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1

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

2013-01-01

2

Novel AChE Inhibitors for Sustainable Insecticide Resistance Management  

PubMed Central

Resistance to insecticides has become a critical issue in pest management and it is particularly chronic in the control of human disease vectors. The gravity of this situation is being exacerbated since there has not been a new insecticide class produced for over twenty years. Reasoned strategies have been developed to limit resistance spread but have proven difficult to implement in the field. Here we propose a new conceptual strategy based on inhibitors that preferentially target mosquitoes already resistant to a currently used insecticide. Application of such inhibitors in rotation with the insecticide against which resistance has been selected initially is expected to restore vector control efficacy and reduce the odds of neo-resistance. We validated this strategy by screening for inhibitors of the G119S mutated acetylcholinesterase-1 (AChE1), which mediates insensitivity to the widely used organophosphates (OP) and carbamates (CX) insecticides. PyrimidineTrione Furan-substituted (PTF) compounds came out as best hits, acting biochemically as reversible and competitive inhibitors of mosquito AChE1 and preferentially inhibiting the mutated form, insensitive to OP and CX. PTF application in bioassays preferentially killed OP-resistant Culex pipiens and Anopheles gambiae larvae as a consequence of AChE1 inhibition. Modeling the evolution of frequencies of wild type and OP-insensitive AChE1 alleles in PTF-treated populations using the selectivity parameters estimated from bioassays predicts a rapid rise in the wild type allele frequency. This study identifies the first compound class that preferentially targets OP-resistant mosquitoes, thus restoring OP-susceptibility, which validates a new prospect of sustainable insecticide resistance management. PMID:23056599

Alout, Haoues; Labbe, Pierrick; Berthomieu, Arnaud; Djogbenou, Luc; Leonetti, Jean-Paul; Fort, Philippe; Weill, Mylene

2012-01-01

3

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

PubMed Central

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

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

2005-01-01

4

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

PubMed

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(50) values of 9.63?M (for ZLA) and 8.64?M (for ZLB), and prevent AChE-induced amyloid-? (A?) aggregation with IC(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. PMID:22842334

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

2012-10-01

5

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

E-print Network

designed as novel, reversible inhibitors of acetylcholinesterase. On the basis of the X-ray structure. In addition, a subsequent crystal structure of acetylcholinesterase complexed with the most active compound 27

Sussman, Joel L.

6

Acetylcholinesterase inhibitors neostigmine and physostigmine inhibit induction of alpha-amylase activity during seed germination in barley, Hordeum vulgare var. Jyoti  

Microsoft Academic Search

Acetylcholine (ACh) is an important neurotransmitter whose non-neuronal biological roles are being widely accepted. ACh and components of its metabolism are present in plants. ACh and some inhibitors of acetylcholinesterase (AChE) share structural similarity (quaternary ammonium group) with some inhibitors of biosynthesis of a plant hormone, gibberellic acid (GA); e.g., 2-Isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine carboxylate methyl chloride (AMO-1618) inhibits GA biosynthesis as well

Veena Beri; Rajendra Gupta

2007-01-01

7

Synthesis and in vitro evaluation of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide derivatives as reactivators against sarin and VX inhibited human acetylcholinesterase (hAChE).  

PubMed

A series of bis-quaternary pyridinium derivatives 3a-3i of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (2) have been synthesized. The synthesized pyridinium compounds have an amide group in conjugation to the oxime moiety. These compounds were evaluated in vitro for their reactivation efficacy against organophosphorus (OP) nerve agents (NAs) (sarin and VX) inhibited human erythrocyte ghost acetylcholinesterase (hAChE) and compared with the reactivation efficacy of 2-PAM and obidoxime. The pKa values of the synthesized compounds were found closer to the pKa values of 2- and 4-pyridinium oxime reactivators such as 2-PAM and obidoxime. Some of the compounds have shown better reactivation efficacy than 2-PAM, and obidoxime against sarin and VX inhibited AChE. PMID:24721830

Karade, Hitendra N; Valiveti, Aditya Kapil; Acharya, Jyotiranjan; Kaushik, Mahabir Parshad

2014-05-01

8

AChE inhibitor: a regio- and stereo-selective 1,3-dipolar cycloaddition for the synthesis of novel substituted 5,6-dimethoxy spiro[5.3']-oxindole-spiro-[6.3?]-2,3-dihydro-1H-inden-1?-one-7-(substituted aryl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole.  

PubMed

Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11?mol/L. PMID:22142546

Ashraf Ali, Mohamed; Ismail, Rusli; Choon, Tan Soo; Kumar, Raju Suresh; Osman, Hasnah; Arumugam, Natarajan; Almansour, Abdulrahman I; Elumalai, Karthikeyan; Singh, Abhimanyu

2012-01-01

9

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

PubMed Central

Acetylcholinesterase (AChE; EC 3.1.1.7) plays a crucial role in the rapid hydrolysis of the neurotransmitter acetylcholine, in the central and peripheral nervous system and might also participate in non-cholinergic mechanism related to neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-? (A?) peptide accumulation and synaptic alterations. We have previously shown that AChE is able to accelerate the A? peptide assembly into Alzheimer-type aggregates increasing its neurotoxicity. Furthermore, AChE activity is altered in brain and blood of Alzheimer’s patients. The enzyme associated to amyloid plaques changes its enzymatic and pharmacological properties, as well as, increases its resistant to low pH, inhibitors and excess of substrate. Here, we reviewed the effects of IDN 5706, a hyperforin derivative that has potential preventive effects on the development of AD. Our results show that treatment with IDN 5706 for 10?weeks increases brain AChE activity in 7-month-old double transgenic mice (APPSWE–PS1) and decreases the content of AChE associated with different types of amyloid plaques in this Alzheimer’s model. We concluded that early treatment with IDN 5706 decreases AChE–A? interaction and this effect might be of therapeutic interest in the treatment of AD. PMID:21949501

Carvajal, Francisco J.; Inestrosa, Nibaldo C.

2011-01-01

10

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

NASA Astrophysics Data System (ADS)

Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by the channel's cytoplasmic amino terminus. Here we show that the central cavity and inner pore of the K+ channel form the receptor site for both the inactivation gate and small-molecule inhibitors. We propose that inactivation occurs by a sequential reaction in which the gate binds initially to the cytoplasmic channel surface and then enters the pore as an extended peptide. This mechanism accounts for the functional properties of K+ channel inactivation and indicates that the cavity may be the site of action for certain drugs that alter cation channel function.

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

2001-06-01

11

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

2014-01-01

12

Subcellular localization of overexpressed maize AChE gene in rice plant  

PubMed Central

The ACh-mediated system consisting of acetylcholine (ACh), acetylcholine receptor (AChR) and acetylcholinesterase (AChE) is fundamental for nervous system function in animals and insects. Although plants lack a nervous system, both ACh and ACh-hydrolyzing activity have been widely recognized in the plant kingdom. The function of the plant ACh-mediated system is still unclear, despite more than 30 years of research. To understand ACh-mediated systems in plants, we previously purified maize AChE and cloned the corresponding gene from maize seedlings (Plant Physiology). In a recent paper in Planta, we also purified and cloned AChE from the legume plant siratro (Macroptilium atropurpureum). In comparison with electric eel AChE, both plant AChEs showed enzymatic properties of both animal AChE and animal butyrylcholinesterase. On the other hand, based on Pfam protein family analysis, both plant AChEs contain a consensus sequence of the lipase GDSL family, while the animal AChEs possess a distinct alpha/beta-hydrolase fold superfamily sequence, but no lipase GDSL sequence. Thus, neither plant AChE belongs to the well-known AChE family, which is distributed throughout the animal kingdom. To address the possible physiological roles of plant AChEs, we herein report our data from the immunological analysis of the overexpressed maize AChE gene in plants. PMID:19704473

Yamamoto, Kosuke

2008-01-01

13

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.

