinic AChR in Hippocampal Neurons Reveals Regulated Confinement at Glutamatergic and GABAergic Perisynaptic Sites  

PubMed Central

?7 neuronal nicotinic acetylcholine receptors (?7-nAChR) form Ca2+-permeable homopentameric channels modulating cortical network activity and cognitive processing. They are located pre- and postsynaptically and are highly abundant in hippocampal GABAergic interneurons. It is unclear how ?7-nAChRs are positioned in specific membrane microdomains, particularly in cultured neurons which are devoid of cholinergic synapses. To address this issue, we monitored by single particle tracking the lateral mobility of individual ?7-nAChRs labeled with ?-bungarotoxin linked to quantum dots in live rat cultured hippocampal interneurons. Quantitative analysis revealed different modes of lateral diffusion of ?7-nAChR dependent on their subcellular localization. Confined receptors were found in the immediate vicinity of glutamatergic and GABAergic postsynaptic densities, as well as in extrasynaptic clusters of ?-bungarotoxin labeling on dendrites. ?7-nAChRs avoided entering postsynaptic densities, but exhibited reduced mobility and long dwell times at perisynaptic locations, indicative of regulated confinement. Their diffusion coefficient was lower, on average, at glutamatergic than at GABAergic perisynaptic sites, suggesting differential, synapse-specific tethering mechanisms. Disruption of the cytoskeleton affected ?7-nAChR mobility and cell surface expression, but not their ability to form clusters. Finally, using tetrodotoxin to silence network activity, as well as exposure to a selective ?7-nAChR agonist or antagonist, we observed that ?7-nAChRs cell surface dynamics is modulated by chronic changes in neuronal activity. Altogether, given their high Ca2+-permeability, our results suggest a possible role of ?7-nAChR on interneurons for activating Ca2+-dependent signaling in the vicinity of GABAergic and glutamatergic synapses. PMID:20634896

Bürli, Thomas; Baer, Kristin; Ewers, Helge; Sidler, Corinne




E-print Network

:// #12;Dates for your Diary Michaelmas 2005 October Tue 25th ESC Jake Lowenstern (Yellowstone Volcano Observatory) "Intrusion, deformation and gas discharge at the Yellowstone Caldera" Wed 26th SPRI Professor

de Gispert, Adrià


Large families of quaternary sequences with low correlation  

Microsoft Academic Search

A family of quaternary (Z4-alphabet) sequences of length L=2r-1, size M⩾L2+3L+2, and maximum nontrivial correlation parameter Cmax⩽2?(L+1)+1 is presented. The sequence family always contains the four-phase family 𝒜. When r is odd, it includes the family of binary Gold sequences. The sequence family is easily generated using two shift registers, one binary, the other quaternary. The distribution of correlation values

P. Vijay Kumar; Tor Helleseth; A. Robert Calderbank; A. Roger Hammons Jr.



Late Quaternary geotechnical stratigraphy of North Texas continental shelf  

E-print Network

LATE QUATERNARY GEOTECHNICAL STRATIGRAPHY OF NORTH TEXAS CONTINENTAL SHELF A Thesis by JOHN SAL MUNSEY Submitted to the Graduate College of Texas Algi University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE... December 1985 Major Subject: Geology LATE QUATERNARY GEOTECHNICAL STRATIGRAPHY OF NORTH TEXAS CONTINENTAL SHELF A Thesis by JOHN SAL MUNSEY Approved as to style and content by: br' sto er . Mathewson (Cha&r of Committee) Norman R . ' ord (Memb...

Munsey, John Sal



Late quaternary geologic history of the south Texas continental shelf  

E-print Network

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

Pyle, Carroll Anthony



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


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

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



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

NASA Astrophysics Data System (ADS)

The INGV cohoperates with schools of different grades to promote Earth science programs and geophysical knowledge. This is particularly important in areas prone to seismic and volcanic hazards, like Italy. The E&O Group organizes every year school visits to the scientific laboratories of the INGV center of Rome, during which more than 4,000 students interact with scientists and learn about the dynamic Earth. Besides that the E&O Group brings on the road educational activities, carring out projects with schools and partecipating to science festivals. In March 2000 a small size earthquake hit the towns of Subiaco and Agosta, near Rome. This event was strongly felt by teachers and students of the local primary schools, and sprang the idea of a project focused on earthquakes. The aim of the project was to gain knowledge of what causes earthquakes and to familiarize with a phenomenon considered random and unforeseeable. Another goal was to train students and teachers to behave properly during the occurrence of an earthquake. The project was developed starting from the personal experience of the students, with theoretical lessons and practical experiments. The INGV researchers partecipated giving talks and producing educational materials. During the talks they showed that earthquakes are not phenomena so rare and random as thought by most people. They also showed the instruments used to register seismicity, and encouraged kids to produce their own earthquakes jumping close to a portable seismometer. In a second phase the students were divided in groups that investigated different topics of the seismic event, giving a talk to their school mates at the end of the research. The teachers used a cooperative learning approach to stimulate the ability of the kids to team up and work in cooperation. At the end of the project the kids published a book (When the Earth has a belly-ache) and a calendar, that tell about earthquakes using the kid's original drawings. The book illustrates using a kids language, though scientifically correct, what is an earthquake, what can be its effects, and what should be do if an earthquake occurs. The project was presented in a public conference to the local authorities and to the community, extending the issues regarding the natural hazards.

Burrato, P.; Nostro, C.; Tertulliani, A.; Winkler, A.; Casale, P.; Marsili, A.; Castellano, C.; Cultrera, G.; Scarlato, P.; Alfonsi, L.; Ciaccio, M.; Frepoli, A.



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

SciTech Connect

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

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



A Quaternary Geomagnetic Instability Time Scale  

NASA Astrophysics Data System (ADS)

Reversals and excursions of Earth's geomagnetic field create marker horizons that are readily detected in sedimentary and volcanic rocks worldwide. An accurate and precise chronology of these geomagnetic field instabilities is fundamental to understanding several aspects of Quaternary climate, dynamo processes, and surface processes. For example, stratigraphic correlation between marine sediment and polar ice records of climate change across the cryospheres benefits from a highly resolved record of reversals and excursions. The temporal patterns of dynamo behavior may reflect physical interactions between the molten outer core and the solid inner core or lowermost mantle. These interactions may control reversal frequency and shape the weak magnetic fields that arise during successive dynamo instabilities. Moreover, weakening of the axial dipole during reversals and excursions enhances the production of cosmogenic isotopes that are used in sediment and ice core stratigraphy and surface exposure dating. The Geomagnetic Instability Time Scale (GITS) is based on the direct dating of transitional polarity states recorded by lava flows using the 40Ar/39Ar method, in parallel with astrochronologic age models of marine sediments in which O isotope and magnetic records have been obtained. A review of data from Quaternary lava flows and sediments yields a GITS comprising 10 polarity reversals and 27 excursions during the past 2.6 million years. Nine of the ten reversals bounding chrons and subchrons are associated with 40Ar/39Ar ages of transitionally-magnetized lava flows. The tenth, the Guass-Matuyama chron boundary, is tightly bracketed by 40Ar/39Ar dated ash deposits. Of the 27 well-documented excursions, 14 occurred during the Matuyama chron and 13 during the Brunhes chron; 19 have been dated directly using the 40Ar/39Ar method on transitionally-magnetized volcanic rocks and form the backbone of the GITS. Excursions are clearly not the rare phenomena once thought. Rather, during the Quaternary period, they occur nearly three times as often as full polarity reversals. I will address analytical issues, including the size and consistency of system blanks, that have led to the recognition of minor (1%) discrepencies between the 40Ar/39Ar age for a particular reversal or excursion and the best astrochronologic estimates from ODP sediment cores. For example, re-analysis of lava flows from Haleakala volcano, Maui that record in detail the Matuyama-Brunhes polarity reversal have been undertaken with blanks an order of magntitude smaller and more stable than was common a decade ago. Using the modern astrochronologic calibration of 28.201 Ma for the age of the Fish Canyon sanidine standard, results thus far yield an 40Ar/39Ar age of 772 × 11 ka for the reversal that is identical to the most precise and accurate astrochronologic age of 773 × 2 ka for this reversal from ODP cores. Similarly, new dating of sanidine in the Cerro Santa Rosa I rhyolite dome, New Mexico reveals an age of 932 × 5 ka for the excursion it records, in perfect agreement with astrochronologically dated ODP core records. Work underway aims at refining the 40Ar/39Ar ages that underpin the entire GITS by further eliminating the bias between the radioisotopic and astrochronologically determined ages for several reversals and excursions.

Singer, B. S.



NSC23766, a widely used inhibitor of Rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors.  


Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride]. We found that NSC23766 inhibits the M2 muscarinic acetylcholine receptor (M2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rho-dependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly Gi??-mediated, adenosine-induced activation of Gi protein-regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K(+) current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A1 receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca(2+) concentrations in human embryonic kidney 293 (HEK-293) cells expressing M1, M2, or M3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M2 and M3 mAChR crystal structures confirmed this interpretation. PMID:23887096

Levay, Magdolna; Krobert, Kurt Allen; Wittig, Karola; Voigt, Niels; Bermudez, Marcel; Wolber, Gerhard; Dobrev, Dobromir; Levy, Finn Olav; Wieland, Thomas



Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors  

PubMed Central

Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell survival. SphK phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has been implicated in cancer growth and survival. SphK exists as two different isotypes, namely SphK1 and SphK2, which play different roles inside the cell. In this report, we describe SphK inhibitors based on the immunomodulatory drug, FTY720, which is phosphorylated by SphK2 to generate a S1P mimic. Structural modification of FTY720 provided a template for synthesizing new inhibitors. A diversity-oriented synthesis generated a library of SphK inhibitors with a novel scaffold and headgroup. We have discovered subtype selective inhibitors with Ki’s in the low micromolar range. This is the first report describing quaternary ammonium salts as SphK inhibitors. PMID:22137932

Raje, Mithun R.; Knott, Kenneth; Kharel, Yugesh; Bissel, Philippe; Lynch, Kevin R.; Santos, Webster L.



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

Microsoft Academic Search

BackgroundThe 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,

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



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

Microsoft Academic Search

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 com- pounds. The dominant fungal-growth-promoting substance produced by strain AcH 505, auxofuran, was isolated, and its effect on the levels of

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



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

NASA Astrophysics Data System (ADS)

The inhibitive action of some quaternary ammonium salts towards the corrosion of aluminium in hydrochloric acid was tested by thermometric, mass loss and polarization measurements. Parallelism between the different methods was established. It is suggested that the tested compounds act as cathodic inhibitors. The inhibitors appear to function through adsorption, following the Temkin adsorption isotherm. The values of free energy of adsorption have been calculated and discussed. The inhibitor character of the additives depends upon the concentration as well as the composition of the inhibitor. Within the given homolegous series the contribution of the functional group to adsorption increases with the length of the chain. The aim of this article is to throw some light on the mechanism of inhibition of these bulky molecules on the corrosion of aluminium in hydrochloric acid. L'action inhibitrice de certains sels d'ammonium quaternaires vis-à-vis de la corrosion de l'aluminium dans l'acide chlorhydrique en solution a été testée par des mesures thermiques de perte de matière et de polarisation. Il est suggéré que les composés testés agissent comme des inhibiteurs cathodiques, fonctionnant par adsorption suivant l'isotherme de Temkin. Les énergies libres d'adsorption ont été calculées et discutées. Le caractère inhibiteur des additifs dépend aussi bien de leur concentration que de leur composition. Pour une série d'inhibiteurs homologues, la contribution à l'adsorption du groupe fonctionnel augmente avec la longueur de la chaîne. Le but de cet article est de mieux comprendre le mécanisme d'inhibition de ces grosses molécules sur la corrosion de l'aluminium dans l'acide chlorhydrique.

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



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

SciTech Connect

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

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



Late Quaternary mammalian zoogeography of eastern Washington  

NASA Astrophysics Data System (ADS)

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.

Lyman, R. Lee; Livingston, Stephanie D.



Macrocyclic proteasome inhibitors.  


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

Krahn, D; Ottmann, C; Kaiser, M



Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis.  


Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in synaptic transmission at the neuromuscular junction causing fluctuating muscle weakness with a decremental response to repetitive nerve stimulation or altered jitter in single-fiber electromyography (EMG). Approximately 80% of all myasthenia gravis patients have autoantibodies against the nicotinic acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis cases. The autoimmune target in the remaining cases is unknown. Recently, low-density lipoprotein receptor-related protein (LRP4) has been identified as the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates MuSK, which leads to the formation of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors (AChRs) in the junctional plasma membrane. In the present study we tested if autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To this end we analyzed 13 sera from patients with generalized myasthenia gravis but without antibodies against AChR or MuSK. The results showed that 12 out of 13 antisera from double-seronegative MG patients bound to proteins concentrated at the neuromuscular junction of adult mouse skeletal muscle and that approximately 50% of the tested sera specifically bound to HEK293 cells transfected with human LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that LRP4 is a novel target for autoantibodies and is a diagnostic marker in seronegative MG patients. PMID:21814823

Pevzner, Alexandra; Schoser, Benedikt; Peters, Katja; Cosma, Nicoleta-Carmen; Karakatsani, Andromachi; Schalke, Berthold; Melms, Arthur; Kröger, Stephan



Bacterial adhesion inhibition of the quaternary ammonium functionalized silica nanoparticles.  


Quaternary ammonium compounds have been considered as excellent antibacterial agents due to their effective biocidal activity, long term durability and environmentally friendly performance. In this work, 3-(trimethoxysilyl)-propyldimethyloctadecylammonium chloride as a quaternary ammonium silane was applied for the surface modification of silica nanoparticles. The quaternary ammonium silane provided silica surface with hydrophobicity and antibacterial properties. In addition, the glass surface which was coated with the surface modified silica nanoparticles presented bacterial growth inhibition activity. For comparison of bacterial growth resistance, hydrophobic silane (alkyl functionalized silane) modified silica nanoparticles and pristine silica nanoparticles were prepared. As a result of bacterial adhesion test, the quaternary ammonium functionalized silica nanoparticles exhibited the enhanced inhibition performance against growth of Gram-negative Escherichia coli (96.6%), Gram-positive Staphylococcus aureus (98.5%) and Deinococcus geothermalis (99.6%) compared to pristine silica nanoparticles. These bacteria resistances also were stronger than that of hydrophobically modified silica nanoparticles. It could be explained that the improved bacteria inhibition performance originated from the synergistic effect of hydrophobicity and antibacterial property of quaternary ammonium silane. Additionally, the antimicrobial efficacy of the fabricated nanoparticles increased with decreasing size of the nanoparticles. PMID:21115282

Song, Jooyoung; Kong, Hyeyoung; Jang, Jyongsik



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).  