1998-01-01

14

A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease  

Microsoft Academic Search

Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a

Narihiro Toda; Keiko Tago; Shinji Marumoto; Kazuko Takami; Mayuko Ori; Naho Yamada; Kazuo Koyama; Shunji Naruto; Kazumi Abe; Reina Yamazaki; Takao Hara; Atsushi Aoyagi; Yasuyuki Abe; Tsugio Kaneko; Hiroshi Kogen

2003-01-01

15

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

PubMed

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

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

2012-07-01

16

Bactericidal Activity of ACH-702 against Nondividing and Biofilm Staphylococci  

PubMed Central

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

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

2012-01-01

17

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

Microsoft Academic Search

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

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

2011-01-01

18

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

2013-01-01

19

In silico studies in probing the role of kinetic and structural effects of different drugs for the reactivation of tabun-inhibited AChE.  

PubMed

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

2013-01-01

20

JournalofPhysiology Acetycholinesterase (AChE) is a key enzyme in cholinergic  

E-print Network

acetylcholinesterase overexpression induces multilevelled aberrations in mouse neuromuscular physiology Noa Farchi-hydrolysing enzyme acetylcholinesterase (AChE) is a notable consequence of exposure to anticholinesterase drugs

Hochner, Binyamin

21

Design, synthesis and structure–Activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease  

Microsoft Academic Search

We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by

Narihiro Toda; Keiko Tago; Shinji Marumoto; Kazuko Takami; Mayuko Ori; Naho Yamada; Kazuo Koyama; Shunji Naruto; Kazumi Abe; Reina Yamazaki; Takao Hara; Atsushi Aoyagi; Yasuyuki Abe; Tsugio Kaneko; Hiroshi Kogen

2003-01-01

22

Expression of acetylcholine (ACh) and ACh-synthesizing activity in Archaea  

Microsoft Academic Search

Acetylcholine (ACh) is known generally as the neurotransmitter in the mammalian central and peripheral cholinergic nervous systems. However, ACh is also widely expressed in non-neuronal animal tissues and in plants, fungi and bacteria, where it is likely involved in the transport of water, electrolytes and nutrients, and in modulating various other cell functions. We have investigated the expression of ACh

Tomoya Yamada; Takeshi Fujii; Tamotsu Kanai; Taku Amo; Tadayuki Imanaka; Hiroshi Nishimasu; Takayoshi Wakagi; Hirofumi Shoun; Masahiro Kamekura; Yoichi Kamagata; Takeshi Kato; Koichiro Kawashima

2005-01-01

23

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

PubMed

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

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

2014-12-01

24

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

Microsoft Academic Search

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

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

2012-01-01

25

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

PubMed

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

Chandar, Nellore Bhanu; Ganguly, Bishwajit

2013-08-25

26

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

PubMed Central

BACKGROUND AND PURPOSE The roles played by endothelium-derived NO and prostacyclin and by endothelial cell hyperpolarization in ACh-induced relaxation have been well characterized in arteries. However, the mechanisms underlying ACh-induced relaxation in veins remain to be fully clarified. EXPERIMENTAL APPROACH ACh-induced smooth muscle cell (SMC) hyperpolarization and relaxation were measured in endothelium-intact and -denuded preparations of rabbit jugular vein. KEY RESULTS In endothelium-intact preparations, ACh (?10?8 M) marginally increased the intracellular concentration of Ca2+ ([Ca2+]i) in endothelial cells but did not alter the SMC membrane potential. However, ACh (10?10–10?8 M) induced a concentration-dependent relaxation during the contraction induced by PGF2? and this relaxation was blocked by the NO synthase inhibitor N?-nitro-l-arginine. ACh (10?8–10?6 M) concentration-dependently increased endothelial [Ca2+]i and induced SMC hyperpolarization and relaxation. These SMC responses were blocked in the combined presence of apamin [blocker of small-conductance Ca2+-activated K+ (SKCa, KCa2.3) channel], TRAM 34 [blocker of intermediate-conductance Ca2+-activated K+ (IKCa, KCa3.1) channel] and margatoxin [blocker of subfamily of voltage-gated K+ (KV) channel, KV1]. CONCLUSIONS AND IMPLICATIONS In rabbit jugular vein, NO plays a primary role in endothelium-dependent relaxation at very low concentrations of ACh (10?10–10?8 M). At higher concentrations, ACh (10?8?3 × 10?6 M) induces SMC hyperpolarization through activation of endothelial IKCa, KV1 and (possibly) SKCa channels and produces relaxation. These results imply that ACh regulates rabbit jugular vein tonus through activation of two endothelium-dependent regulatory mechanisms. PMID:22595036

Itoh, Takeo; Maekawa, Takashi; Shibayama, Yasushi

2012-01-01

27

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

Microsoft Academic Search

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

Ronald J. Polinsky

1998-01-01

28

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

PubMed Central

Functional architecture of the AChE active center appears to be characterized by both structural “rigidity”, necessary to stabilize the catalytic triad as well as by flexibility in accommodating the different, high affinity AChE ligands. These seemingly conflicting structural properties of the active center are demonstrated through combination of structural methods with kinetic studies of the enzyme and its mutant derivatives with plethora of structurally diverse ligands and in particular with series of stereoselective covalent and noncovalent AChE ligands. Thus, steric perturbation of the acyl pocket precipitates in a pronounced stereoselectivity toward methylphosphonates by disrupting the stabilizing environment of the catalytic histidine rather than through steric exclusion demonstrating the functional importance of the “rigid” environment of the catalytic machinery. The acyl pocket, the cation-binding subsite (Trp86) and the peripheral anionic subsite were also found to be directly involved in HuAChE stereoselectivity toward charged chiral phosphonates, operating through differential positioning of the ligand cationic moiety within the active center. Residue Trp86 is also a part of the “hydrophobic patch” which seems flexible enough to accommodate the structurally diverse ligands like tacrine, galanthamine and the two diastereomers of huperzine A. Also, we have recently discovered further aspects of the role of both the unique structure and the flexibility of the “hydrophobic patch” in determining the reactivity and stereoselectivity of HuAChE toward certain carbamates including analogs of physostigmine. In these cases the ligands are accommodated mostly through hydrophobic interactions and their stereoselectivity delineates precisely the steric limits of the pocket. Hence, the HuAChE stereoselectivity provides a sensitive tool in the in depth exploration of the functional architecture of the active center. These studies suggest that the combination of “rigidity” and flexibility within the HuAChE gorge are an essential element of its molecular design. PMID:18471807

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

2008-01-01

29

Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors  

Microsoft Academic Search

The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into

Wolfgang Sippl; Jean-Marie Contreras; Isabelle Parrot; Yveline M. Rival; Camille G. Wermuth

2001-01-01

30

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

PubMed Central

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. PMID:23959117

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

2013-01-01

31

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

PubMed Central

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

2014-01-01

32

Time evolution of the quaternary structure of Escherichia coli aspartate transcarbamoylase upon reaction with the natural substrates and a slow, tight-binding inhibitor.  

PubMed

Here, we present a study of the conformational changes of the quaternary structure of Escherichia coli aspartate transcarbamoylase, as monitored by time-resolved small-angle X-ray scattering, upon combining with substrates, substrate analogs, and nucleotide effectors at temperatures between 5 and 22 degrees C, obviating the need for ethylene glycol. Time-resolved small-angle X-ray scattering time courses tracking the T-->R structural change after mixing with substrates or substrate analogs appeared to be a single phase under some conditions and biphasic under other conditions, which we ascribe to multiple ligation states producing a time course composed of multiple rates. Increasing the concentration of substrates up to a certain point increased the T-->R transition rate, with no further increase in rate beyond that point. Most strikingly, after addition of N-phosphonacetyl-l-aspartate to the enzyme, the transition rate was more than 1 order of magnitude slower than with the natural substrates. These results on the homotropic mechanism are consistent with a concerted transition between structural and functional states of either low affinity, low activity or high affinity, high activity for aspartate. Addition of ATP along with the substrates increased the rate of the transition from the T to the R state and also decreased the duration of the R-state steady-state phase. Addition of CTP or the combination of CTP/UTP to the substrates significantly decreased the rate of the T-->R transition and caused a shift in the enzyme population towards the T state even at saturating substrate concentrations. These results on the heterotropic mechanism suggest a destabilization of the T state by ATP and a destabilization of the R state by CTP and CTP/UTP, consistent with the T and R state crystallographic structures of aspartate transcarbamoylase in the presence of the heterotropic effectors. PMID:18823998

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

2008-12-01

33

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

Microsoft Academic Search

Al adjuvants are used in vaccines to increase the immune response. NTPDase and AChE play a pivotal role and act in the regulation of the immune system. The effect of Al exposure in vitro and in vivo on NTPDase and AChE activities in the lymphocytes of rats was determined. In vitro, ATP hydrolysis was decreased by 20.4% and 17.3% and

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

2010-01-01

34

Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation  

Microsoft Academic Search

The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes

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

2004-01-01

35

Lycopodiaceae from Panama: A new source of acetylcholinesterase inhibitors  

Microsoft Academic Search

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,

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

2012-01-01

36

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

2009-01-01

37

Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations.  