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

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



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

E-print Network

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

Hamelryck, Thomas


Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors.  


This study presents the synthesis of 15 new tacrine dimers as well as the Ki and IC50 results, studies of the kinetic mechanism, and molecular docking analysis of the dimers in relation to the cholinesterases hAChE, hBChE, EeAChE and eqBChE. In addition to spectroscopic characterization, X-ray structure determination was performed for two of the new compounds. These new dimers were found to be mixed nanomolar inhibitors of the evaluated targets with a broad and significant selectivity profile, and these properties are dependent on both the type of the linker and the volume of the hydroacridine alicyclic ring. The results indicate that the aromatic linkers play a significant role in generating specific interactions with the half-gorge region of the catalytic center. Thus, these types of linkers can positively modulate the electronic properties of the tacrine dimers studied with an improvement of their cholinesterase inhibition activity. PMID:24186541

de Aquino, Roney Anderson Nascimento; Modolo, Luzia Valentina; Alves, Rosemeire Brondi; de Fátima, Ângelo



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

PubMed Central

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

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



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

PubMed Central

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

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



Proton pump inhibitors  


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


Quaternary half-metallic Heusler ferromagnets for spintronics applications  

NASA Astrophysics Data System (ADS)

This work reports on three quaternary Heusler compounds NiFeMnGa, NiCoMnGa, and CuCoMnGa. In contrast to their ternary relatives, quaternary Heusler compounds are still rarely investigated. A very large pool of interesting materials lies thus idle waiting for exploration. The difficulty consists in choosing prospective compositions, and trial and error is elaborate and expensive. We have identified several candidates employing ab initio electronic-structure calculations. The compounds were synthesized, and the structural and magnetic properties were investigated experimentally. CuCoMnGa is a quaternary Heusler compound; NiFeMnGa and NiCoMnGa are unreported half-metallic ferromagnetic materials with potential for spintronics applications.

Alijani, Vajiheh; Winterlik, Juergen; Fecher, Gerhard H.; Naghavi, S. Shahab; Felser, Claudia



Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity  

SciTech Connect

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

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



Quaternary Science Reviews 26 (2007) 11491191 Erratum to: Severnaya Zemlya, Arctic Russia: a nucleation area for  

E-print Network

: a nucleation area for Kara Sea ice sheets during the Middle to Late Quaternary [Quaternary Science Reviews 25, Quaternary Sciences, Lund University, So¨lvegatan 12, SE-22362 Lund, Sweden b Institute of Arctic and Alpine of Sweden, Villava¨gen 18, P.O. Box 670, SE-75128 Uppsala, Sweden h VSEGEI (A.P. Karpinsky All Russia

Möller, Per


Ice Age Earth: Late Quaternary geology and climate  

SciTech Connect

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

Dawson, A.G.



PACAP induces plasticity at autonomic synapses by nAChR-dependent NOS1 activation and AKAP-mediated PKA targeting.  


Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide found at synapses throughout the central and autonomic nervous system. We previously found that PACAP engages a selective G-protein coupled receptor (PAC1R) on ciliary ganglion neurons to rapidly enhance quantal acetylcholine (ACh) release from presynaptic terminals via neuronal nitric oxide synthase (NOS1) and cyclic AMP/protein kinase A (PKA) dependent processes. Here, we examined how PACAP stimulates NO production and targets resultant outcomes to synapses. Scavenging extracellular NO blocked PACAP-induced plasticity supporting a retrograde (post- to presynaptic) NO action on ACh release. Live-cell imaging revealed that PACAP stimulates NO production by mechanisms requiring NOS1, PKA and Ca(2+) influx. Ca(2+)-permeable nicotinic ACh receptors composed of ?7 subunits (?7-nAChRs) are potentiated by PKA-dependent PACAP/PAC1R signaling and were required for PACAP-induced NO production and synaptic plasticity since both outcomes were drastically reduced following their selective inhibition. Co-precipitation experiments showed that NOS1 associates with ?7-nAChRs, many of which are perisynaptic, as well as with heteromeric ?3*-nAChRs that generate the bulk of synaptic activity. NOS1-nAChR physical association could facilitate NO production at perisynaptic and adjacent postsynaptic sites to enhance focal ACh release from juxtaposed presynaptic terminals. The synaptic outcomes of PACAP/PAC1R signaling are localized by PKA anchoring proteins (AKAPs). PKA regulatory-subunit overlay assays identified five AKAPs in ganglion lysates, including a prominent neuronal subtype. Moreover, PACAP-induced synaptic plasticity was selectively blocked when PKA regulatory-subunit binding to AKAPs was inhibited. Taken together, our findings indicate that PACAP/PAC1R signaling coordinates nAChR, NOS1 and AKAP activities to induce targeted, retrograde plasticity at autonomic synapses. Such coordination has broad relevance for understanding the control of autonomic synapses and consequent visceral functions. PMID:25168001

Jayakar, Selwyn S; Pugh, Phyllis C; Dale, Zack; Starr, Eric R; Cole, Samantha; Margiotta, Joseph F



Effect of Licofelone-A Dual COX/5-LOX Inhibitor in Intracerebroventricular Streptozotocin-Induced Behavioral and Biochemical Abnormalities in Rats.  


The present study was designed to investigate the effect of licofelone-a dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitor in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficit and biochemical abnormalities in rats. ICV-STZ is a widely used model of sporadic Alzheimer's disease. In this study, STZ was administered intracerebroventricular (ICV)-bilaterally 3 mg/kg in rats. The STZ-injected rats were treated with different doses of licofelone (2.5, 5, and 10 mg/kg, p.o.) for 21 days. Cognitive functions were assessed by using Morris water maze and passive avoidance task. Levels of malondialdehyde (MDA), nitrite, reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were determined to check oxidative stress and cholinergic function. Cytokine levels (IL-1? and TNF-?) were also determined as markers of neuroinflammation. Administration of STZ caused a significant increase in AChE activity and cognitive dysfunction. Increased oxidative stress and the proinflammatory cytokine levels were also observed following STZ administration in rats. Licofelone treatment attenuated STZ-induced cholinergic hypofunction and cognitive deficit in rats. In addition, licofelone attenuated STZ-induced oxidative stress and elevated cytokine levels. The cognitive enhancement following licofelone administration in STZ rats may be due to its ability to restore cholinergic functions or its antioxidant activity. These observed results suggest the therapeutic potential of dual COX/5-LOX inhibitors in neurodegenerative disorders associated with oxidative stress and cognitive impairment. PMID:25204299

Kumar, Ashok; Sharma, Sorabh; Prashar, Ashwani; Deshmukh, Rahul



Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds.  


Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020). PMID:7490731

Sugimoto, H; Iimura, Y; Yamanishi, Y; Yamatsu, K



Morphological aspects of neuromuscular junctions and gene expression of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle of rats with heart failure.  


HF is syndrome initiated by a reduction in cardiac function and it is characterized by the activation of compensatory mechanisms. Muscular fatigue and dyspnoea are the more common symptoms in HF; these may be due in part to specific skeletal muscle myopathy characterized by reduced oxidative capacity, a shift from slow fatigue resistant type I to fast less fatigue resistant type II fibers and downregulation of myogenic regulatory factors (MRFs) gene expression that can regulate gene expression of nicotinic acetylcholine receptors (nAChRs). In chronic heart failure, skeletal muscle phenotypic changes could influence the maintenance of the neuromuscular junction morphology and nAChRs gene expression during this syndrome. Two groups of rats were studied: control (CT) and Heart Failure (HF), induced by a single intraperitoneal injection of monocrotaline (MCT). At the end of the experiment, HF was evaluated by clinical signs and animals were sacrificed. Soleus (SOL) muscles were removed and processed for morphological, morphometric and molecular NMJ analyses. Our major finding was an up-regulation in the gene expression of the alpha1 and epsilon subunits of nAChR and a spot pattern of nAChR in SOL skeletal muscle in this acute monocrotaline induced HF. Our results suggest a remodeling of nAChR alpha1 and epsilon subunit during heart failure and may provide valuable information for understanding the skeletal muscle myopathy that occurs during this syndrome. PMID:21928074

de Souza, Paula Aiello Tomé; Matheus, Selma Maria Michelin; Castan, Eduardo Paulino; Campos, Dijon Henrique Salomé; Cicogna, Antônio Carlos; Carvalho, Robson Francisco; Dal-Pai-Silva, Maeli



Modes of Oceanic and Atmospheric Circulation During the Quaternary  

Microsoft Academic Search

Paleoclimatic evidence shows that the ocean and atmosphere have undergone major changes during the Quaternary. For atmospheric mean circulation, data are consistent with changes in strength and shifts in position of major atmospheric circulation features (e.g., the westerly wind belt), whereas the structure of these main features appears to have persisted. For the ocean, evidence points to qualitative reorganizations in



Effects of Quaternary Sea Level Cycles on Strontium in Seawater  

Microsoft Academic Search

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

Heather M Stoll; Daniel P Schrag



Application of Analytic Geometry to Ternary and Quaternary Diagrams.  

ERIC Educational Resources Information Center

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

MacCarthy, Patrick




E-print Network

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

Zreda, Marek


QUATERNARY RESEARCH 46, 211218 (1996) ARTICLE NO. 0061  

E-print Network

QUATERNARY RESEARCH 46, 211­218 (1996) ARTICLE NO. 0061 Influence of Changing Atmospheric for Groundwater Research, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1 AND GLEN M. MACDONALD of changing climate. As we discuss below, the d18 Op recordsimulations using isotopic water tracers. 1996

Edwards, Thomas W.D.



E-print Network

LATE QUATERNARY EVOLUTION OF THE NORTHEAST FAN, OFFSHORE NOVA SCOTIA Matthew Robichaud Submitted of Earth Sciences Dalhousie University, Halifax, Nova Scotia March 2006 #12;jt Dalhousie University Department of Earth Sciences Halifax, Nova Scotia Canada B3H 3|5 (902) 494-2358 FAX 1902) 494-f>8«9 DATE

Beaumont, Christopher


Lignin biogeochemistry: from modern processes to Quaternary archives  

NASA Astrophysics Data System (ADS)

Lignin has been analysed as a proxy for vegetation change in the Quaternary science literature since the early 1990s in archives such as peat, lakes, and intertidal and marine sediment cores. Historically, it has been regarded as comparatively resistant to various types of degradation in comparison to other plant components. However, studies of modern biogeochemical processes affecting organic carbon have demonstrated significant degradation and alteration of lignin as it is transported through the terrestrial biosphere, including phase changes from particulate to dissolved organic matter, mineral binding and decay due to biotic and abiotic processes. The literature of such topics is vast, however it is not particularly useful to Quaternary research without a comprehensive review to link our understanding of modern processes involving lignin to Quaternary environments. This review will outline the current state of the art in lignin phenol research that is relevant to the Quaternary scientist, and highlight the potential future applications for this important biomarker for vegetation change and terrestrial organic carbon cycling.

Jex, Catherine N.; Pate, Gary H.; Blyth, Alison J.; Spencer, Robert G. M.; Hernes, Peter J.; Khan, Stuart J.; Baker, Andy



Impact of Quaternary Structure Dynamics on Allosteric Drug Discovery  

PubMed Central

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

Jaffe, Eileen K.



European quaternary refugia: a factor in large carnivore extinction?  

Microsoft Academic Search

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

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



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

PubMed Central

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

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



In vivo pharmacological interactions between a type II positive allosteric modulator of ?7 nicotinic ACh receptors and nicotinic agonists in a murine tonic pain model  

PubMed Central

Background and Purpose The ?7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that ?7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the ?7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II ?7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model. Experimental Approach We assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective ?7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice. Key Results We found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and ?7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of ?7 nAChRs. Conclusions and Implications Our results demonstrate that type II ?7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous ?7 agonist choline. PMID:23004024

Freitas, K; Negus, SS; Carroll, FI; Damaj, MI



Identification of key amino acid differences contributing to neonicotinoid sensitivity between two nAChR ? subunits from Pardosa pseudoannulata.  


Chemical insecticides are still primary methods to control rice planthoppers in China, which not only cause environmental pollution, insecticide residue and insecticide resistance, but also have negative effects on natural enemies, such as Pardosa pseudoannulata (the pond wolf spider), an important predatory enemy of rice planthoppers. Neonicotinoids insecticides, such as imidacloprid and thiacloprid, are insect-selective nAChRs agonists that are used extensively in the areas of crop protection and animal health, but have hypotoxicity to P. pseudoannulata. In the present study, two nAChR ? subunits, Pp?1 or Pp?8, were found to be successfully expressed with r?2 in Xenopus oocytes, but with much different sensitivity to imidacloprid and thiacloprid on two recombinant receptors Pp?1/r?2 and Pp?8/r?2. Key amino acid differences were found in and between the important loops for ligand binding. In order to well understand the relationship between the amino acid differences and neonicotinoid sensitivities, different segments in Pp?8 or Pp?1 with key amino acid differences were introduced into the corresponding regions of Pp?1 or Pp?8 to construct chimeras and then co-expressed with r?2 subunit in Xenopus oocytes. The results from chimeras of both Pp?8 and Pp?1 showed that segments ?5, ?6, and ?7 contributed to neonicotinoid sensitivities directly between two receptors. Although the segment ?4 including all loop B region had no direct influences on neonicotinoid sensitivities, it could more remarkably influence neonicotinoid sensitivities when co-introductions with ?5, ?6 or ?7. So, key amino acid differences in these four segments were important to neonicotinoid sensitivities, but the difference in ?4 was likely ignored because of its indirect effects. PMID:25459289

Meng, Xiangkun; Zhang, Yixi; Guo, Beina; Sun, Huahua; Liu, Chuanjun; Liu, Zewen



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


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

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



The First Dual ChE/FAAH Inhibitors: New Perspectives for Alzheimer's Disease?  

PubMed Central

The treatment of Alzheimer's disease (AD) still remains an area of significant unmet need, with drugs that only target the symptoms of the disease. Therefore, there is considerable need for disease-modifying therapies. The complex etiology of AD prompts scientists to develop multitarget strategies to combat causes and symptoms. To this aim, we designed, synthesized, and tested four new carbamates as dual cholinesterase-FAAH inhibitors. The dual activity of these compounds could lead to a potentially more effective treatment for the counteraction of AD progression, because they would allow regulation of both ACh and eCB signaling and improve neuronal transmission and/or counteract neuroinflammation. PMID:24900454



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

NASA Astrophysics Data System (ADS)

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.

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



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

SciTech Connect

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

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



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

SciTech Connect

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.

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



Comparative experimental analysis of the a-C:H deposition processes using CH{sub 4} and C{sub 2}H{sub 2} as precursors  

SciTech Connect

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 25 GPa was formed in the C{sub 2}H{sub 2} discharge when the mean energy per deposited carbon atom was approximately 50 eV. The hardness obtained with the CH{sub 4} discharge was lower at 17 GPa and less sensitive to changes in the process parameters. It was found that the creation of hard (hardness >15 GPa) a-C:H films from both precursors is possible if the mean energy per deposited carbon atom exceeds only {approx}15 eV. 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.

Peter, S.; Graupner, K.; Grambole, D.; Richter, F. [Institute of Physics, Chemnitz University of Technology, D-09107 Chemnitz (Germany); Institute of Ion Beam Physics and Materials Research, Forschungszentrum Rossendorf, D-01314 Dresden (Germany); Institute of Physics, Chemnitz University of Technology, D-09107 Chemnitz (Germany)



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

E-print Network

prepared by the CFUBM magnetron sputtering method Yong Seob Park a , Byungyou Hong a,b,* a School and nec- essary for the applications of the films. Magnetron sputtering has been used to grow amorphous]. In this study, the a-C:H films produced by a closed-field unbalanced magnetron (CFUBM) sputtering 0022

Hong, Byungyou


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

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…

Barrineau, Irene T., Ed.


Effect of a nicotine vaccine on nicotine binding to the beta2-nAChRs in vivo in human tobacco smokers  

PubMed Central

Objective Nicotine acts in the brain to promote smoking in part by binding to the beta2-containing nicotinic acetylcholine receptors (?2*-nAChRs) and acting in the mesolimbic reward pathway. The effects of nicotine from smoking one tobacco cigarette are significant (80% of ?2*-nAChRs occupied for >6h). This likely contributes to the maintenance of smoking dependence and low cessation outcomes. Development of nicotine vaccines provides potential for alternative treatments. We used [123I]5IA-85380 SPECT to evaluate the effect of 3?-AmNic-rEPA on the amount of nicotine that binds to the ?2*-nAChRs in the cortical and subcortical regions in smokers. Method Eleven smokers (36years (SD=13); 19cig/day (SD=11) for 10years (SD=7) who were dependent on nicotine (Fagerström Test of Nicotine Dependence score =5.5 (SD=3); plasma nicotine 9.1 ng/mL (SD=5)) participated in 2 SPECT scan days: before and after immunization with 4–400?g doses of 3?-AmNic-rEPA. On SPECT scan days, 3 30-min baseline emission scans were obtained, followed by administration of IV nicotine (1.5mg/70kg) and up to 9 30-min emission scans. Results ?2*-nAChR availability was quantified as VT/fP and nicotine binding was derived using the Lassen plot approach. Immunization led to a 12.5% reduction in nicotine binding (F=5.19, df=1,10, p=0.05). Significant positive correlations were observed between nicotine bound to ?2*-nAChRs and nicotine injected before but not after vaccination (p=0.05 vs. p=0.98). There was a significant reduction in the daily number of cigarettes and desire for a cigarette (p=.01 and p=.04, respectively). Conclusions This proof-of-concept study demonstrates that immunization with nicotine vaccine can reduce the amount of nicotine binding to ?2*-nAChRs and disrupt the relationship between nicotine administered vs. nicotine available to occupy ?2*-nAChRs. PMID:23429725

Esterlis, Irina; Hannestad, Jonas O.; Perkins, Evgenia; Bois, Frederic; D’Souza, D. Cyril; Tyndale, Rachel F.; Seibyl, John P.; Hatsukami, Dorothy M.; Cosgrove, Kelly P.; O’Malley, Stephanie S.



Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome.  


Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30?g/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1-7 (IC50=12.8±1.5 to 65.2±4.5?M) showed stronger NA inhibitory activity than the tertiary alkaloids 8-10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor-ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth. PMID:25277281

Kim, Jang Hoon; Ryu, Young Bae; Lee, Woo Song; Kim, Young Ho



Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells  

PubMed Central

Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are associated with aberrant gene expression in breast cancer development. However, the precise molecular mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human breast cancer cells with inhibitors targeting the zinc cofactor dependent class I/II HDAC, but not NAD+ dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of histone lysine-specific demethylase 1 (LSD1) and a key chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacological inhibitor, pargyline, or siRNA resulted in increased acetylation of H3K9 (AcH3K9). However, siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with histone deacetylases in human breast cancer cells. Inhibition of histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic therapy of breast cancer. PMID:21452019

Vasilatos, Shauna N.; Boric, Lamia; Shaw, Patrick G.; Davidson, Nancy E.



Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells.  


Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are associated with aberrant gene expression in breast cancer development. However, the precise molecular mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human breast cancer cells with inhibitors targeting the zinc cofactor dependent class I/II HDAC, but not NAD(+) dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of histone lysine-specific demethylase 1 (LSD1) and a key chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacological inhibitor, pargyline, or siRNA resulted in increased acetylation of H3K9 (AcH3K9). However, siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with histone deacetylases in human breast cancer cells. Inhibition of histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic therapy of breast cancer. PMID:21452019

Huang, Yi; Vasilatos, Shauna N; Boric, Lamia; Shaw, Patrick G; Davidson, Nancy E



A new spin gapless semiconductors family: Quaternary Heusler compounds  

NASA Astrophysics Data System (ADS)

By using first-principles calculations, we investigate the band structures of a series of quaternary LiMgPdSn-type Heusler compounds. Our calculation results show that five compounds, CoFeMnSi, CoFeCrAl, CoMnCrSi, CoFeVSi and FeMnCrSb, possess unique electronic structures characterized by a half-metallic gap in one spin direction while they have a zero-width gap in the other spin direction showing a spin gapless semiconducting behavior. We further analyse the electronic and magnetic properties of all quaternary Heusler alloys involved, and reveal a semi-empirical general rule (the total valence electrons number should be 26 or 28) for indentifying spin gapless semiconductors in Heusler compounds. The influences of lattice distortion and main-group element change have also been discussed.

Xu, G. Z.; Liu, E. K.; Du, Y.; Li, G. J.; Liu, G. D.; Wang, W. H.; Wu, G. H.



Unexpected primitive rodents in the Quaternary of Argentina  

NASA Astrophysics Data System (ADS)

This article describes the first fossils recorded in the Hernandarias Formation (Pleistocene) in Entre Ríos province (eastern Argentina). They are represented by three teeth assigned to the caviomorph rodents (Rodentia, Mammalia) Aenigmys diamantensis gen. et sp. nov. and Eumysops. To establish the phylogenetic affinities of the two most enigmatic teeth, their enamel microstructure was studied. Aenigmys diamantensis is considered the most primitive taxon of a clade formed by Dinomyidae-Neoepiblemidae-Heptaxodontidae. Evidence of the close relationships among these families also is presented herein. The new fossils reinforce previous hypotheses about the survival of primitive Brazilian taxa after their extinction in the Pampas and Patagonia of southern South America. They also show that the diversity of caviomorph rodents during the Quaternary was greater than supposed and that an important Quaternary extinction, not previously detected, affected several lineages. With the available evidence, it is not possible to determine if these rodents indicate a warm pulse or a particular biogeographic situation in Entre Ríos.

Vucetich, María G.; Vieytes, Emma C.; Verzi, Diego H.; Noriega, Jorge I.; Tonni, Eduardo P.



Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of A?PP via M1 mAChRs  

PubMed Central

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

Nelson, Amy R.; Kolasa, Krystyna; McMahon, Lori L.



Mutations in GFPT1 that underlie limb-girdle congenital myasthenic syndrome result in reduced cell-surface expression of muscle AChR.  


Mutations in GFPT1 underlie a congenital myasthenic syndrome (CMS) characterized by a limb-girdle pattern of muscle weakness. Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is a key rate-limiting enzyme in the hexosamine biosynthetic pathway providing building blocks for the glycosylation of proteins and lipids. It is expressed ubiquitously and it is not readily apparent why mutations in this gene should cause a syndrome with symptoms restricted to muscle and, in particular, to the neuromuscular junction. Data from a muscle biopsy obtained from a patient with GFPT1 mutations indicated that there were reduced endplate acetylcholine receptors. We, therefore, further investigated the relationship between identified mutations in GFPT1 and expression of the muscle acetylcholine receptor. Cultured myotubes derived from two patients with GFPT1 mutations showed a significant reduction in cell-surface AChR expression (Pt1 P < 0.0001; Pt2 P = 0.0097). Inhibition of GFPT1 enzymatic activity or siRNA silencing of GFPT1 expression both resulted in reduced AChR cell-surface expression. Western blot and gene-silencing experiments indicate this is due to reduced steady-state levels of AChR ?, ?, ?, but not ? subunits rather than altered transcription of AChR-subunit RNA. Uridine diphospho-N-acetylglucosamine, a product of the hexosamine synthetic pathway, acts as a substrate at an early stage in the N-linked glycosylation pathway. Similarity between CMS due to GFPT1 mutations and CMS due to DPAGT1 mutations would suggest that reduced endplate AChR due to defective N-linked glycosylation is a primary disease mechanism in this disorder. PMID:23569079

Zoltowska, Katarzyna; Webster, Richard; Finlayson, Sarah; Maxwell, Susan; Cossins, Judith; Müller, Juliane; Lochmüller, Hanns; Beeson, David



Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence.  


Myasthenia gravis is a typical acetylcholine receptor (AChR) antibody-mediated autoimmune disease in which thymus frequently presents follicular hyperplasia or thymoma. It is now widely accepted that the thymus is probably the site of AChR autosensitization and autoantibody production. However, the exact mechanism that triggers intrathymic AChR antibody production is still unknown. T follicular helper cells, recently identified responsible for B cell maturation and antibody production in the secondary lymphoid organs, were involved in many autoimmune diseases. Newly studies found T follicular helper (Tfh) cells increased in the peripheral blood of myasthenia gravis (MG). Whether it appears in the thymus of MG and its role in the intrathymic B cells help and autoantibody production is unclear. Therefore, this study aims to determine in more detail whether Tfh/B cell interaction exist in MG thymus and to address its role in the ectopic germinal centers (GCs) formation and AChR antibody production. We observed the frequency of Tfh cells and its associated transcription factor Bcl-6, key cytokine IL-21 enhanced both in the thymocytes and peripheral blood mononuclear cells (PBMCs) of MG patients. In parallel, we also showed increased B cells and autoantibody titers in MG peripheral blood and thymus. Confocal microscope results demonstrated Tfh and B cells co-localized within the ectopic GCs in MG thymus, suggesting putative existence of Tfh/B cells interaction. In vitro studies further showed dynamic behavior of Tfh/B cells interaction and Tfh cells induced autoantibody secretion might through its effector cytokine IL-21. Altogether, our data demonstrated that intrathymic Tfh/B cells interaction played a key role in thymic ectopic GCs formation and anti-AChR antibody production, which might trigger MG occurrence. PMID:25407929

Zhang, Xiaoyan; Liu, Shasha; Chang, Ting; Xu, Jiang; Zhang, Chunmei; Tian, Feng; Sun, Yuanjie; Song, Chaojun; Yi, Wei; Lin, Hong; Li, Zhuyi; Yang, Kun



Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs  

PubMed Central

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

Neveu, Cedric; Cabaret, Jacques; Cortet, Jacques; Peineau, Nicolas; Abongwa, Melanie; Courtot, Elise; Robertson, Alan P.; Martin, Richard J.



An explanation for laser-induced spallation effect in a-C:H films: Altered phase evolution route caused by hydrogen doping  

SciTech Connect

The laser-induced spalling effect has been recognized as a unique phenomenon for amorphous carbon (a-C) films during laser processing. In this work, the origin of spalling effect was investigated by ablating two different types of a-C film: hydrogenated a-C (a-C:H) and nonhydrogenated a-C with an Nd-yttrium aluminum garnet laser system. Comparisons of ablating results demonstrated that the spalling effect only occurred in a-C:H rather than nonhydrogenated a-C. Laser heating simulation indicated that the temperature distributions in both films after laser pulse are similar with a high temperature gradient in depth direction. Annealing test results, Raman spectra and nanoindentation show that with the increase in annealing temperature, a-C film transforms into grassy carbon directly, while a-C:H experiences two subprocess under heating: the hydrogen mobilization and rearrangement of C-C network at a relatively low temperature range resulting in a denser C-C network and raised film density; the graphitization at high temperature which would lower the film density. We propose that the reason of laser-induced spalling effect in a-C:H might depend on two aspects: (1) the heat source like laser pulse which could produce a high temperature gradient in depth direction within ultrashort time and (2) the unique evolution process of film microstructure under heating. Based on above model, the spalling effect is ascribed to the concentrated stress caused by different structure evolution subprocess at different depth in a-C:H during the laser irradiation. It is remarkable that the conclusions deduced from our model are proven to be in good agreement with our experimental results and the previous articles reported by others.

Ding Qi; Hu Tianchang [Lanzhou Institute of Chemical Physics, State Key Laboratory of Solid Lubrication, Chinese Academy of Sciences, Lanzhou 730000 (China); Graduate School, Chinese Academy of Sciences, Beijing 100039 (China); Wang Liping; Hu Litian; Wang Yunfeng [Lanzhou Institute of Chemical Physics, State Key Laboratory of Solid Lubrication, Chinese Academy of Sciences, Lanzhou 730000 (China); Zhang Yaonan [Cold and Arid Regions Environmental and Engineering Research Institute, Chinese Academy of Sciences, Lanzhou 730000 (China)



The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of ?7*nAChR function  

PubMed Central

The human ?7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the ?7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca++, that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. Schizophrenic patients have low levels of ?7*nAChR, as measured by binding of the ligand [125I]-?-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene (CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of ?7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with ?7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans. PMID:21718690

Araud, Tanguy; Graw, Sharon; Berger, Ralph; Lee, Michael; Neveu, Estelle; Bertrand, Daniel; Leonard, Sherry



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

PubMed Central

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

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



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

SciTech Connect

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.