PubMed

Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE-compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding. PMID:24836068

Vitorovi?-Todorovi?, Maja D; Koukoulitsa, Catherine; Jurani?, Ivan O; Mandi?, Ljuba M; Drakuli?, Branko J

2014-06-23

38

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

PubMed

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

2014-01-01

39

Cerebro-protective effects of ENA713, a novel acetylcholinesterase inhibitor, in closed head injury in the rat  

Microsoft Academic Search

Focal ischemic brain damage and diffuse brain swelling occur in severe cases of traumatic head injury. Ischemia decreases brain acetylcholine (ACh) levels and head trauma upregulates acetylcholinesterase (AChE) in experimental animal models. The present study determined whether a brain-selective AChE inhibitor, ENA713, given once, up to 2 h after closed head injury (CHI) could reduce the vasogenic edema and accelerate

Yun Chen; Esther Shohami; Roman Bass; Marta Weinstock

1998-01-01

40

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

PubMed

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

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

2013-10-15

41

Impaired hippocampal plasticity and errors in cognitive performance in mice with maladaptive AChE splice site  

E-print Network

, The Hebrew University of Jerusalem, Israel 91904 Keywords: acetylcholinesterase, cognition errors, LTP performance. Under stress, alternative splicing changes priority from synaptic acetylcholinesterase (ACh

Hochner, Binyamin

42

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

Microsoft Academic Search

During prolonged exposure of postjunctional nicotinic acetylcholine receptors (nAChR) of skeletal muscle to acetylcholine (ACh), agonist-activated nAChR (nAChRa) gradually fall into a refractory “desensitized” state (nAChRd), which no longer supports the high-conductance channel openings characteristic of the initially active nAChRa. In the present study, the possibility was examined that nAChRd, rather than simply constituting a passive “trap” for nAChRa, may

Arthur A. Manthey

2006-01-01

43

New Acetylcholinesterase Inhibitors for Alzheimer's Disease  

PubMed Central

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds. PMID:22216416

Mehta, Mona; Adem, Abdu; Sabbagh, Marwan

2012-01-01

44

Isocorilagin, a cholinesterase inhibitor from Phyllanthus niruri.  

PubMed

Drugs that have dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) produce better clinical efficacy against Alzheimer's disease (AD) than those that selectively inhibit one enzyme. A dual cholinesterase inhibitory-guided fractionation of Phyllanthus niruri leaves afforded isocorilagin, a bioactive tannin possessing good inhibitory activities against AChE (IC50: 0.49 microM) and BChE (IC50: 4.20 microM). Interestingly, isocorilagin was relatively 2- to 3-fold more potent than galanthamine, the clinically used inhibitor. The kinetic analyses suggested that isocorilagin was a non-competitive inhibitor for AChE and an uncompetitive inhibitor for BChE, with calculated Ki values of 1.49 microM and 2.86 microM, respectively. In silico molecular docking revealed that isocorilagin effectively blocked the substrate entry by forming hydrogen bonding with residues at the entrance of the AChE active site. With BChE, the compound completely docked inside and occupied the active site of the enzyme. This study demonstrated for the first time the potent cholinesterase inhibitory activities of isocorilagin, a promising lead that is worthy of further investigation. PMID:24868872

Koay, Yee-Hui; Basiri, Alireza; Murugaiyah, Vikneswaran; Chan, Kit-Lam

2014-04-01

45

Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study.  

PubMed

Oximate anions are used as potential reactivating agents for OP-inhibited AChE because of they possess enhanced nucleophilic reactivity due to the ?-effect. We have demonstrated the process of reactivating the VX-AChE adduct with formoximate and hydroxylamine anions by applying the DFT approach at the B3LYP/6-311 G(d,p) level of theory. The calculated results suggest that the hydroxylamine anion is more efficient than the formoximate anion at reactivating VX-inhibited AChE. The reaction of formoximate anion and the VX-AChE adduct is a three-step process, while the reaction of hydroxylamine anion with the VX-AChE adduct seems to be a two-step process. The rate-determining step in the process is the initial attack on the VX of the VX-AChE adduct by the nucleophile. The subsequent steps are exergonic in nature. The potential energy surface (PES) for the reaction of the VX-AChE adduct with hydroxylamine anion reveals that the reactivation process is facilitated by the lower free energy of activation (by a factor of 1.7 kcal mol(-1)) than that of the formoximate anion at the B3LYP/6-311 G(d,p) level of theory. The higher free energy of activation for the reverse reactivation reaction between hydroxylamine anion and the VX-serine adduct further suggests that the hydroxylamine anion is a very good antidote agent for the reactivation process. The activation barriers calculated in solvent using the polarizable continuum model (PCM) for the reactivation of the VX-AChE adduct with hydroxylamine anion were also found to be low. The calculated results suggest that V-series compounds can be more toxic than G-series compounds, which is in accord with earlier experimental observations. PMID:21850569

Khan, Md Abdul Shafeeuulla; Ganguly, Bishwajit

2012-05-01

46

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.

2009-01-01

47

Nonlinear mixed effects pharmacokinetic\\/pharmacodynamic analysis of the cholinesterase inhibitor pyridostigmine bromide in Chinese males  

Microsoft Academic Search

Pyridostigmine is a reversible inhibitor of acetylcholinesterase (AChE). The objective of the present analysis was to characterise the population pharmacokinetics \\/ pharmacodynamics (PK\\/PD) of pyridostigmine given as pyridostigmine bromide. Fifty healthy Chinese males received 7 doses of 30 mg of pyridostigmine bromide each every 8 hours orally. Plasma concentrations of pyridostigmine and red blood cell (RBC) AChE activity were determined

Seng Kok Yong; Loke Weng Keong; Moochhala Shabbir; Jon Deoon Lee

2009-01-01

48

Quaternary Research Center  

NSDL National Science Digital Library

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

49

Endosulfan exposure inhibits brain AChE activity and impairs swimming performance in adult zebrafish (Danio rerio).  

PubMed

Endosulfan is a broad spectrum organochlorine pesticide that is still widely in use in many developing countries. Following application, endosulfan can get to watercourses through surface runoff from agricultural fields and disturb the non-target aquatic animals including freshwater fish species. Given that the activity of the enzyme acetylcholinesterase (AChE) is one of the most recurrently used biomarkers of exposure to pesticides and there are controversial results concerning the effects of endosulfan exposure and AChE activity in fish, the aim of the present study was to evaluate the effects of endosulfan in brain AChE activity and its gene expression pattern using adult zebrafish (Danio rerio) as an animal model. Moreover, we have analyzed the effects of endosulfan exposure in different parameters of zebrafish swimming activity and in long-term memory formation. After 96 h of exposition, fish in the 2.4 ?g endosulfan/L group presented a significant decrease in AChE activity (9.44 ± 1.038 ?mol SCh h(-1) mg protein(-1); p=0.0205) when compared to the control group (15.87 ± 1.768 ?mol SCh h(-1) mg protein(-1); p=0.0205) which corresponds to approximately 40%. The down-regulation of brain AChE activity is not directly related with the transcriptional control as demonstrated by the RT-qPCR analysis. Our results reinforce AChE activity inhibition as a pathway of endosulfan-induced toxicity in brain of fish species. In addition, exposure to 2.4 ?g endosulfan/L during 96 h impaired all exploratory parameters evaluated: decreased line crossings (?21%, 273.7 ± 28.12 number of line crossings compared to the control group 344.6 ± 21.30, p=0.0483), traveled distance (?20%, 23.44 ± 2.127 m compared to the control group 29.39 ± 1.585, p=0.0281), mean speed (?25%, 0.03 ± 0.003 m/s compared to the control group 0.04 ± 0.002, p=0.0275) and body turn angle (?21%, 69,940 ± 4871 absolute turn angle compared to the control group 88,010 ± 4560, p=0.0114). These results suggest that endosulfan exposure significantly impairs animals' exploratory performance, and potentially compromises their ecological and interspecific interaction. Our results also showed that the same endosulfan exposure did not compromise animals' performance in the inhibitory avoidance apparatus. These findings provide further evidence of the deleterious effects of endosulfan exposure in the nervous system. PMID:22459995

Pereira, Vanessa Maynart; Bortolotto, Josiane Woutheres; Kist, Luiza Wilges; Azevedo, Mariana Barbieri de; Fritsch, Rachel Seemann; Oliveira, Renata da Luz; Pereira, Talita Carneiro Brandão; Bonan, Carla Denise; Vianna, Monica Ryff; Bogo, Maurício Reis

2012-06-01

50

Lycopodiaceae from Panama: a new source of acetylcholinesterase inhibitors.  