Sharma, Bhupesh, E-mail:; Sharma, P.M.



Interband Transitions in Cubic Nitride Quaternary Alloys Double Quantum Wells  

NASA Astrophysics Data System (ADS)

In this work we present the theoretical photoluminescence spectra from strained and doped double quantum wells based on nitrides quaternary alloys. The calculations are performed within the k.p framework by means of the solution of the 8×8 effective mass Kane Hamiltonian. We show red and blue shifts in energy as the spike and wells widths are changed. The exchange-correlation effects are responsible for changes in the optical electronic transitions.

Rodrigues, S. C. P.; dos Santos, O. F. P.; Scolfaro, L. M. R.; Sipahi, G. M.; da Silva, E. F.



Precise timing and rate of massive late Quaternary soil denudation  

Microsoft Academic Search

Strontium isotopes are a unique tool to study soil-erosion dynamics. Changes in Sr isotope ratios (87Sr\\/86Sr) provide a record of late Quaternary landscape denudation of the Edwards Plateau of central Texas, United States. The use of Sr isotopes as a tracer for soil erosion is based on the observation that, in central Texas, the 87Sr\\/86Sr ratio of soil correlates with

M. Jennifer Cooke; Libby A. Stern; Jay L. Banner; Lawrence E. Mack; Thomas W. Stafford; Rickard S. Toomey



Quaternary fluvial archives: achievements of the Fluvial Archives Group  

NASA Astrophysics Data System (ADS)

In their geomorphological and sedimentary records, rivers provide valuable archives of environments and environmental change, at local to global scales. In particular, fluvial sediments represent databanks of palaeoenvironment and palaeoclimatic (for example) of fossils (micro- and macro-), sedimentary and post-depositional features and buried soils. Well-dated sequences are of the most value, with dating provided by a wide range of methods, from radiometric (numerical) techniques to included fossils (biostratigraphy) and/or archaeological material. Thus Quaternary fluvial archives can also provide important data for studies of Quaternary biotic evolution and early human occupation. In addition, the physical disposition of fluvial sequences, be it as fragmented terrace remnants or as stacked basin-fills, provides valuable information about geomorphological and crustal evolution. Since rivers are long-term persistent features in the landscape, their sedimentary archives can represent important frameworks for regional Quaternary stratigraphy. Fluvial archives are distributed globally, being represented on all continents and across all climatic zones, with the exception of the frozen polar regions and the driest deserts. In 1999 the Fluvial Archives Group (FLAG) was established, as a working group of the Quaternary Research Association (UK), aimed at bringing together those interested in such archives. This has evolved into an informal organization that has held regular biennial combined conference and field-trip meetings, has co-sponsored other meetings and conference sessions, and has presided over two International Geoscience Programme (IGCP) projects: IGCP 449 (2000-2004) 'Global Correlation of Late Cenozoic Fluvial Deposits' and IGCP 518 (2005-2007) 'Fluvial sequences as evidence for landscape and climatic evolution in the Late Cenozoic'. Through these various activities a sequence of FLAG publications has appeared, including special issues in a variety of journals, amassing a substantial volume of information on fluvial archives worldwide. This presentation will highlight some of these data and will describe important patterns observed and interpretations arising therefrom.

Bridgland, David; Cordier, Stephane; Herget, Juergen; Mather, Ann; Vandenberghe, Jef; Maddy, Darrel



Vegetation ecotone dynamics in Southwest Alaska during the Late Quaternary  

Microsoft Academic Search

To examine Late Quaternary vegetation change across the modern vegetation gradient from continuous boreal forest (central Alaska) to Betula shrub tundra (Bristol Bay region), pollen records from Idavain and Snipe Lakes are described and compared to those of four other sites in southwest Alaska. Major features of the vegetation history at Idavain Lake include herb-dominated tundra (ca 14–12kaBP), mixed herb\\/Betula

Linda B. Brubaker; Patricia M. Anderson; Feng Sheng Hu



Quaternary subsidence zones in Albania: some case studies  

Microsoft Academic Search

The Neotectonic evolution of Albania, from the Middle Pleistocene to the present day, is characterised by a general uplift\\u000a that began after the Pliocene. Subsidence took place locally and led to the formation of graben-shaped Quaternary lakes and\\u000a plains. During this period, graben lakes were formed at Shkodra, Ohrid, Prespa and Butrinti, whereas at Korça, Elbasani, Zadrima,\\u000a Tirana, Myzeqe, etc.,

Sh. Aliaj; G. Baldassarre; D. Shkupi



Late Quaternary vegetation and fire dynamics on Mount Kenya  

Microsoft Academic Search

Pollen and charcoal data generated from a 1469cm core, radiocarbon dated to 26,43014C yr BP, recovered from Rumuiku Swamp on the southeast of Mount Kenya, are used to document changes in the distribution and composition of montane vegetation and fire regimes over the Late Quaternary. Throughout the transition from the Last Glacial Maximum (LGM), high resolution (sub-centennial scale) analysis documents

Stephen M. Rucina; Veronica M. Muiruri; Rahab N. Kinyanjui; Katy McGuiness; Rob Marchant



A Quaternary volcanic ash deposit in western Missouri  

Microsoft Academic Search

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



Composite aromatic boxes for enzymatic transformations of quaternary ammonium substrates.  


Cation-? interactions to cognate ligands in enzymes have key roles in ligand binding and enzymatic catalysis. We have deciphered the key functional role of both charged and aromatic residues within the choline binding subsite of CTP:phosphocholine cytidylyltransferase and choline kinase from Plasmodium falciparum. Comparison of quaternary ammonium binding site structures revealed a general composite aromatic box pattern of enzyme recognition sites, well distinguished from the aromatic box recognition site of receptors. PMID:25283789

Nagy, Gergely N; Marton, Lívia; Contet, Alicia; Ozohanics, Olivér; Ardelean, Laura-Mihaela; Révész, Agnes; Vékey, Károly; Irimie, Florin Dan; Vial, Henri; Cerdan, Rachel; Vértessy, Beáta G



Facile and general synthesis of quaternary 3-aminooxindoles.  


A novel approach to the valuable quaternary 3-aminooxindole skeleton is reported on the basis of intramolecular arylation of enolates of substituted amino acids. The reaction tolerates dialkyl- and arylalkylamines as well as a range of carbon substituents (primary and secondary alkyl, aryl). The cyclization of N-indolyl-substituted substrates is accompanied by direct C-H arylation of the indole, leading to indolo-fused benzodiazepines. PMID:18533669

Marsden, Stephen P; Watson, Emma L; Raw, Steven A



Mapping a buried Quaternary valley and pre-Quaternary faults through seismic methods in Copenhagen, Denmark.  

NASA Astrophysics Data System (ADS)

Limited knowledge of the subsurface geology motivates the use of geophysical techniques before large engineering projects are conducted. These applications are normally restricted to satisfy the project aims, like mapping the near surface sediments, unconsolidated rocks and/or geological structures that may affect the construction locally. However, the applications can also contribute to the general knowledge of the regional geology around the location of interest. This report highlights the mapping of a buried Quaternary valley and identification of regional faults by a reflection and refraction seismic survey performed in Copenhagen. A 13.9 Km seismic survey was carried out at Copenhagen city along six crooked lines in order to determine the velocity fields in the near subsurface segment of a planned metro line and reflection patterns in deeper levels. The aim of the survey was to collect information needed for designing the underground metro. In particular it was sought to map the interface between Quaternary sedimentary layers of clay, till and sand, and the underlying layers of Palaeogene limestone found between 7 and 40 m below the ground surface. The data acquisition was carried out using a 192 channels array, receiver groups with 5 m spacing and a Vibroseis as a source at 5 m spacing following a roll along technique to complete the survey spreads. The urban environment demanded extensive survey planning including traffic control, notifications to residents and a fluent coordination with municipal authorities in order to minimize disturbances and ensure data acquisition. The reflection data was processed under a conventional scheme and the refraction data was interpreted using a non-linear traveltime tomography algorithm. The reflection results indicate the presence of faults oriented NW-SE to NNW-SSE affecting the limestone sequences. The faults may be associated to the Sorgenfrei-Tornquist Zone at the transition between the Danish Basin and the Baltic Shield. The refraction interpretation allowed the mapping of the velocity distribution in the upper sediments and their interface with the underlying limestone sequences. In this work two sections along the northern part of the survey are presented and discussed. The cases show the ability of the seismic results to image the presence of a buried valley that has been previously reported but was geophysically mapped for the first time under these investigations. The results delineate the sediments-limestone interface as the depth to the limestone increases. These results are validated through borehole data from locations along the surveyed lines. Other minor lateral variations are also observed and compared to a geological model. The location of the buried valley corresponds to a fault zone observed in the reflection seismic investigation. Accordingly, the location of the valley may in part have been controlled by the faults. The overall results of the seismic investigations are currently being used as part of the design basis for the construction of the metro line and may be useful for future engineering projects in the area. In general, the investigation results demonstrated that in addition to meet specific project objectives near surface geophysics has the potential to provide insights to the general understanding of geological processes. The authors wish to acknowledge Metroselskabet I/S for permission in presenting the results, and the Cityringen Joint Venture partners COWI, Arup and Systra.

Martinez, Kerim; Alfredo Mendoza, Jose; Henrik, Olsen



Ecological impacts of the late Quaternary megaherbivore extinctions.  


As a result of the late Quaternary megafaunal extinctions (50,000-10,000 before present (BP)), most continents today are depauperate of megaherbivores. These extinctions were time-transgressive, size- and taxonomically selective, and were caused by climate change, human hunting, or both. The surviving megaherbivores often act as ecological keystones, which was likely true in the past. In spite of this and extensive research on the causes of the Late Quaternary Extinctions, the long-term ecological consequences of the loss of the Pleistocene megafauna remained unknown until recently, due to difficulties in linking changes in flora and fauna in paleorecords. The quantification of Sporormiella and other dung fungi have recently allowed for explicit tests of the ecological consequences of megafaunal extirpations in the fossil pollen record. In this paper, I review the impacts of the loss of keystone megaherbivores on vegetation in several paleorecords. A growing number of studies support the hypothesis that the loss of the Pleistocene megafauna resulted in cascading effects on plant community composition, vegetation structure and ecosystem function, including increased fire activity, novel communities and shifts in biomes. Holocene biota thus exist outside the broader evolutionary context of the Cenozoic, and the Late Quaternary Extinctions represent a regime shift for surviving plant and animal species. PMID:24649488

Gill, Jacquelyn L



Multiple sources of alkanes in Quaternary oceanic sediment of Antarctica  

USGS Publications Warehouse

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.

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



(Liquid + liquid) equilibria of methanol + isooctane + methylcyclohexane + ethylbenzene quaternary system at T = 303.15 K  

Microsoft Academic Search

Tie line data of {methanol+isooctane+methylcyclohexane}, {methanol+ethylbenzene+methylcyclohexane}, and {methanol+ethylbenzene+isooctane} ternary systems were obtained at T=303.15K. A quaternary system {methanol+isooctane+methylcyclohexane+ethylbenzene} was also studied at the same temperature. In order to obtain the binodal surface of the quaternary system, four quaternary sectional planes with several methylcyclohexane\\/isooctane ratios were studied. Experimental results show that the binodal surface in the solid diagram is small and

Mónica B. Gramajo de Doz; Alicia M. Cases



Cholinesterase inhibitors from the roots of Harpagophytum procumbens.  


Inhibition of cholinesterase has been proposed to be a therapeutic target for the treatment of Alzheimer's diseases. In our preliminary screening study on the acetylcholinesterase (AChE) inhibitory activity, an ethyl acetate soluble fraction of the roots of Harpagophytum procumbens (Pedaliaceae) was found to inhibit AChE activity at the concentration of 100 ?g/mL. Ten compounds (1-10) were isolated from the active fraction and evaluated for their inhibitory effect on AChE and butyrylcholinesterase (BChE). Among the isolates, verbascosides (5, 6, and 8) containing a caffeoyl and a 3,4-dihydroxyphenethyl groups in their structures, showed effective AChE inhibitory activity and also possessed BChE inhibitory activity. The findings suggest that verbascoside derivatives may be partially related to the anti-Alzheimer effect of this medicinal plant. PMID:24374905

Bae, Yoon Ho; Cuong, To Dao; Hung, Tran Manh; Kim, Jeong Ah; Woo, Mi Hee; Byeon, Jeong Su; Choi, Jae Sue; Min, Byung Sun



Polycationic antimicrobial dendrimers: a comparison of alkyl pyridinium,quaternary ammonium, quaternary phosphonium and tertiary sulfonium salts  

NASA Astrophysics Data System (ADS)

Polycationic biocides usually kill bacteria through the interactions of the positively charged head groups with negatively charged bacteria and the interactions of the hydrophobic segments with phospholipid cell membranes, which implies that high local charge densities and a large number of hydrophobic groups would lead to enhanced biocidal potency. The advent of dendrimers offers us the first-ever opportunity to achieve the desired high local density. We have demonstrated that dimethyl dodecyl ammonium chloride functionalized polypropylene imine dendrimers are over 100 times more potent than their small molecule ounterparts. In this study, quaternary ammonium, quaternary phosphonium, alkyl pyridinium and tertiary sulfonium salts based on polypropylene imine dendrimers have been synthesized and characterized. Their antimicrobial properties have been quantified with a novel bioluminescence method. The structure-activity relationship of these polycationic dendrimers has also been investigated to elucidate the molecular mechanism for the enhanced antimicrobial effects.

Chen, Chris; Cooper, Stuart



The complete nucleotide sequence of the TL-DNA of the Agrobacterium tumefaciens plasmid pTiAch5.  

PubMed Central

We have determined the complete primary structure (13 637 bp) of the TL-region of Agrobacterium tumefaciens octopine plasmid pTiAch5 . This sequence comprises two small direct repeats which flank the TL-region at each extremity and are involved in the transfer and/or integration of this DNA segment in plants. TL-DNA specifies eight open-reading frames corresponding to experimentally identified transcripts in crown gall tumor tissue. The eight coding regions are not interrupted by intervening sequences and are separated from each other by AT-rich regions. Potential transcriptional control signals upstream of the 5' and 3' ends of all the transcribed regions resemble typical eukaryotic signals: (i) transcriptional initiation signals ('TATA' or Goldberg- Hogness box) are present upstream to the presumed translational start codons; (ii) ' CCAAT ' sequences are present upstream of the proposed 'TATA' box; (iii) polyadenylation signals are present in the 3'-untranslated regions. Furthermore, no Shine-Dalgarno sequences are present upstream of the presumed translational start codons. PMID:6327292

Gielen, J; De Beuckeleer, M; Seurinck, J; Deboeck, F; De Greve, H; Lemmers, M; Van Montagu, M; Schell, J



Role of aqueous Bryoria capillaris (Ach.) extract as a genoprotective agent on imazalil-induced genotoxicity in vitro.  


In recent years, a number of studies have suggested that lichens might be the easily accessible sources of natural drugs that could be used as a possible food supplement. Extensive research is being carried out to explore the importance of lichen species, which are known to contain a variety of pharmacological active compounds. On the other hand, imazalil (IMA), a commonly used fungicide in both agricultural and clinical domains, is suspected to produce very serious toxic effects in vertebrates. In this context, the antigenotoxic effect of aqueous Bryoria capillaris (Ach.) extract (BCE) was studied against the genotoxic damage induced by IMA on cultured human lymphocytes using chromosomal aberrations (CA) and micronucleus (MN) as cytogenetic parameters. Human peripheral lymphocytes were treated in vitro with varying concentrations of BCE (5, 10, 25, 50 and 100 µg/mL), tested in combination with IMA (336 µg/mL). BCE alone was not genotoxic, and when combined with IMA treatment, it reduced the frequency of CAs and the rates of MN. A clear dose-dependent decrease in the genotoxic damage of IMA was observed, suggesting a genoprotective role of BCE. The results of the present study suggest that this plant extract per se do not have genotoxic potential, but can modulate the genotoxicity of IMA on peripheral human lymphocytes in vitro. In conclusion, our findings may have an important application in the protection of cultured human lymphocyte from the genetic damage and side effects induced by agricultural and medical chemicals that are hazardous to people. PMID:22661402

Turkez, Hasan; Aydin, Elanur; Aslan, Ali



Database and Map of Quaternary Faults and Folds in Peru and its Offshore Region  

USGS Publications Warehouse

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.

Machare, Jose; Fenton, Clark H.; Machette, Michael N.; Lavenu, Alain; Costa, Carlos; Dart, Richard L.



JOURNAL OF QUATERNARY SCIENCE (2001) 16(7) 595602 Copyright 2001 John Wiley & Sons, Ltd.  

E-print Network

to Quaternary climate change (Harland, 1994). Compared with planktonic foraminifers, coccolithophores at northern continental margin sites and in Arctic basins. This increased recognition of the utility

Long, Bernard


Nicotine Induces the Up-regulation of the ?7-Nicotinic Receptor (?7-nAChR) in Human Squamous Cell Lung Cancer Cells via the Sp1/GATA Protein Pathway*  

PubMed Central

Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the ?7-nicotinic acetylcholine receptor (?7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on ?7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased ?7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of ?7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of ?7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of ?7-nAChR mRNA and ?7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of ?7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the ?7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of ?7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking. PMID:24089524

Brown, Kathleen C.; Perry, Haley E.; Lau, Jamie K.; Jones, Dennie V.; Pulliam, Joseph F.; Thornhill, Brent A.; Crabtree, Clayton M.; Luo, Haitao; Chen, Yi. Charlie; Dasgupta, Piyali



A Novel Route to Recognizing Quaternary Ammonium Cations Using Electrospray Mass Spectrometry  

NASA Astrophysics Data System (ADS)

Characterizing and elucidating structures is a commonplace and necessary activity in the pharmaceutical industry with mass spectrometry and NMR being the primary tools for analysis. Although many functional groups are readily identifiable, quaternary ammonium cations have proven to be difficult to unequivocally identify using these techniques. Due to the lack of an N-H bond, quaternary ammonium groups can only be detected in the 1H NMR spectra by weak signals generated from long-range 14N-H coupling, which by themselves are inconclusive evidence of a quaternary ammonium functional group. Due to their low intensity, these signals are frequently not detected. Additionally, ions cannot be differentiated in a mass spectrum as an M+ or [M + H]+ ion without prior knowledge of the compound's structure. In order to utilize mass spectrometry as a tool for determining this functionality, ion cluster formation of quaternary ammonium cations and non-quaternary amines was studied using electrospray ionization. Several mobile phase modifiers were compared; however, the addition of small amounts of trifluoroacetic acid proved superior in producing characteristic and intense [M +2TFA]- clusters for compounds containing quaternary ammonium cations when using negative electrospray. By fragmenting this characteristic ion using CID, nearly all compounds studied could be unambiguously identified as containing a quaternary ammonium cation or a non-quaternary amine attributable to the presence (non-quaternary amine) or absence (quaternary ammonium cation) of the resulting [2TFA + H]- ion in the product spectra. This method of analysis provides a rapid, novel, and reliable technique for indicating the presence of quaternary ammonium cations in order to aid in structural elucidation.

Shackman, Holly M.; Ding, Wei; Bolgar, Mark S.



Multifunctional organic corrosion inhibitor  

Microsoft Academic Search

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

Charles K. Nmai



Oooh, Your Aching Head!  


... it, a headache is not a pain in your brain . Your brain tells you when other parts of your body ... nerves send a rush of pain messages to your brain, and you end up with a headache. Different ...


EXCELLENTIA CoLumbIA ENgINEErINg70 ach year as many as one in five Americans get the flu. More than 200,000 end  

E-print Network

HEALTH EXCELLENTIA CoLumbIA ENgINEErINg70 E ach year as many as one in five Americans get the flu. More than 200,000 end up in the hospital for complications, and 36,000 die from flu-related causes viruses invade cells so they can help develop anti-viral drugs to prevent diseases like the flu and AIDS

Hone, James


Tricks of Perspective: Insights and Limitations to the Study of Macroscopic Currents for the Analysis of nAChR Activation and Desensitization  

PubMed Central

Activation, inactivation, and desensitization are key features of ion channel behavior. We endeavor to understand these processes at the level of the single molecules and extrapolate from such microscopic models the behavior of ion channels in contexts of cellular physiology and therapeutics. In the case of ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs), it is also important to consider the nature of the dynamic changes in the chemical stimulus required for activation. The amplitude and time course of the agonist pulse provided to nAChR at a fast synapse will be vastly different from those of the ACh stimulus presented to presynaptic receptors in the brain and neither of these physiological processes will resemble the stimuli presented by nicotine self-administration or with systemic delivery of a therapeutic agent. Likewise, specific experimental protocols will provide unique stimulus profiles, which will impact the relationship between the macroscopic data and the underlying molecular processes. In this work, ion channel simulations intended to model heteromeric neuronal nAChR are conducted under varying conditions of agonist presentation, and the impact of a key microscopic process, desensitization, is studied on the macroscopic responses. With instantaneous jumps in agonist concentrations, the microscopic desensitization rate impacts essentially all aspects of the macroscopic responses, rise rates, decay rates, and both peak and steady-state currents. In contrast, with an agonist pulse like that used in Xenopus oocyte experiments, microscopic desensitization rates have a profound impact on peak current amplitude and very little effect on the kinetics of the macroscopic responses. PMID:19672724

Papke, Roger L.



Activation of the ?7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT1a receptor antagonist  

PubMed Central

The ?7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the ?7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both ?7 and non-?7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the ?7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamine-induced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT1a receptor antagonist WAY-100135. However the ?7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that ?7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the ?7 receptors. PMID:23321689

Pandya, Anshul A.; Yakel, Jerrel L.



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

PubMed Central

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

Cativiela, Carlos; Ordóñez, Mario



One-pot asymmetric synthesis of quaternary pyrroloindolones through a multicatalytic N-allylation/hydroacylation sequence.  


An intramolecular, quaternary carbon center forming hydroacylation of ?-substituted acrylates has been discovered. This interesting transformation can be readily incorporated into a multicatalytic tandem process enabled by a combination of nucleophilic tertiary amine and N-heterocyclic carbene catalysis. With no additional stoichiometric base required, this transformation affords the quaternary pyrroloindolones with high levels of enantioselectivity. PMID:25079294

Lu, Hong; Lin, Jun-Bing; Liu, Jin-Yu; Xu, Peng-Fei



Pre-Quaternary landforms in the low latitude context: the example of Australia  

Microsoft Academic Search

Direct effects of Quaternary glaciation and periglacial activity affected only comparatively small areas of southeastern Australia. Certainly, volcanicity continued in a few districts, extensive new planation surfaces were formed, dunefields were widely developed, and there were important developments at the coastline and offshore, during this period, but many pre-Quaternary terrains persist in the contemporary landscape. Tertiary volcanic plains and plateaux

C. R. Twidale; E. M. Campbell




Microsoft Academic Search

This paper integrates recent efforts to map the distribution of biomes for the late Quaternary with the detailed evidence that plant species have responded individual- istically to climate change at millennial timescales. Using a fossil-pollen data set of over 700 sites, we review late-Quaternary vegetation history in northern and eastern North America across levels of ecological organization from individual taxa

John W. Williams; Bryan N. Shuman; Thompson Webb; Patrick J. Bartlein; Phillip L. Leduc



River response to Quaternary subsidence due to evaporite solution (Gállego River, Ebro Basin, Spain)  

Microsoft Academic Search

The stream terrace evolution of the Gállego river during the Quaternary was controlled by both climatic change and subsidence. Quaternary terrace deposits, overlying Tertiary clay and limestone, are between 2 and 5 m thick, whereas above evaporite formations the alluvial deposits may be as much as 110 m thick. Chronologically, the first period of alluvial thickening involved the stream terraces

Gerardo Benito; Alfredo Pérez-González; F. Gutiérrez; M. J. Machado



JOURNAL OF QUATERNARY SCIENCE (2002) 17(8) 789795 Copyright 2002 John Wiley & Sons, Ltd.  

E-print Network

Quaternary refugia: a factor in large carnivore extinction? HANNAH J. O'REGAN,* ALAN TURNER and DAVID M in large carnivore extinction?. J. Quaternary Sci., Vol. 17 pp. 789­795. ISSN 0267-8179. Received 17 April 2002; Revised 18 June 2002; Accepted 3 July 2002 ABSTRACT: The extinction of large carnivores in Europe

Brown, Richard


An aminostratigraphy for the British Quaternary based on Bithynia opercula.  


Aminostratigraphies of Quaternary non-marine deposits in Europe have been previously based on the racemization of a single amino acid in aragonitic shells from land and freshwater molluscs. The value of analysing multiple amino acids from the opercula of the freshwater gastropod Bithynia, which are composed of calcite, has been demonstrated. The protocol used for the isolation of intra-crystalline proteins from shells has been applied to these calcitic opercula, which have been shown to more closely approximate a closed system for indigenous protein residues. Original amino acids are even preserved in bithyniid opercula from the Eocene, showing persistence of indigenous organics for over 30 million years. Geochronological data from opercula are superior to those from shells in two respects: first, in showing less natural variability, and second, in the far better preservation of the intra-crystalline proteins, possibly resulting from the greater stability of calcite. These features allow greater temporal resolution and an extension of the dating range beyond the early Middle Pleistocene. Here we provide full details of the analyses for 480 samples from 100 horizons (75 sites), ranging from Late Pliocene to modern. These show that the dating technique is applicable to the entire Quaternary. Data are provided from all the stratotypes from British stages to have yielded opercula, which are shown to be clearly separable using this revised method. Further checks on the data are provided by reference to other type-sites for different stages (including some not formally defined). Additional tests are provided by sites with independent geochronology, or which can be associated with a terrace stratigraphy or biostratigraphy. This new aminostratigraphy for the non-marine Quaternary deposits of southern Britain provides a framework for understanding the regional geological and archaeological record. Comparison with reference to sites yielding independent geochronology, in combination with other lines of evidence, allows tentative correlation with the marine oxygen isotope record. PMID:23396683

Penkman, Kirsty E H; Preece, Richard C; Bridgland, David R; Keen, David H; Meijer, Tom; Parfitt, Simon A; White, Tom S; Collins, Matthew J



Buried Quaternary Valleys In NW Europe - Aquifers and Drilling Hazards  

NASA Astrophysics Data System (ADS)

Buried Quaternary valleys are extremely widespread in the formerly glaciated, low- land areas of NW Europe (Huuse &Lykke-Andersen 2000, Fig. 4). The valleys may be several hundred metres deep, some kilometres across and few to several tens of kilometres long. Most of the deep valleys have irregular length profiles with sills and basins, unlike standard subaerial river systems. We interpret these as overdeepened valleys, formed mainly by subglacial meltwater erosion. Buried valleys located on- shore often provide sheltered reservoirs of clean groundwater, and much attention is presently focused on locating onshore valleys and quantifying their potential as groundwater aquifers. In nearshore areas, buried valleys may be a risk factor by pro- viding pathways of salt-water intrusion of onshore groundwater aquifers. Far offshore, buried valleys are located in the shallow subsurface above the prolific oil and gas fields of the central North Sea. Here, the valleys pose a risk for drilling operations by hosting shallow gas and potentially unstable sediments. The central North Sea is now largely covered by 3D seismic data, which often image the buried valleys in a level of de- tail much greater than that available onshore. Hence offshore valleys imaged by 3D seismic data may be used as analogues for groundwater reservoirs onshore NW Eu- rope. Here, we present examples of buried valleys from onshore, nearshore and far offshore locations, to illustrate how genetically and morphologically identical valleys may benefit or hamper the exploitation of subsurface accummulations of groundwater and hydrocarbons. Huuse, M. &Lykke-Andersen, H. 2000. Buried Quaternary valleys in the eastern Dan- ish North Sea: morphology and origin. Quaternary Science Reviews 19, 1233-1253.