PubMed

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

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

2013-03-01

51

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

PubMed Central

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

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

2012-01-01

52

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.

Hill, Christopher

53

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

PubMed Central

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

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

2014-01-01

54

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

PubMed

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

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

2014-01-01

55

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

2002-01-01

56

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

PubMed Central

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

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

2013-01-01

57

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

PubMed Central

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.; Perez de Leon, Adalberto A.; Bloomquist, Jeffrey R.

2013-01-01

58

In Vitro Effect of H2O 2, Some Transition Metals and Hydroxyl Radical Produced Via Fenton and Fenton-Like Reactions, on the Catalytic Activity of AChE and the Hydrolysis of ACh.  

PubMed

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

2014-11-01

59

Ache at the settlement: Contrasts between farming and foraging  

Microsoft Academic Search

The Northern Ache comprise a small continuously interacting population with a shared community history. Full-time hunter-gatherers until recently, they now divide their time between mobile foraging and settled farming. Here we describe adult time allocation at the settlement and contrast it with our previous descriptions of time allocation during foraging periods. We report that at the settlement men and women

Kristen Hawkes; Hillard Kaplan; Kim Hill; Ana Magdalena Hurtado

1987-01-01

60

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

61

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

2014-01-01

62

Inhibition of alpha 7-containing nicotinic ACh receptors by muscarinic M1 ACh receptors in rat hippocampal CA1 interneurones in slices.  

PubMed

Cys-loop ligand-gated nicotinic ACh receptors (nAChRs) and G protein-coupled muscarinic ACh receptors (mAChRs) are expressed on rat hippocampal interneurones where they can regulate excitability, synaptic communication and cognitive function. Even though both nAChRs and mAChRs appear to co-localize to the same interneurones, it is not clear whether there is crosstalk between them. We utilized patch-clamp techniques to investigate this issue in rat hippocampal CA1 interneurones in slices under conditions where synaptic transmission was blocked. The alpha7 nAChR-mediated currents were activated by choline, and when the activation of this receptor was preceded by the activation of the M(1) mAChR subtype, the amplitude of alpha7 responses was significantly reduced in a rapidly reversible and voltage-independent manner, without any change in the kinetics of responses. This M(1) mAChR-mediated inhibition of alpha7 nAChRs was through a PLC-, calcium- and PKC-dependent signal transduction cascade. These data show that M(1) mAChRs and alpha7 nAChRs are functionally co-localized on individual rat hippocampal interneurones where the activation of these particular mAChRs inhibits alpha7 nAChR function. This information will help to understand how these cholinergic receptor systems might be regulating neuronal excitability in the hippocampus in a manner that has relevance for synaptic plasticity and cognition. PMID:19124535

Shen, Jian-xin; Tu, Bin; Yakel, Jerrel L

2009-03-01

63

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.

64

Gypsogenin derivatives: an unexpected class of inhibitors of cholinesterases.  

PubMed

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

2014-10-01

65

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

PubMed

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

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

2013-01-01

66

Development of a dynamic model for real-time determination of membrane-bound acetylcholinesterase activity upon perfusion with inhibitors and reactivators  

Microsoft Academic Search

Quantitative predictions of the course of acetylcholinesterase (AChE) activity, following interference of inhibitors and reactivators, are usually obscured by the time-dependent changes of all reaction partners. To mimic these dynamics we developed an in vitro model. Immobilized human erythrocyte ghosts in a bioreactor were continuously perfused while AChE activity was monitored by a modified Ellman method. The perfusion system consisted

Saskia Eckert; Peter Eyer; Harald Mückter; Franz Worek

2006-01-01

67

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.

2013-01-01

68

Endogenous ACh enhances striatal NMDA-responses via M1-like muscarinic receptors and PKC activation.  

PubMed

Cortical glutamatergic fibres and cholinergic inputs arising from large aspiny interneurons converge on striatal spiny neurons and play a major role in the control of motor activity. We have investigated the interaction between excitatory amino acids and acetylcholine (ACh) on striatal spiny neurons by utilizing intracellular recordings, both in current- and in voltage-clamp mode in rat brain slices. Muscarine (0.3-10 microM) produced a reversible and dose-dependent increase in the membrane depolarizations/inward currents induced by brief applications of N-methyl-D-aspartate (NMDA), while it did not affect the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-induced responses. These concentrations of muscarine did not alter the membrane potential and the current-voltage relationship of the recorded cells. Neostigmine (0.3-10 microM), an ACh-esterase inhibitor, mimicked this facilitatory effect. The facilitatory effects of muscarine and neostigmine were antagonized either by scopolamine (3 microM) or by pirenzepine (10-100 nM), an antagonist of M1-like muscarinic receptors, but not by methoctramine (300 nM), an antagonist of M2-like muscarinic receptor. Accordingly, these facilitatory effects were mimicked by McN-A-343 (1-10 microM), an agonist of M1-like muscarinic receptors, but not by oxotremorine (300 nM), an agonist of M2-like receptors. Tetrodotoxin (TTX) did not block the facilitatory effect produced by the activation of muscarinic receptors suggesting that this effect is postsynaptically mediated. The action of neostigmine was prevented either by the intracellular calcium (Ca2+) chelator BAPTA (200 mM) or by preincubating the slices with inhibitors of protein kinase C (PKC) (staurosporine 100 nM or calphostin C 1 microM). McN-A-343 did not alter the excitatory post synaptic potentials (EPSPs) evoked by corticostriatal stimulation in the presence of physiological concentration of magnesium (Mg2+ 1.2 mM), while it enhanced the duration of these EPSPs recorded in the absence of external magnesium. Our data show that endogenous striatal ACh exerts a positive modulatory action on NMDA responses via M1-like muscarinic receptors and PKC activation. PMID:9758158

Calabresi, P; Centonze, D; Gubellini, P; Pisani, A; Bernardi, G

1998-09-01

69

Monitoring enzyme reaction and screening of inhibitors of acetylcholinesterase by quantitative matrix-assisted laser desorption/ionization Fourier transform mass spectrometry.  

PubMed

A matrix-assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS)-based assay was developed for kinetic measurements and inhibitor screening of acetylcholinesterase. Here, FTMS coupled to MALDI was applied to quantitative analysis of choline using the ratio of choline/acetylcholine without the use of additional internal standard, which simplified the experiment. The Michaelis constant (K(m)) of acetylcholinesterase (AChE) was determined to be 73.9 micromol L(-1) by this approach. For Huperzine A, the linear mixed inhibition of AChE reflected the presence of competitive and noncompetitive components. The half maximal inhibitory concentration (IC(50)) value of galantamine obtained for AChE was 2.39 micromol L(-1). Inhibitory potentials of Rhizoma Coptidis extracts were identified with the present method. In light of the results the referred extracts as a whole showed inhibitory action against AChE. The use of high-resolution FTMS largely eliminated the interference with the determination of ACh and Ch, produced by the low-mass compounds of chemical libraries for inhibitor screening. The excellent correlation with the reported kinetic parameters confirms that the MS-based assay is both accurate and precise for determining kinetic constants and for identifying enzyme inhibitors. The obvious advantages were demonstrated for quantitative analysis and also high-throughput characterization. This study offers a perspective into the utility of MALDI-FTMS as an alternate quantitative tool for inhibitor screening of AChE. PMID:18789720

Xu, Zhe; Yao, Shengjun; Wei, Yuanlong; Zhou, Jing; Zhang, Li; Wang, Cuihong; Guo, Yinlong

2008-12-01

70

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.