Huuse, M.; Lykke-Andersen, H.; Piotrowski, J.


An aminostratigraphy for the British Quaternary based on Bithynia opercula  

PubMed Central

Aminostratigraphies of Quaternary non-marine deposits in Europe have been previously based on the racemization of a single amino acid in aragonitic shells from land and freshwater molluscs. The value of analysing multiple amino acids from the opercula of the freshwater gastropod Bithynia, which are composed of calcite, has been demonstrated. The protocol used for the isolation of intra-crystalline proteins from shells has been applied to these calcitic opercula, which have been shown to more closely approximate a closed system for indigenous protein residues. Original amino acids are even preserved in bithyniid opercula from the Eocene, showing persistence of indigenous organics for over 30 million years. Geochronological data from opercula are superior to those from shells in two respects: first, in showing less natural variability, and second, in the far better preservation of the intra-crystalline proteins, possibly resulting from the greater stability of calcite. These features allow greater temporal resolution and an extension of the dating range beyond the early Middle Pleistocene. Here we provide full details of the analyses for 480 samples from 100 horizons (75 sites), ranging from Late Pliocene to modern. These show that the dating technique is applicable to the entire Quaternary. Data are provided from all the stratotypes from British stages to have yielded opercula, which are shown to be clearly separable using this revised method. Further checks on the data are provided by reference to other type-sites for different stages (including some not formally defined). Additional tests are provided by sites with independent geochronology, or which can be associated with a terrace stratigraphy or biostratigraphy. This new aminostratigraphy for the non-marine Quaternary deposits of southern Britain provides a framework for understanding the regional geological and archaeological record. Comparison with reference to sites yielding independent geochronology, in combination with other lines of evidence, allows tentative correlation with the marine oxygen isotope record. PMID:23396683

Penkman, Kirsty E.H.; Preece, Richard C.; Bridgland, David R.; Keen, David H.; Meijer, Tom; Parfitt, Simon A.; White, Tom S.; Collins, Matthew J.



Quaternary Fault and Fold Database for the United States: California  

NSDL National Science Digital Library

This interactive map shows the major fault systems of the Quaternary for the State of California. It is subdivided into 1x2 degree sheets, each of which is linked to a more detailed map. Users can select a sheet and see an enlargement of the area. Individual fault systems are numbered and keyed to a legend which provides a link to a written synopsis of information for the fault, including fault type and geologic history. Links are also provided to more extensive reports for the faults, including a "complete" report with references.


Appearance of half-metallicity in the quaternary Heusler alloys  

Microsoft Academic Search

I report systematic first-principle calculations of the quaternary Heusler alloys like Co$_2$[Cr$_{1-x}$Mn$_x$]Al, Co$_2$Mn[Al$_{1-x}$Sn$_x$] and [Fe$_{1-x}$Co$_x$]$_2$MnAl. I show that when the two limiting cases (x=0 or 1) correspond to a half-metallic compound, so do the intermediate cases. Moreover the total spin moment $M_t$ in $\\\\mu_B$ scales linearly with the total number of valence electrons $Z_t$ (and thus with the concentration $x$)

Iosif Galanakis



Quaternary Faults and Folds by State and Region  

NSDL National Science Digital Library

This interactive map of the United states provides access to maps of Quaternary faults and folds by state or region (for example, the Gulf Coast). Clicking on the colored areas of the map links the user to state/regional maps and further, to 1x2 degree sheets for each area. On the sheets, users can find faults numbered and indexed to a legend. Links from the legend provide access to written information, where available, for each fault. There are three levels of written reports, ranging from a brief synopsis to a "complete" report that includes references.


Charophytes as lacustrine biomarkers during the quaternary in North Africa  

NASA Astrophysics Data System (ADS)

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.

Soulié-Märsche, I.


Aromatase inhibitors in pediatrics.  


Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution. PMID:22024975

Wit, Jan M; Hero, Matti; Nunez, Susan B



Late Quaternary Lacustrine Pollen Records from Southwestern Beringia  

NASA Astrophysics Data System (ADS)

Sediment cores from three lakes in the Upper Kolyma region, northeast Russia, provide the first well-dated continuous record of late Quaternary vegetation change from far southwestern Beringia. The oldest pollen zone, tentatively assigned to the Karginsk (mid-Wisconsinan) Interstade, indicates an Artemisia shrub tundra with Pinus pumila, Betula, and Alnus at mid- to low elevations. With the onset of the Sartan (late Wisconsinan) Stade, Pinus disappeared, probably indicating severely cold, dry winters and cool summers. As conditions deteriorated further, an Artemisia -Gramineae tundra developed. Selaginella rupestris and minor herb taxa indicate the presence of poor soils and disturbed ground. This herb tundra was replaced by a short-lived (< 1000 yr) Betula-Alnus shrub tundra followed by the rapid establishment of a Larix dahurica forest with a Betula exilis-ericales-lichen understory. Populus suaveolens and Chosenia may have formed limited hardwood gallery forests at this time. Modern vegetation associations probably developed during the early Holocene with the arrival of Pinus pumila ca. 9000 yr B.P. This shrub became important in the forest understory and, with B. exilis, formed a belt of shrub tundra beyond altitudinal treeline. Comparison of the Upper Kolyma and Alaskan pollen records indicates that important differences in vegetation types and timing of vegetation change occurred across Beringia during the late Quaternary.

Lozhkin, Anatoly V.; Anderson, Patricia M.; Eisner, Wendy R.; Ravako, Lilia G.; Hopkins, David M.; Brubaker, Linda B.; Colinvaux, Paul A.; Miller, Michael C.



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


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

Raes, Niels; Cannon, Charles H; Hijmans, Robert J; Piessens, Thomas; Saw, Leng Guan; van Welzen, Peter C; Slik, J W Ferry



Late quaternary environments, Denali National Park and Preserve, Alaska  

USGS Publications Warehouse

Late Quaternary pollen, plant macrofossils, and insect fossils were studied from sites along three rivers in the foothills north of the Alaska Range in Denali National Park and Preserve. The aim was to carry out a reconaissance of late Quaternary organic sediments in the region, emphasizing the mid-Wisconsin, or Boutellier interstadial interval. Samples of probable early- to mid-Boutellier age (ca. 60 000 to 40 000 B.P.) from Unit 2 at the Toklat High Bluffs site indicate open boreal woodland with dense alder shrub vegetation. Organic Unit 1 at the Foraker River Slump site indicates open taiga with shrubs of probable Boutellier age. Fossil evidence from the youngest horizon in this unit indicates graminoid tundra environments, marking the transition from interstadial to late Wisconsin glacial environments. Early Holocene samples from the Foraker exposures suggest birch shrub tundra; coniferous forest apparently became established only alter 6500 B.P. Local variations in forest composition at the Foraker and Sushana sites were probably the result of disturbances, such as fire.

Elias, S.A.; Short, S.K.; Waythomas, C.F.



Distribution and metabolism of quaternary amines in salt marshes  

NASA Technical Reports Server (NTRS)

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.

King, Gary M.



Liquefaction potential of Quaternary alluvium in Bolu settlement area, Turkey  

NASA Astrophysics Data System (ADS)

Groundwater bearing alluvial units in the seismically active settlement areas may bring out probable damage on the urban and built environment due to liquefaction. Bolu settlement area and surroundings are located in the North Anatolian Fault Zone. Geotechnical boreholes were drilled in order to determine the distribution of the geological units, to obtain representative soil samples and to measure groundwater level. Quaternary aged alluvium is the main geological unit in the South of study area. Stiffness and consistency of the soils were determined by Standart penetration test. P and S wave velocities of soil have been measured along the seismic profiles. The index and physical properties of the samples have also been tested in the laboratory. Liquefaction potential and safety factor of the sandy levels in Quaternary aged alluvium were investigated by different methods based on SPT and V s. Liquefaction seems to be a significant risk in case of an earthquake with a max = 0.48 g and M w = 7.5 at different levels of the boreholes. This situation may bring out environmental problems in the future.

Ulamis, Koray; Kilic, Recep



Late Quaternary terrestrial vertebrate coprolites from New Zealand  

NASA Astrophysics Data System (ADS)

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.

Wood, Jamie R.; Wilmshurst, Janet M.



Quaternary geochronology using the U?Th?Pb method  

NASA Astrophysics Data System (ADS)

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 206Ph and 208Ph to be detected at the level of 0.001%. Igneous rocks hosting minerals with a range in 238U/204Pb values of 100 can be dated with uncertainties of approximately ±15-20 kyr. A Quaternary rhyolite dated at 1.19 Ma by K?Ar yields a 238U? 206Ph age of 1.03 ± 0.10 Ma. A Holocene dacite (9.5 ka) has uniform 206Pb/207Pb to within 0.0015% in groundmass phases, but 1 mm plagioclase phenocrysts have lower 206Pb/207Pb by 0.105 ± 0.002% indicating contamination of the magma after plagioclase crystallization. High precision 206Pb/207Ph ratios may be a useful new tool for petrogenetic studies.

Getty, Stephen R.; Depaolo, Donald J.



Clinical and Electrophysiologic Responses to Acetylcholinesterase Inhibitors in MuSK-Antibody-Positive Myasthenia Gravis: Evidence for Cholinergic Neuromuscular Hyperactivity  

PubMed Central

Background and Purpose Patients with muscle-specific tyrosine kinase (MuSK) antibody (MuSK-Ab)-positive myasthenia gravis (MG) show distinct responses to acetylcholinesterase inhibitors (AChEIs). Although clinical responses to AChEIs in MuSK-Ab MG are reasonably well known, little is known about the electrophysiologic responses to AChEIs. We therefore investigated the clinical and electrophysiologic responses to AChEIs in MuSK-Ab-positive MG patients. Methods We retrospectively reviewed the medical records and electrodiagnostic findings of 17 MG patients (10 MuSK-Ab-positive and 7 MuSK-Ab-negative patients) who underwent electrodiagnostic testing before and after a neostigmine test (NT). Results The frequency of intolerance to pyridostigmine bromide (PB) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (50% vs. 0%, respectively; p=0.044), while the maximum tolerable dose of PB was lower in the former (90 mg/day vs. 480 mg/day, p=0.023). The frequency of positive NT results was significantly lower in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (40% vs. 100%, p=0.035), while the nicotinic side effects of neostigmine were more frequent in the former (80% vs. 14.3%, p=0.015). Repetitive compound muscle action potentials (R-CMAPs) developed more frequently after NT in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (90% vs. 14.3%, p=0.004). The frequency of a high-frequency-stimulation-induced decrement-increment pattern (DIP) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (100% vs. 17.7%, p=0.003). Conclusions These results suggest that MuSK-Ab-positive MG patients exhibit unique and hyperactive responses to AChEIs. Furthermore, R-CMAP and DIP development on a standard AChEI dose may be a distinct neurophysiologic feature indicative of MuSK-Ab-positive MG. PMID:24829597

Shin, Ha Young; Park, Hyung Jun; Lee, Hyo Eun; Choi, Young-Chul



Combined QSAR studies of inhibitor properties of O-phosphorylated oximes toward serine esterases involved in neurotoxicity, drug metabolism and Alzheimer's disease.  


Oxime reactivation of serine esterases (EOHs) inhibited by organophosphorus (OP) compounds can produce O-phosphorylated oximes (POXs). Such oxime derivatives are of interest, because some of them can have greater anti-EOH potencies than the OP inhibitors from which they were derived. Accordingly, inhibitor properties of 58 POXs against four EOHs, along with pair-wise selectivities between them, have been analysed using different QSAR approaches. EOHs (with their abbreviations and consequences of inhibition in parentheses) comprised acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity). QSAR techniques encompassed linear regression and backpropagation neural networks in conjunction with fragmental descriptors containing labelled atoms, Molecular Field Topology Analysis (MFTA), Comparative Molecular Similarity Index Analysis (CoMSIA), and molecular modelling. All methods provided mostly consistent and complementary information, and they revealed structural features controlling the 'esterase profiles', i.e. patterns of anti-EOH activities and selectivities of the compounds of interest. In addition, MFTA models were used to design a library of compounds having a cognition-enhancement esterase profile suitable for potential application to the treatment of Alzheimer's disease. PMID:22587543

Makhaeva, G F; Radchenko, E V; Baskin, I I; Palyulin, V A; Richardson, R J; Zefirov, N S



Cholinesterase inhibitors: new roles and therapeutic alternatives  

Microsoft Academic Search

An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain which makes the function of BuChE of difficult interpretation. In human brain, BuChE is

Ezio Giacobini



The inhibition of release of endothelium-derived relaxant factor by manoalide, a potent inhibitor of phospholipase A2.  

PubMed Central

1 The inhibitory action of manoalide on vascular relaxation was characterized. Manoalide was a potent inhibitor of endothelium-dependent relaxations in the isolated aorta of the rabbit. Responses to acetylcholine (ACh), A23187 and substance P were reduced by manoalide in a dose-dependent manner whilst those to nitroglycerin were unaffected. 2 Repeated washing of manoalide-treated tissues did not restore the relaxant response to ACh, indicating an irreversible action of manoalide. Scanning electron microscopic studies revealed that the endothelium remained intact on manoalide-treated tissues. 3 Rabbit aortae from which the endothelium had been removed relaxed in response to perfusion with ACh when delivered via an upstream endothelium-bearing tissue, indicating release of an endothelium-derived relaxant factor (EDRF). Incubation of the tissue without endothelium with manoalide (100 nM; 30 min) or inclusion of manoalide in the superfusate at a point just distal to the endothelium bearing tissue did not reduce the relaxant potency of EDRF. 4 Contractile responses of the guinea-pig isolated ileum to ACh were not affected by manoalide and, furthermore, binding of [3H]-quinuclidinyl benzilate to striatal membranes was not reduced by manoalide except at very high concentrations. 5 Manoalide therefore appears to inhibit vascular relaxation with a selectivity directed towards that mediated by EDRF. A direct antagonism of neither cholinoceptors nor EDRF receptors occurs and it is suggested that manoalide acts at a site within the endothelium to inhibit the synthesis and/or release of EDRF. Based upon these and previous data the possibility that EDRF is lipid-like or controlled by an arachidonic acid metabolite must continue to be considered. PMID:2827828

Long, C. J.; Sarau, H. M.; Berkowitz, B. A.



Neuroprotective role of Indirubin-3'-monoxime, a GSK? inhibitor in high fat diet induced cognitive impairment in mice.  


Recent studies have highlighted that diabetes mellitus (DM) is a strong risk factor for Alzheimer's disease (AD). Insulin resistance and/or hyperinsulinemia is one of the main characteristics of type 2 DM. Numerous epidemiological studies have demonstrated that insulin resistance contributes to AD pathogenesis. However the molecular mechanisms of association between these still remain elusive. Among the various possible mechanisms, the GSK-3? activity has been reported to be impaired in insulin-resistance, type 2 DM and AD. Thus, the present study was designed to explore the neuroprotective role of GSK3 ? inhibitor, Indirubin-3'-monoxime (IMX) in insulin resistance induced cognitive impairment. Further, we have explored the possible molecular mechanism involved in cognitive impairment associated with insulin resistance. The mice subjected to high fat diet exhibited characteristic features of insulin resistance viz. increased serum glucose, triglycerides, cholesterol, insulin levels and impaired spatial learning and memory ability along with reduced brain insulin level, elevated oxidative stress and acetylcholinesterase (AChE) activity. The observed changes occurred concurrently with reduced brain derived neurotrophic factor. In contrast, the mice treated with IMX showed a significant reduction in plasma glucose, triglycerides, cholesterol, insulin levels and improvement in learning and memory performance, attenuated the oxidative stress and AChE activity. Moreover, IMX dose dependently augment the brain insulin and BDNF levels in HFD fed mice. Based upon these findings it could be suggested that GSK3 ? inhibition could prove to be beneficial in insulin resistance induced cognitive deficit and this neuroprotection could be the result of enhanced BDNF based synaptic plasticity. PMID:25234596

Sharma, Sorabh; Taliyan, Rajeev



Are calcineurin inhibitors safer than mTOR inhibitors?  

PubMed Central

Isakova et al. report that kidney transplant recipients on mammalian target of rapamycin (mTOR) inhibitors do not have a lower risk of allograft failure but do have a higher risk of death than those on calcineurin inhibitors. Careful consideration is, therefore, required before converting to mTOR inhibitors to preserve renal function. PMID:23183834

Yeh, Heidi; Markmann, James F.



Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors.  


A novel series of chalcone derivatives (4a-8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The logP values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC50: 4.68?mol/L) was 2-fold more potent than Rivastigmine against AChE (IC50: 10.54?mol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE. PMID:25260958

Liu, Hao-Ran; Liu, Xian-Jun; Fan, Hao-Qun; Tang, Jing-Jing; Gao, Xiao-Hui; Liu, Wu-Kun



Quaternary history of the piedmont reach of Río Diamante, Argentina  

NASA Astrophysics Data System (ADS)

The Río Diamante is located in a segment of the southern Central Andes that is transitional in terms of morphology and foreland tectonics (33-37°S). The piedmont reach of the river flows eastwards between the main mountain front and the San Rafael Block (the southernmost foreland uplift to the east of the southern Central Andes). Unlike adjacent rivers, the Río Diamante has incised into pre-Quaternary bedrock to form a deep canyon across the piedmont. Five fill and strath terraces were mapped, correlated, and surveyed along the ˜35 km piedmont reach to determine their paleo-long profiles. Chronological data for the terraces were provided by geochemical correlation of interbedded tephras to a previously dated ignimbrite, as well as by eight cosmogenic 10Be ages, and suggest a synchronous relationship between fill terrace deposition and glaciation upstream. Terraces are tentatively correlated with oxygen isotope stages 16 (Qt1), 12 (Qt2), 4 (Qt3) and 2 (Qt4 and Qt5). Minor spatial variation in incision along the reach is apparent from the long profile of the Qt2 strath (˜450 ka), which shows low-amplitude folding. The long-term reach average rate of bedrock incision is estimated to be ˜0.1-0.5 m/kyr and the recent shorter term (post-OIS 2) rate is estimated at ˜2 m/kyr. Mid and late Quaternary uplift of the piedmont area is a likely cause for the incision; however, other possible explanations include a delayed response to pre-mid Quaternary uplift, or a response to changes in climate and sediment supply on a tectonically stable portion of the piedmont flanked by subsiding basins. Base-level fall due to subsidence on the eastern side of the San Rafael Block creating a westward migrating knickzone may have contributed to the incision, but the depth of incision is greater than the observed subsidence and no major knickzone is present in the modern river profile of the study reach. Studies such as this on piedmont geomorphic processes are important for understanding the topographic and tectonic transitions that characterise the southern Central Andes.

Baker, Sophie E.; Gosse, John C.; McDonald, Eric V.; Evenson, Edward B.; Martínez, Oscar



Quaternary history and contemporary patterns in a currently expanding species  

PubMed Central

Background Quaternary climatic oscillations had dramatic effects on species evolution. In northern latitudes, populations had to survive the coldest periods in refugial areas and recurrently colonized northern regions during interglacials. Such a history usually results in a loss of genetic diversity. Populations that did not experience glaciations, in contrast, probably maintained most of their ancestral genetic diversity. These characteristics dramatically affected the present-day distribution of genetic diversity and may influence the ability of species to cope with the current global changes. We conducted a range-wide study of mitochondrial genetic diversity in the pine processionary moth (Thaumetopoea pityocampa/T. wilkinsoni complex, Notodontidae), a forest pest occurring around the Mediterranean Basin and in southern Europe. This species is responding to the current climate change by rapid natural range expansion and can also be accidentally transported by humans. Our aim was to assess if Quaternary climatic oscillations had a different effect across the species' range and to determine if genetic footprints of contemporary processes can be identified in areas of recent introduction. Results We identified three main clades that were spatially structured. In most of Europe, the genetic diversity pattern was typical for species that experienced marked glaciation cycles. Except in refugia, European populations were characterized by the occurrence of one main haplotype and by a strong reduction in genetic diversity, which is expected in regions that were rapidly re-colonized when climatic conditions improved. In contrast, all other sub-clades around the Mediterranean Basin occurred in limited parts of the range and were strongly structured in space, as is expected in regions in which the impact of glaciations was limited. In such places, genetic diversity was retained in most populations, and almost all haplotypes were endemic. This pattern was extreme on remote Mediterranean islands (Crete, Cyprus, Corsica) where highly differentiated, endemic haplotypes were found. Recent introductions were typified by the existence of closely-related haplotypes in geographically distant populations, which is difficult to detect in most of Europe because of a lack of overall genetic structure. Conclusion In regions that were not prone to marked glaciations, recent moth introductions/expansions could be detected due to the existence of a strong spatial genetic structure. In contrast, in regions that experienced the most intense Quaternary climatic oscillations, the natural populations are not genetically structured, and contemporary patterns of population expansion remain undetected. PMID:19732434

Kerdelhué, Carole; Zane, Lorenzo; Simonato, Mauro; Salvato, Paola; Rousselet, Jérôme; Roques, Alain; Battisti, Andrea



Quaternary Reorganization of North American Mid-continent Drainage Systems  

NASA Astrophysics Data System (ADS)

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.

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



The ?7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat  

PubMed Central

BACKGROUND AND PURPOSE Agonists selective for the ?7 nicotinic acetylcholine (nACh) receptor produce anti-hyperalgesic effects in rodent models of inflammatory pain, via direct actions on spinal pain circuits and possibly via attenuated release of peripheral pro-inflammatory mediators. Increasingly, allosteric modulation of ligand-gated receptors is recognized as a potential strategy to obtain desired efficacy in the absence of the putative adverse effects associated with agonist activation. EXPERIMENTAL APPROACH We compared the anti-hyperalgesic and anti-inflammatory effects of the ?7 nACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA). KEY RESULTS When administered before carrageenan, both diclofenac (30 mg·kg?1) and PNU-120596 (30 mg·kg?1) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg·kg?1) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU-120596 attenuated the carrageenan-induced increase in levels of TNF-? and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac was considerably more efficacious. Formalin-induced nocifensive behaviours were only reversed by compound B, albeit at doses which disrupted motor performance. CONCLUSIONS AND IMPLICATIONS ?7 nACh receptor PAMs could prove to be useful in the treatment of inflammatory pain conditions, which respond poorly to NSAIDs or in situations where NSAIDs are contra-indicated. PMID:22536953

Munro, G; Hansen, RR; Erichsen, HK; Timmermann, DB; Christensen, JK; Hansen, HH



Control of Quaternary sea-level changes on gas seeps  

NASA Astrophysics Data System (ADS)

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.

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



Quaternary prevention, an answer of family doctors to overmedicalization  

PubMed Central

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

Jamoulle, Marc



Quaternary soil salinity events and Australian vegetation history  

NASA Astrophysics Data System (ADS)

A late Quaternary history of Australian soil salinization is produced by comparing Chenopodiaceae and Casuarina pollen curves. Although salinity development varied between sites, its occurrence was generally associated with arid phases and when high rainfall or high sea level caused regionally high groundwater tables. Soil salinization contributed to the shift from Casuarina- to Eucalyptus-dominance of interglacial sclerophyll vegetation. The deposition of saline sediments deflated from the Murray Basin seems more likely than Aboriginal burning to have caused the decline of Casuarina at Lake George. Soil salinization probably resulted in other vegetation changes and must be taken into account in environmental reconstructions. The renewed increase in soil salinity caused by European land-use practices and an associated decline in Casuarina are evident in the pollen records of many sites.

Crowley, G. M.


Luminescence studies on nitride quaternary alloys double quantum wells  

NASA Astrophysics Data System (ADS)

We present theoretical photoluminescence (PL) spectra of undoped and p-doped Al xIn 1- x- yGa yN/Al XIn 1- X- YGa YN double quantum wells (DQWs). The calculations were performed within the k.p method by means of solving a full eight-band Kane Hamiltonian together with the Poisson equation in a plane wave representation, including exchange-correlation effects within the local density approximation. Strain effects due to the lattice mismatch are also taken into account. We show the calculated PL spectra, analyzing the blue and red-shifts in energy as one varies the spike and the well widths, as well as the acceptor doping concentration. We found a transition between a regime of isolated quantum wells and that of interacting DQWs. Since there are few studies of optical properties of quantum wells based on nitride quaternary alloys, the results reported here will provide guidelines for the interpretation of forthcoming experiments.

Rodrigues, S. C. P.; dos Santos, O. F. P.; Scolfaro, L. M. R.; Sipahi, G. M.; da Silva, E. F., Jr.



Asynchronous extinction of late Quaternary sloths on continents and islands.  


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 approximately 11,000 radiocarbon years before present (yr BP) or slightly less in North America, approximately 10,500 yr BP in South America, and approximately 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

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



Exposure to common quaternary ammonium disinfectants decreases fertility in mice.  


Quaternary ammonium compounds (QACs) are antimicrobial disinfectants commonly used in commercial and household settings. Extensive use of QACs results in ubiquitous human exposure, yet reproductive toxicity has not been evaluated. Decreased reproductive performance in laboratory mice coincided with the introduction of a disinfectant containing both alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC). QACs were detected in caging material over a period of several months following cessation of disinfectant use. Breeding pairs exposed for six months to a QAC disinfectant exhibited decreases in fertility and fecundity: increased time to first litter, longer pregnancy intervals, fewer pups per litter and fewer pregnancies. Significant morbidity in near term dams was also observed. In summary, exposure to a common QAC disinfectant mixture significantly impaired reproductive health in mice. This study illustrates the importance of assessing mixture toxicity of commonly used products whose components have only been evaluated individually. PMID:25483128

Melin, Vanessa E; Potineni, Haritha; Hunt, Patricia; Griswold, Jodi; Siems, Bill; Werre, Stephen R; Hrubec, Terry C



Asynchronous extinction of late Quaternary sloths on continents and islands  

PubMed Central

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

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.



[Synthesis and biological evaluation of tetrahydrocoptisine quaternary ammonium compounds].  


The goal of treatment of metabolic syndrome is the prevention of diabetes and cardiovascular events. A series of novel tetrahydrocoptisine quaternary ammonium compounds were prepared to evaluate their action of hypoglycemia and hypolipidemia for finding the therapeutic agents of metabolic syndrome. Starting from the coptisine hydrochloride (2), fifteen target compounds were synthesized by reduction and substitution of the 7-N position. All of the target compounds were characterized by 1H NMR and HR-MS. Their hypoglycemic activities were evaluated in HepG2 cell and hypolipidemic activities of compounds with better hypoglycemic activity were tested further in vivo. Results indicated that compounds 5, 7, 8 and 9 exhibited better hypoglycemic activities in vitro and compounds 5 and 8 exhibited good hypolipidemic activities in high-fat-diet (HFD) induced hyperlipidemia mice and (or) hamsters. However, the activity is not as good as simvastatin. PMID:23460970

Wang, Dong-Mei; Wei, Jin-Zhao; Fan, Bao-Yan; Liu, Quan; Zhu, Hai-Bo; Shen, Zhu-Fang; Wu, Song



Tertiary and quaternary solutions for plane Couette flow  

NASA Astrophysics Data System (ADS)

The plane Couette system does not exhibit any secondary solutions bifurcating from the primary solution of constant shear. Since the work of Nagata (1990) it has been well known that three-dimensional steady solutions exist. Here the manifold of those steady solutions is explored in the parameter space of the problem and their instabilities are investigated. These instabilities usually lead to time-periodic solutions whose properties do not differ much from those of the steady solutions except that the amplitude varies in time. In some cases travelling wave solutions which are asymmetric with respect to the midplane of the layer are found as quaternary states of flow. Similarities with longitudinal vortices recently observed in experiments are discussed.

Clever, R. M.; Busse, F. H.



Quaternary stratigraphic usage in North America: A brief survey  

NASA Astrophysics Data System (ADS)

A survey of North American Quaternary workers shows that a majority of those polled believe the distinction between the geologic-climate stratigraphic term “Wisconsin Glaciation” and the chrono-stratigraphic term “Wisconsinan Stage” is important in North America. More than two-thirds of the respondents indicated that they favor use of local or regional geographic terms for the last glaciation outside of central and eastern North America. A majority also advocated informal use of local or regional names for subdivisional stratigraphic units. Almost three-fourths of the respondents suggested that the Pleistocene-Holocene boundary be placed at 10,000 14C yr B.P. Most feel that the pre-Wisconsin glacial stage terminology should be retained, but in a revised, well-dated stratigraphic system. *Present addresses: (Nelson) Engineering and Research Center, U.S. Water and Power Resources Service, Denver Federal Center, Denver, Colorado 80225; (Locke) Department of Geology, Williams College, Williamstown, Massachusetts 01267

Nelson, Alan R.; Locke, William W., III



Quaternary prevention, an answer of family doctors to overmedicalization.  