2007-02-27

71

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

PubMed Central

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

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

2014-01-01

72

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

PubMed

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

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

2014-11-15

73

Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide.  

PubMed

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition approximately 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 +/- 0.2 microM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396', P398', and L399'), (ii) ionic interactions for the cationic nitrogen with Glu-466' or -467'. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki' = 11.3-42.8 microM). The quaternized analogues of the 2-chlorophenyl phenyl sulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. brucei rhodesiense STIB900, T. cruzi Tulahuan, and Leishmania donovani HU3. The N-acyl-2-amino-4-chlorophenyl sulfides were active against Plasmodium falciparum. The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design. PMID:16335933

Parveen, Seheli; Khan, Mohammed O F; Austin, Susan E; Croft, Simon L; Yardley, Vanessa; Rock, Peter; Douglas, Kenneth T

2005-12-15

74

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

2014-01-01

75

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

PubMed

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

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

2013-10-22

76

Exploring Different Virtual Screening Strategies for Acetylcholinesterase Inhibitors  

PubMed Central

The virtual screening problems associated with acetylcholinesterase (AChE) inhibitors were explored using multiple shape, and structure-based modeling strategies. The employed strategies include molecular docking, similarity search, and pharmacophore modeling. A subset from directory of useful decoys (DUD) related to AChE inhibitors was considered, which consists of 105 known inhibitors and 3732 decoys. Statistical quality of the models was evaluated by enrichment factor (EF) metrics and receiver operating curve (ROC) analysis. The results revealed that electrostatic similarity search protocol using EON (ET_combo) outperformed all other protocols with outstanding enrichment of >95% in top 1% and 2% of the dataset with an AUC of 0.958. Satisfactory performance was also observed for shape-based similarity search protocol using ROCS and PHASE. In contrast, the molecular docking protocol performed poorly with enrichment factors <30% in all cases. The shape- and electrostatic-based similarity search protocol emerged as a plausible solution for virtual screening of AChE inhibitors. PMID:24294601

Mishra, Nibha; Basu, Arijit

2013-01-01

77

Immediate and delayed effects of lead on AChE, GSH-T and thiols in the substantia nigra, neostriatum and cortex of the rat brain.  

PubMed

We studied the effects, at 10 and 30 min, of a single dose (10 mg kg(-1)) of lead chloride, administered by the intraperitoneal route, on the activities of acetylcholinesterase (AChE) and glutathione transferase (GSH-T) and on the concentrations of total and non-protein thiols in substantia nigra compacta (SNCO) and substantia nigra reticulata (SNRE), caudate putamen (CAU) and cerebral cortex (CC) from adult male rats in comparison with the effects of this metal at 24 and 72 h. The main immediate effects of lead consisted of decreased GSH-T activity and total and non-protein thiol concentrations in CAU and CC 10 min after administration. These effects were reversed after 30 min but with increased GSH-T activity in SNCO and AChE activity in SNRE along with diminished concentration of homogenate proteins in SNRE, CAU and CC. The GSH-T activity again was increased in SNCO but the AChE activity was decreased in CC 24 h after Pb administration; total and non-protein thiol concentrations were diminished but homogenate protein concentration was augmented in all areas. Finally, 72 h after Pb administration, AChE and GSH-T activities were decreased in CAU and CC, accompanied by an increased concentration of precipitate and supernatant proteins; supernatant protein concentration also was augmented in SNCO and SNRE; here, again, the concentrations of total and non-protein thiols were diminished and the homogenate protein concentration was augmented in all areas. PMID:11746181

Hernández Gallegos, M E; Ibarra Zannatha, M M; García Osornio, E; Sierra Sánchez, A; Posadas del Rio, F A

2001-01-01

78

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.

2010-01-01

79

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

PubMed

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

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

2014-02-12

80

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

PubMed

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

2014-03-01

81

The Quaternary History of Scandinavia  

NASA Astrophysics Data System (ADS)

During the Quaternary Period, Scandinavia's mountains were the source for repeated glaciation that covered much of eastern, central and western Europe. With a particular emphasis on Denmark, Norway, Sweden and Finland, this text describes how these glaciations, and their intervening warmer stages, affected Scandinavia and the surrounding areas. In particular, this account focuses on the last cold stage, the Weichselian, with its extensive Late Weichselian glaciation and the subsequent deglaciation, and on the last 10,000 years, the Holocene, with its well documented environmental changes. The Quaternary History of Scandinavia provides a cross-frontier synthesis of how the glaciation affected this vast region.

Donner, Joakim

2005-08-01

82

MusÃÂée AchÃÂémÃÂénide  

NSDL National Science Digital Library

Drawing on the expertise of a number of well-regarded institutions, the online MusÃÂée AchÃÂémÃÂénide 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.

83

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

PubMed Central

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

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

2007-01-01

84

Quaternary alkaloids of Argemone mexicana.  

PubMed

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

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

2010-02-01

85

Quaternary uplift of southern Italy  

Microsoft Academic Search

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

Rob Westaway

1993-01-01

86

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

PubMed

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

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

2012-07-01

87

Mysterious ?6-containing nAChRs: function, pharmacology, and pathophysiology  

PubMed Central

Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (?2-?10) and three beta (?2, ?3, and ?4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although ?4?2- and ?7-nAChRs are the two major functional nAChR types in the CNS, ?6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of ?6*-nAChRs have been assessed with the use of ?6 subunit blockers such as ?-conotoxin MII and PIA, and also by using ?6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), ?6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, ?6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson's disease (PD). Thus, ?6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of ?6*-nAChR function, pharmacology and pathophysiology. PMID:19498417

Yang, Ke-chun; Jin, Guo-zhang; Wu, Jie

2009-01-01

88

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

PubMed

Milk is one of the most beneficial aliments and is highly recommended in normal conditions; however, in certain disorders, like irritable bowel syndrome, cow milk and dairy products worsen the gastric symptoms and their use is not recommended. Among the most recognized milk-induced gatrointestinal symptoms are abdominal pain, nausea and vomiting, which are processes controlled by cholinergic and serotonergic transmission. Whether the presence of bioavailable ACh and 5-HT in milk may contribute to normal peristalsis, or to the developing of these symptoms, is not known. In this work we attempt to determine whether the content of free ACh and 5-HT is of physiological significance in milk from four different species: cow (bovine), goat, camel and human. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to identify and quantify free ACh and 5-HT in milk, and activation of the serotonergic and cholinergic ionotropic receptors was investigated using electrophysiological experiments. Our principal hypothesis was that milk from these four species had sufficient free ACh and 5-HT to activate their correspondent receptors expressed in a heterologous system. Our results showed a more complex picture, in which free ACh and 5-HT and their ability to activate cholinergic and serotonergic receptors are not correlated. This work is a first step to elucidate whether 5-HT and ACh, at the concentrations present in the milk, can be associated to a direct function in the GI. PMID:24820623

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

2014-07-25

89

Sperm Epidermal Growth Factor Receptor (EGFR) Mediates ?7 Acetylcholine Receptor (AChR) Activation to Promote Fertilization  

PubMed Central

To attain fertilization the spermatozoon binds to the egg zona pellucida (ZP) via sperm receptor(s) and undergoes an acrosome reaction (AR). Several sperm receptors have been described in the literature; however, the identity of this receptor is not yet certain. In this study, we suggest that the ?7 nicotinic acetylcholine receptor (?7nAChR) might be a sperm receptor activated by ZP to induce epidermal growth factor receptor (EGFR)-mediated AR. We found that isolated ZP or ?7 agonists induced the AR in sperm from WT but not ?7-null spermatozoa, and the induced AR was inhibited by ?7 or EGFR antagonists. Moreover, ?7-null sperm showed very little binding to the egg, and microfluidic affinity in vitro assay clearly showed that ?7nAChR, as well as EGFR, interacted with ZP3. Induction of EGFR activation and the AR by an ?7 agonist was inhibited by a Src family kinase (SFK) inhibitor. In conclusion we suggest that activation of ?7 by ZP leads to SFK-dependent EGFR activation, Ca2+ influx, and the acrosome reaction. PMID:22577141

Jaldety, Yael; Glick, Yair; Orr-Urtreger, Avi; Ickowicz, Debby; Gerber, Doron; Breitbart, Haim

2012-01-01

90

An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3-CA1 synapses in the hippocampus of adult rats.  

PubMed

Studies in humans and rodents support a role for muscarinic ACh receptor (mAChR) and nicotinic AChR in learning and memory, and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms. Acetylcholinesterase (AChE) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer's disease in hopes of rescuing cognitive function, caused, in part, by degeneration of cholinergic innervation to the hippocampus and cortex. Unfortunately, therapeutic efficacy is moderate and inconsistent, perhaps due to unanticipated mechanisms. M1 mAChRs bidirectionally control synaptic strength at CA3-CA1 synapses; weak pharmacological activation using carbachol (CCh) facilitates potentiation, whereas strong agonism induces muscarinic long-term depression (mLTD) via an ERK-dependent mechanism. Here, we tested the prediction that accumulation of extracellular ACh via inhibition of AChE is sufficient to induce LTD at CA3-CA1 synapses in hippocampal slices from adult rats. Although AChE inhibition with eserine induces LTD, it unexpectedly does not share properties with mLTD induced by CCh, as reported previously. Eserine-LTD was prevented by the M3 mAChR-preferring antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), and pharmacological inhibition of MEK was completely ineffective. Additionally, pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD. Finally, long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability, likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh. Thus these findings extend current literature by showing that pharmacological AChE inhibition causes a prolonged decrease in presynaptic glutamate release at CA3-CA1 synapses, in addition to inducing a likely postsynaptic form of LTD. PMID:25143547

Mans, Robert Alan; Warmus, Brian A; Smith, Caroline C; McMahon, Lori L

2014-11-15

91

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.

92

A Speculative Model of AChR Gating at the Frog Neuromuscular Junction  

NSDL National Science Digital Library

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

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

2003-09-02

93

Andrei Sher and Quaternary science  

NASA Astrophysics Data System (ADS)

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

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

2011-08-01

94

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

PubMed Central

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

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

2013-01-01

95

Quaternary ecology: A paleoecological perspective  

SciTech Connect

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

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

1991-01-01

96

Quaternary glaciation of Mount Everest  

Microsoft Academic Search

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

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

2009-01-01

97

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

PubMed

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

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

2004-02-01

98

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

E-print Network

3-Fluoro-2,4-dioxa-3-phosphadecalins as Inhibitors of Acetylcholinesterase. A Reappraisal of acetylcholinesterase revealed hitherto overlooked properties as far as the kinetic mechanisms of interaction to be suitable for the investigation of molecular interactions with acetylcholinesterase (ACh

Rüedi, Peter

99

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

2009-01-01

100

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

PubMed Central

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

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

2012-01-01

101

Determinants of quaternary association in legume lectins  

PubMed Central

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. The class of proteins called legume lectins is an interesting model system to investigate this problem, because they have very high sequence and tertiary structure homology, with diverse forms of quaternary association. Hence, we have used legume lectins as a probe in this paper to (1) gain novel insights about the relationship between sequence and quaternary structure; (2) identify the sequence motifs that are characteristic of a given type of quaternary association; and (3) predict the quaternary association from the sequence motif. PMID:15215518

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

2004-01-01

102

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

PubMed

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

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

2014-02-15

103

The effect of pesticides and metals on acetylcholinesterase (AChE) in various tissues of blue mussel (Mytilus trossulus L.) in short-term in vivo exposures at different temperatures.  

PubMed

The purpose of the study was to assess the impact of short-term exposure to selected toxicants as well as metal accumulation upon acetylcholinesterase (AChE) in the blue mussel, Mytilus trossulus L., in laboratory in vivo experiments. Mussels were exposed for up to 48 hours to a mixture of copper (Cu(2+), 400 microg L(-1)) and cadmium (Cd(2+), 200 microg L(-1)), to dichlorvos (DDVP, 100 microg L(-1)), and to carbaryl (100 microg L(-1)) at two temperatures: 5 degrees C and 20 degrees C. Samples were collected after 0, 6, 12, 24, and 48 hours of exposure, and AChE activity and metal concentration (where applicable) were analysed in gills, digestive gland, mantle+muscles, and the whole soft tissue. Very strong AChE inhibition was observed in response to the dichlorvos treatment, mainly in gills. Carbaryl and the metals caused a short-term inhibition effect. Considerable differences in AChE activity between the two temperatures were noticed. In particular, the metals were accumulated much faster at 20 degrees C than at 5 degrees C, especially in gills. No correlation between AChE activity and metal concentration was found. Gills turned out to be the optimal tissue for AChE activity analysis in short-term studies. PMID:20401786

Kopecka-Pilarczyk, Justyna

2010-05-01

104

Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons  

Microsoft Academic Search

S 24795 evoked methyllycaconitine-sensitive inward currents in voltage-clamped hippocampal interneurons with maximum amplitude about 14% that of ACh-evoked responses. Experiments with rat ?7 receptors expressed in Xenopus oocytes confirmed that S 24795 is a partial agonist of ?7 nAChR with an EC50 of 34±11?M and Imax of approximately 10% relative to ACh. When 60?M ACh was co-applied to ?7-expressing oocytes

Gretchen Lopez-Hernandez; Andon N. Placzek; Jeffrey S. Thinschmidt; Pierre Lestage; Caryn Trocme-Thibierge; Philippe Morain; Roger L. Papke

2007-01-01

105

The human adult subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ overloading.  

PubMed

Slow-channel congenital myasthenic syndrome, caused by mutations in subunits of the endplate ACh receptor (AChR), results in prolonged synaptic currents and excitotoxic injury of the postsynaptic region by Ca2+ overloading. The Ca2+ overloading could be due entirely to the prolonged openings of the AChR channel or could be abetted by enhanced Ca2+ permeability of the mutant channels. We therefore measured the fractional Ca2+ current, defined as the percentage of the total ACh-evoked current carried by Ca2+ ions (Pf), for AChRs harbouring the alphaG153S or the alphaV249F slow-channel mutation, and for wild-type human AChRs in which Pf has not yet been determined. Experiments were performed in transiently transfected GH4C1 cells and human myotubes with simultaneous recording of ACh-evoked whole-cell currents and fura-2 fluorescence signals. We found that the Pf of the wild-type human endplate AChR was unexpectedly high (Pf approximately 7%), but neither the alphaV249F nor the alphaG153S mutation altered Pf. Fetal human AChRs containing either the wild-type or the mutated alpha subunit had a much lower Pf (2-3%). We conclude that the Ca2+ permeability of human endplate AChRs is higher than that reported for any other human nicotinic AChR, with the exception of alpha7-containing AChRs (Pf > 10%); and that neither the alphaG153S nor the alphaV249F mutations affect the Pf of fetal or adult endplate AChRs. However, the intrinsically high Ca2+ permeability of human AChRs probably predisposes to development of the endplate myopathy when opening events of the AChR channel are prolonged by altered AChR-channel kinetics. PMID:16527851

Fucile, Sergio; Sucapane, Antonietta; Grassi, Francesca; Eusebi, Fabrizio; Engel, Andrew G

2006-05-15

106

Ancient biomolecules in Quaternary palaeoecology  

NASA Astrophysics Data System (ADS)

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

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

2012-02-01

107

4 Hz EMF treated physiological solution depresses Ach-induced neuromembrane current.  

PubMed

The effect of 4 Hz EMF treated physiological solution (PS) on acetylcholine (Ach) sensitivity of the snail neuron was studied. The 4 Hz EMF treated normal PS at room temperature (23 degrees C) has a depressing effect on Ach induced current, while in cold medium (12 degrees C) this effect disappeared. EMF treated, ouabain containing, K-free PS elevates the Ach-induced current at room temperature. It is suggested that the metabotropic effect of EMF treated PS is due to the activation of cGMP-dependent Na:Ca exchange, leading to the decrease of the number of functional active receptors in the membrane, through Na-K pump-induced cell shrinkage, and to increase the receptors affinity to Ach, as the result of decrease of intracellular Ca concentration. PMID:15197765

Ayrapetyan, S N; Hunanyan, A Sh; Hakobyan, S N

2004-07-01

108

JournalofPhysiologyPhysiologyinPress Acetylcholine (ACh) is the major endogenous ligand for  

E-print Network

desensitization of rat a4b2 neuronal nicotinic receptors K. G. Paradiso and Joe Henry Steinbach Department of Anesthesiology, Washington University, St Louis, MO 63110, USA We examined desensitization by acetylcholine (ACh

Steinbach, Joe Henry

109

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

2009-01-01

110

Quaternary glaciation of the Himalayan-Tibetan  

Microsoft Academic Search

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

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

111

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

PubMed

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

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

2013-04-15

112

Synthesis, cytotoxicity and molecular modelling studies of new phenylcinnamide derivatives as potent inhibitors of cholinesterases.  