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

Jamoulle, Marc



Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer's disease patients.  


Acetylcholinesterase inhibitors (AChEIs) are the most widely used symptomatic treatment for mild to severe Alzheimer's disease (AD) patients, while N-methyl-d-aspartic acid (NMDA) receptor antagonist memantine is licensed for use in moderate to severe AD patients. In this article, the effect of these compounds on resting state eyes-closed electroencephalographic (EEG) rhythms in AD patients is reviewed to form a knowledge platform for the European Innovative Medicine Initiative project "PharmaCog" (IMI Grant Agreement No. 115009) aimed at developing innovative translational models for drug testing in AD. Indeed, quite similar EEG experiments and the same kind of spectral data analysis can be performed in animal models of AD and in elderly individuals with prodromal or manifest AD. Several studies have shown that AChEIs affect both resting state EEG rhythms and cognitive functions in AD patients. After few weeks of successful treatment, delta (0-3 Hz) or theta (4-7 Hz) rhythms decrease, dominant alpha rhythms (8-10 Hz) increase, and cognitive functions slightly improve. Beneficial effects of these rhythms and cognitive functions were also found in AD responders to the long-term successful treatment (i.e. 6-12 months). In contrast, only one study has explored the long-term effects of memantine on EEG rhythms in AD patients, showing reduced theta rhythms. The present review enlightens the expected effects of AChEIs on resting state EEG rhythms in AD patients as promising EEG markers for the development of translational protocols both within the PharmaCog project and for wider use. PMID:23098644

Babiloni, Claudio; Del Percio, Claudio; Bordet, Regis; Bourriez, Jean-Luis; Bentivoglio, Marina; Payoux, Pierre; Derambure, Philippe; Dix, Sophie; Infarinato, Francesco; Lizio, Roberta; Triggiani, Antonio Ivano; Richardson, Jill C; Rossini, Paolo M



Are seawater Sr/Ca variations preserved in Quaternary foraminifera?  

SciTech Connect

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.

Stoll, H.M.; Schrag, D.P.; Clemens, S.C.



Quaternary intraplate deformation in the southeastern Sierras Pampeanas, Argentina  

NASA Astrophysics Data System (ADS)

Neogene strain from the subducting Nazca plate is widely distributed in theAndean foreland as a result of flat-lying subduction beneath central westernArgentina (28°-33°S latitude). This fact is indicated byuplifted basement blocks bounded by reverse faults as far as 600 kms eastof the Chilean trench axis. Some deformation in the southern Sierras deCórdoba (southeastern Sierras Pampeanas) indicates significantdisplacements during Quaternary and even late Holocene time. Thisregion has low to moderate seismicity characterized by earthquakemagnitudes 6.7 with no associated noticeable surface ruptures.This paper presents information recently gathered on the most conspicuousregional structures of the area (El Molino, Sierra Chica and Las Lagunasfaults). The last movement along the El Molino fault thrust basement rocksover organic-rich (0.8-1.3 ka) sediment and fault relationships suggestprevious Quaternary displacements. Along the Sierra Chica fault,Precambrian basement has been thrust a minimum of 13.5 m overPleistocene conglomerates, and faulting also affects latePleistocene-Holocene fluvial sediments. The Las Lagunas fault has beenregarded as the source of the 1934 Ms 5.5 and 6.0 earthquakes, whichheavily damaged the nearby village of Sampacho. The faulted surface isburied under Holocene loess, but its trace is expressed as a 24-km-longrectilinear scarp, despite continuous modification due to land use.Although we lack detailed information on probable rupture lengths duringlarge Sierras Pampeanas thrust earthquakes, some preliminary considerationsare made for the regional seismic hazard of these structures. The geologicevidence described here identifies these faults as possible sources of strongearthquakes in the future.

Costa, Carlos H.; Murillo, M. Victoria; Sagripanti, Guillermo L.; et al.


Quaternary incised valleys in southern Brazil coastal zone  

NASA Astrophysics Data System (ADS)

High-resolution seismic records obtained in the Rio Grande do Sul coastal zone, southern Brazil, revealed that prominent valleys and channels developed in the area before the installation of actual coastal plain. Landwards, the paleoincisions can be linked with the present courses of the main river dissecting the area. Oceanwards, they can be linked with related features previously recognized in the continental shelf and slope by means of seismic and morphostructural studies. Based mainly on seismic, core data and geologic reasoning, it can be inferred that the coastal valleys were incised during forced regression events into the coastal prism deposited during previous sea level highstand events of the Quaternary. Seismic data has revealed paleovalleys up to 10 km wide and, in some places, infilled with up to 40 m thick of sediments. The results indicated two distinct periods of cut-and-fill events in the Patos Lagoon area. The filling of the younger incision system is mainly Holocene and its onset is related to the last main regressive event of the Pleistocene, when the sea level fell about 130 m below the actual position. The older incision and filling event is related to the previous regressive-transgressive events of the Middle and Late Pleistocene. The fluvial discharge fed delta systems on the shelf edge during the sea level lowstands. The subsequent transgressions drowned the incised drainage, infilling it and closing the inlets formerly connecting the coastal river to the ocean. The incised features may have played a significant role on the basin-margin architecture, facies distribution and accommodation space during the multitude of up and down sea level events of the Quaternary.

Weschenfelder, Jair; Baitelli, Ricardo; Corrêa, Iran C. S.; Bortolin, Eduardo C.; dos Santos, Cristiane B.



Quaternary Stratigraphy and Paleogeography of the Galilee Coastal Plain, Israel  

NASA Astrophysics Data System (ADS)

The Quaternary deposits in the Galilee coastal plain comprise alternating calcareous sandstone, red loam, dark clay, and uncemented sand. The calcareous sandstone in the lower part of the sequence represents a Pliocene to early Pleistocene marine transgression, and is covered unconformably by the late Quaternary sequence. The base of this sequence has an estimated age of ?500,000 yr. It is covered unconformably by marine calcareous sandstone in the west, which represents the global high sea-level stand of isotope stage 7.1, and is known as one of the 'Tyrrhenian' events in the Mediterranean area. The overlying members represent the low sea-level stand of stage 6, the first a red paleosol indicating a relatively wet phase and the second an eolianite unit representing a drier phase. The eolianite forms longitudinal, subparallel ridges that formed contemporaneously. The overlying marine sandstone, which contains one of the diagnostic fossils of the 'Tyrrhenian' events, the gastropodStrombus buboniusLMK, accumulated during the global high stand of stage 5.5. The last glacial period left no sedimentary record. The Holocene is represented by a marine clay unit that is covered by sand. The present study establishes a complete and detailed chronostratigraphic sequence for an eastern Mediterranean beach, which contains the gastropodS. buboniusLMK.S. buboniuson the Galilee coast is attributed to stage 5.5 and, therefore, establishes an east-west Mediterranean correlation, which can be used for linking Mediterranean events to paleo-sea levels and global climate changes.

Sivan, Dorit; Gvirtzman, Gedaliahu; Sass, Eytan



New direct thrombin inhibitors  

Microsoft Academic Search

Direct thrombin inhibitors (DTIs) are a class of anticoagulants that bind selectively to thrombin and block its interaction\\u000a with its substrates. Dabigatran etexilate and AZD0837, the new generation of DTIs, are now under intense development, and\\u000a are potentially of great interest for internists. Dabigatran etexilate is a potent, non-peptidic small molecule that specifically\\u000a and reversibly inhibits both free and clot-bound

Alessandro Squizzato; Francesco Dentali; Luigi Steidl; Walter Ageno



The late Quaternary limnological history of Lake Kinneret (Sea of Galilee), Israel  

E-print Network

The late Quaternary limnological history of Lake Kinneret (Sea of Galilee), Israel N. Hazana , M) during the Neogene­Quartenary periods. We reconstructed the limnological history (level and composition

Marco, Shmuel "Shmulik"


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

E-print Network

in limited detail. Raney and Collins (1994) mapped the Quaternary sediments along the East Franklin Mountains concurrently with the present study. Lovejoy and Seager (1978) suggested that the mechanism responsible for the East Franklin Mountains fault...

Scherschel, Craig A.



Antibacterial properties of poly(quaternary ammonium) modified gold and titanium dioxide nanoparticles.  


We report excellent antibacterial effect induced by amine-functionalized gold and titanium dioxide nanoparticles without external excitations. The idea originates from the excellent antibacterial property of quaternary ammonium salts. The effects of poly(quaternary ammonium) and polyacrylate sodium functional groups as nanoparticle surfactants are compared to show that poly(quaternary ammonium) functional groups are the main cause of the induced antibacterial effect. 99.999% of E. coli can be destructed in 10 minutes by simply mixing bacteria with nanoparticle dispersions. The effect of nanoparticle concentrations on the antibacterial property is evaluated. Time required to significantly suppress bacteria growth is studied. The result indicates that the excellent antibacterial property can be introduced to any nanomaterials by using poly(quaternary ammonium) functional groups as surfactants. The engineered nanoparticles can find enormous applications such as self-cleaning surfaces, waste water treatment, Lab-on-a-Chip devices and many more. PMID:22905506

Wan, Weijie; Yeow, John T W



OMVPE Growth of Quaternary (Al,Ga,In)N for UV Optoelectronics (title change from A)  

SciTech Connect

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.




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

E-print Network

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...

Lotto, Linda L



Neutrophil Elastase Inhibitors  

PubMed Central

Introduction Chronic obstructive pulmonary disease (COPD) constitutes a worldwide health problem. There is currently an urgent and unmet need for the development of small molecule therapeutics capable of blocking and/or reversing the progression of the disorder. Recent studies have greatly illuminated our understanding of the multiple pathogenic processes associated with COPD. Of paramount importance is the key role played by proteases, oxidative stress, apoptosis, and inflammation. Insights gained from these studies have made possible the exploration of new therapeutic approaches. Areas covered An overview of major developments in COPD research with emphasis on low molecular weight neutrophil elastase inhibitors is described in this review. Expert opinion Great strides have been made toward our understanding of the biochemical and cellular events associated with COPD. However, our knowledge regarding the inter-relationships among the multiple pathogenic mechanisms and their mediators involved is till limited. The problem is further compounded by the unavailability of suitable validated biomarkers for assessing the efficacy of potential therapeutic interventions. The complexity of COPD suggests that effective therapeutic interventions may require the administration of more than one agent such as, for instance, an HNE or MMP-12 inhibitor with an anti-inflammatory agent such as a phosphodiesterase-4 inhibitor, or a dual function agent capable of disrupting the cycle of proteolysis, apoptosis, inflammation and oxidative stress PMID:21235378

Groutas, William C.; Dou, Dengfeng; Alliston, Kevin R.



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

PubMed Central

The Quaternary has been described as an important time for genetic diversification and speciation. This is based on the premise that Quaternary climatic conditions fostered the isolation of populations and, in some instances, allopatric speciation. However, the 'Quaternary Ice-Age speciation model' rests on two key assumptions: (i) that biotic responses to climate change during the Quaternary were significantly different from those of other periods in Earth's history; and (ii) that the mechanisms of isolation during the Quaternary were sufficient in time and space for genetic diversification to foster speciation. These assumptions are addressed by examining the plant fossil record for the Quaternary (in detail) and for the past 410 Myr, which encompasses previous intervals of icehouse Earth. Our examination of the Quaternary record indicates that floristic responses to climate changes during the past 1.8 Myr were complex and that a distinction has to be made between those plants that were able to withstand the extremes of glacial conditions and those that could not. Generation times are also important as are different growth forms (e.g. herbaceous annuals and arborescent perennials), resulting in different responses in terms of genetic divergence rates during isolation. Because of these variations in the duration of isolation of populations and genomic diversification rates, no canonical statement about the predominant floristic response to climatic changes during the Quaternary (i.e. elevated rates of speciation or extinction, or stasis) is currently possible. This is especially true because of a sampling bias in terms of the fossil record of tree species over that of species with non-arborescent growth forms. Nevertheless, based on the available information, it appears that the dominant response of arborescent species during the Quaternary was extinction rather than speciation or stasis. By contrast, our examination of the fossil record of vascular plants for the past 410 Myr indicates that speciation rates often increased during long intervals of icehouse Earth (spanning up to 50 Myr). Therefore, longer periods of icehouse Earth than those occurring during the Quaternary may have isolated plant populations for sufficiently long periods of time to foster genomic diversification and allopatric speciation. Our results highlight the need for more detailed study of the fossil record in terms of finer temporal and spatial resolution than is currently available to examine the significance of intervals of icehouse Earth. It is equally clear that additional and detailed molecular studies of extant populations of Quaternary species are required in order to determine the extent to which these 'relic' species have genomically diversified across their current populations. PMID:15101573

Willis, Katherine J; Niklas, Karl J



Algicidal Activity of a Surface-Bonded Organosilicon Quaternary Ammonium Chloride  

PubMed Central

The hydrolysis product of a quaternary amine-containing organosilicon salt, 3-(trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride, was found to exhibit algicidal activity while chemically bonded to a variety of substrates. Six representative species of Chlorophyta, Cyanophyta, and Chrysophyta were used to evaluate the algicidal activity. Substrate-bonded 14C-labeled organosilicon quaternary ammonium salt when attached to nonwoven fibers was durable to repeated washings, and algicidal activity could not be attributed to slow release of the chemical. Images PMID:4632852

Walters, P. A.; Abbott, E. A.; Isquith, A. J.



Superconductivity and magnetism and their interplay in quaternary borocarbides RNi2B2C  

Microsoft Academic Search

Since 1986, most of the interest in superconductivity became focused on high-Tc cuprates. The discovery of the superconducting quaternary borocarbide system Y–Ni–B–C with Tc as high as??12?K inspired research into intermetallic superconductors (IMS) once again. Several reasons can be attributed to this revival of interest in IMS: (i) In the tetragonal quaternary magnetic superconductors RNi2B2C, superconductivity and magnetism occur with

L. C. Gupta