PubMed

The present study reports the synthesis of cinnamide derivatives and their biological activity as inhibitors of both cholinesterases and anticancer agents. Controlled inhibition of brain acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may slow neurodegeneration in Alzheimer's diseases (AD). The anticholinesterase activity of phenylcinnamide derivatives was determined against Electric Eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) and some of the compounds appeared as moderately potent inhibitors of EeAChE and hBChE. The compound 3-(2-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3i) showed maximum activity against EeAChE with an IC50 0.29 ± 0.21 ?M whereas 3-(2-chloro-6-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3k) was proved to be the most potent inhibitor of hBChE having IC50 1.18 ± 1.31 ?M. To better understand the enzyme-inhibitor interaction of the most active compounds toward cholinesterases, molecular modelling studies were carried out on high-resolution crystallographic structures. The anticancer effects of synthesized compounds were also evaluated against cancer cell line (lung carcinoma). The compounds may be useful leads for the design of a new class of anticancer drugs for the treatment of cancer and cholinesterase inhibitors for Alzheimer's disease (AD). PMID:24675179

Saeed, Aamer; Mahesar, Parvez Ali; Zaib, Sumera; Khan, Muhammad Siraj; Matin, Abdul; Shahid, Mohammad; Iqbal, Jamshed

2014-05-01

113

Activity of nAChRs Containing ?9 Subunits Modulates Synapse Stabilization via Bidirectional Signaling Programs  

PubMed Central

Although the synaptogenic program for cholinergic synapses of the neuromuscular junction is well known, little is known of the identity or dynamic expression patterns of proteins involved in non-neuromuscular nicotinic synapse development. We have previously demonstrated abnormal presynaptic terminal morphology following loss of nicotinic acetylcholine receptor (nAChR) ?9 subunit expression in adult cochleae. However, the molecular mechanisms underlying these changes have remained obscure. To better understand synapse formation and the role of cholinergic activity in the synaptogenesis of the inner ear, we exploit the nAChR ?9 subunit null mouse. In this mouse, functional acetylcholine (ACh) neurotransmission to the hair cells is completely silenced. Results demonstrate a premature, effusive innervation to the synaptic pole of the outer hair cells in ?9 null mice coinciding with delayed expression of cell adhesion proteins during the period of effusive contact. Collapse of the ectopic innervation coincides with an age-related hyperexpression pattern in the null mice. In addition, we document changes in expression of presynaptic vesicle recycling/trafficking machinery in the ?9 null mice that suggests a bidirectional information flow between the target of the neural innervation (the hair cells) and the presynaptic terminal that is modified by hair cell nAChR activity. Loss of nAChR activity may alter transcriptional activity, as CREB binding protein expression is decreased coincident with the increased expression of N-Cadherin in the adult ?9 null mice. Finally, by using mice expressing the nondesensitizing ?9 L9?T point mutant nAChR subunit, we show that increased nAChR activity drives synaptic hyperinnervation. PMID:19790106

Murthy, Vidya; Taranda, Julian; Elgoyhen, A. Belen; Vetter, Douglas E.

2010-01-01

114

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

PubMed

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

2014-01-01

115

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

2014-01-01

116

NMR Structures of the Transmembrane Domains of the ?4?2 nAChR  

PubMed Central

The ?4?2 nicotinic acetylcholine receptor (nAChR) is the predominant heteromeric subtype of nAChRs in the brain, which has been implicated in numerous neurological conditions. The structural information specifically for the ?4?2 and other neuronal nAChRs is presently limited. In this study, we determined structures of the transmembrane (TM) domains of the ?4 and ?2 subunits in lauryldimethylamine-oxide (LDAO) micelles using solution NMR spectroscopy. NMR experiments and size exclusion chromatography–multi-angle light scattering (SEC-MALS) analysis demonstrated that the TM domains of ?4 and ?2 interacted with each other and spontaneously formed pentameric assemblies in the LDAO micelles. The Na+ flux assay revealed that ?4?2 formed Na+ permeable channels in lipid vesicles. Efflux of Na+ through the ?4?2 channels reduced intra-vesicle Sodium Green™ fluorescence in a time-dependent manner that was not observed in vesicles without incorporating ?4?2. The study provides the structural insight into the TM domains of the ?4?2 nAChR. It offers a valuable structural framework for rationalizing extensive biochemical data collected previously on the ?4?2 nAChR and for designing new therapeutic modulators. PMID:22361591

Bondarenko, Vasyl; Mowrey, David; Tillman, Tommy; Cui, Tanxing; Liu, Lu Tian; Xu, Yan; Tang, Pei

2012-01-01

117

Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.  

PubMed

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

2014-07-01

118

Enantioselective Construction of Remote Quaternary Stereocenters  

PubMed Central

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

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

2014-01-01

119

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

PubMed

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

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

2014-01-01

120

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

PubMed Central

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

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

1989-01-01

121

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

2014-01-01

122

Quaternary geologic map of Minnesota  

NASA Technical Reports Server (NTRS)

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

Goebel, J. E.

1977-01-01

123

Quaternary glaciation of Mount Everest  

NASA Astrophysics Data System (ADS)

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

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

2009-07-01

124

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

NASA Astrophysics Data System (ADS)

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

Stewart, John R.; Cooper, Alan

2008-12-01

125

Xanthenedione derivatives, new promising antioxidant and acetylcholinesterase inhibitor agents.  

PubMed

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

2014-01-01

126

ACH year, approximately 200 of 1 million individuals experience TBI. The population with TBI consists of  

E-print Network

ACH year, approximately 200 of 1 million individuals experience TBI. The population with TBI consists of approximately 25% female patients.25 The effect of sex on TBI outcome is controversial that peak protein degradation and neurodegeneration occurred within 3 days after TBI in male mice, whereas

Schallert, Tim

127

Acrodermatitis continua of Hallopeau (ACH): two cases successfully treated with adalimumab.  

PubMed

Acrodermatitis continua of Hallopeau (ACH), also known as dermatitis repens or acrodermatitis perstans, is a rare acropustular eruption, characterized by sterile pustules, paronychia and atrophic skin changes, onychodystrophy and osteolysis of the distal phalanges of the fingers and toes. While some consider ACH a distinct entity, many believe it to be a variant of pustular psoriasis, especially as cases of ACH progressing to generalized pustular psoriasis. The treatment options used are various; however, its typical cyclic recurrences, which induce important physical and psychological morbidity, may render this pathology difficult to treat. Hence, it was considered important to review the evolution of?treatment?options available thus far including use of biologics. Hereby, we report two patients with ACH who were successfully treated with adalimumab. By analogy to the efficacy of TNF-? antagonists in the?treatment?of generalized pustular psoriasis, the two patients we report illustrate the long-term efficacy and safety of adalimumab in the?treatment?of? Hallopeau's acrodermatitis refractory to therapies. PMID:24215490

Di Costanzo, Luisa; Napolitano, Maddalena; Patruno, Cataldo; Cantelli, Mariateresa; Balato, Nicola

2014-12-01

128

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

PubMed

The Amaryllidaceae family is well known for its pharmacologically active alkaloids. An important approach to treat Alzheimer’s disease involves the inhibition of the enzyme acetylcholinesterase (AChE). Galanthamine, an Amaryllidaceae alkaloid, is an effective, selective, reversible, and competitive AchE inhibitor. This work was aimed at studying the alkaloid composition of four wild Argentinian Amarillydaceae species for the first time, as well as analyzing their inhibitory activity on acetylcholinesterase. Alkaloid content was characterized by means of GC-MS analysis. Chloroform basic extracts from Habranthus jamesonii, Phycella herbertiana, Rhodophiala mendocina and Zephyranthes filifolia collected in the Argentinian Andean region all contained galanthamine, and showed a strong AChE inhibitory activity (IC50 between 1.2 and 2 µg/mL). To our knowledge, no previous reports on alkaloid profiles and AChEIs activity of wild Argentinian Amarillydaceae species have been publisihed. The demand for renewable sources of industrial products like galanthamine and the need to protect plant biodiversity creates an opportunity for Argentinian farmers to produce such crops. PMID:23149565

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

2012-01-01

129

The effect of pesticides and metals on acetylcholinesterase (AChE) in various tissues of blue mussel (Mytilus trossulus L.) in short-term in vivo exposures at different temperatures  

Microsoft Academic Search

The purpose of the study was to assess the impact of short-term exposure to selected toxicants as well as metal accumulation upon acetylcholinesterase (AChE) in the blue mussel, Mytilus trossulus L., in laboratory in vivo experiments. Mussels were exposed for up to 48 hours to a mixture of copper (Cu, 400 ? g L) and cadmium (Cd, 200 ? g

Justyna Kopecka-Pilarczyk

2010-01-01

130

Long-term depression in rat CA1-subicular synapses depends on the G-protein coupled mACh receptors.  

PubMed

The subiculum, which is the primary target of CA1 pyramidal neurons and sending efferent fibres to many brain regions, serves as a hippocampal interface in the neural information processes between hippocampal formation and neocortex. Long-term depression (LTD) is extensively studied in the hippocampus, but not at the CA1-subicular synaptic transmission. Using whole-cell EPSC recordings in the brain slices of young rats, we demonstrated that the pairing protocols of low frequency stimulation (LFS) at 3 Hz and postsynaptic depolarization of -50 mV elicited a reliable LTD in the subiculum. The LTD did not cause the changes of the paired-pulse ratio of EPSC. Furthermore, it did not depend on either NMDA receptors or voltage-gated calcium channels (VGCCs). Bath application of the G-protein coupled muscarinic acetylcholine receptors (mAChRs) antagonists, atropine or scopolamine, blocked the LTD, suggesting that mAChRs are involved in the LTD. It was also completely blocked by either the Ca2+ chelator BAPTA or the G-protein inhibitor GDP-beta-S in the intracellular solution. This type of LTD in the subiculum may play a particular role in the neural information processing between the hippocampus and neocortex. PMID:15893398

Li, Hongbin; Zhang, Jichuan; Xiong, Wenyong; Xu, Tianle; Cao, Jun; Xu, Lin

2005-07-01

131

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

2014-01-01

132

Late Quaternary history of Washington Land, North Greenland OLE BENNIKE  

E-print Network

Late Quaternary history of Washington Land, North Greenland OLE BENNIKE Bennike, O. 2002 (September): Late Quaternary history of Washington Land, North Greenland. Boreas, Vol. 31, 260­272. Oslo. ISSN 0300 Quaternary history of the region. The lack of data re ects the inaccessibility of this remote region

Ingólfsson, �lafur

133

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

PubMed Central

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

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

2014-01-01

134

Muscle aches  

MedlinePLUS

Muscle pain is most frequently related to tension, overuse, or muscle injury from exercise or physically-demanding work. In these situations, the pain tends to involve specific muscles and starts during or just after the activity. It is usually ...

135

Enantioselective construction of remote quaternary stereocentres  

NASA Astrophysics Data System (ADS)

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

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

2014-04-01

136

Quaternary deformation mapping with ground penetrating radar  

Microsoft Academic Search

Ground penetrating radar (GPR) was used in a programme of geological and hydrogeological investigations into the Quaternary of west Cumbria, UK. The investigations were part of an extensive programme to determine the suitability of the area for a deep radioactive waste repository. The hydrogeological characteristics of the drift deposits are important since they affect both recharge and discharge. The glacially

J. P Busby; J. W Merritt

1999-01-01

137

Quaternary International 138139 (2005) 14 In Memorium  

E-print Network

awards include being named a fellow of the Geological Society of America in 2004. Geoff's major galvanizing efforts to apply surface exposure dating methods to date moraines in Peru and Bolivia. Results, Geology, Quaternary Research, and GSA Bulletin. Geoff was blessed with a combination of keen intellectual

Howat, Ian M.

138

Late Quaternary fire regimes of Australasia  

Microsoft Academic Search

We have compiled 223 sedimentary charcoal records from Australasia in order to examine the temporal and spatial variability of fire regimes during the Late Quaternary. While some of these records cover more than a full glacial cycle, here we focus on the last 70,000 years when the number of individual records in the compilation allows more robust conclusions. On orbital

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

2011-01-01

139

Structural and mechanical properties of aC:H thin films grown by RF-PECVD  

Microsoft Academic Search

a-C:H thin films have been deposited by plasma enhanced chemical vapor deposition at 13.56 MHz in a large bias voltage range (200–600 V). Their mechanical properties have been studied through different techniques such as nanoindentation, profilometry and finally X-ray reflectometry in order to determine their hardness, elastic modulus, stress level, interfacial fracture energy and density. We show that the hardness,

E Tomasella; L Thomas; M Dubois; C Meunier

2004-01-01

140

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

PubMed Central

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

Graupner, Michael; Gutkin, Boris

2009-01-01

141

Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor  

PubMed Central

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

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

2013-01-01

142

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

Microsoft Academic Search

The aim of this study is to determine the possibility of using Rinodina sophodes (Ach.) Massal., a crustose lichen as polycyclic aromatic hydrocarbons (PAHs) bioaccumulator for evaluation of atmospheric\\u000a pollution in tropical areas of India, where few species of lichens are able to grow. PAHs were identified, quantified and\\u000a compared to evaluate the potential utility of R. sophodes. The limit

Satya; Dalip K. Upreti; D. K. Patel

143

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

NASA Astrophysics Data System (ADS)

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

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

2009-10-01

144

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

PubMed

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

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

2014-05-01

145

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

PubMed Central

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

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

1996-01-01

146

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

PubMed

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

2014-07-21

147

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

PubMed Central

ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of ?1 ?g/ml, comparable to that of the fluoroquinolone moxifloxacin for quinolone-susceptible isolates but superior to that for quinolone-resistant isolates. Biochemical assays involving M. tuberculosis gyrase enzymes indicated that ACH-702 had significantly improved inhibitory activity compared with fluoroquinolones. PMID:20516287

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

2010-01-01

148

Chemical analysis of neurotransmitter candidates in clonal cell lines from Drosophila central nervous system. I. ACh and L-dopa.  

PubMed

To characterize neuronal phenotypes, aminergic neurotransmitters, i.e. acetylcholine (ACh), catecholamine (CA)s and other biogenic amines (serotonin, octopamine), were surveyed in 10 colonial clones from one cell line of Drosophila larval CNS using HPLC-ECD system. ACh, which is a neurotransmitter in Drosophila, was found in 7 out of 10 clones. CAs, their metabolites, and other amines were not detected in any clones. However, all the 10 clones expressed L-dopa, a precursor of CAs. Consequently, seven clones expressed ACh and L-dopa. L-dopa as a novel neurotransmitter candidate was discussed. PMID:7970162

Ui-Tei, K; Nishihara, S; Sakuma, M; Matsuda, K; Miyake, T; Miyata, Y

1994-06-01

149

Immune responses to HTLV-I(ACH) during acute infection of pig-tailed macaques.  

PubMed

Human T cell lymphotropic virus type 1 (HTLV-I) is causally linked to adult T cell leukemia/lymphoma (ATL) and a chronic progressive neurological disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A nonhuman primate model that reproduces disease symptoms seen in HTLV-I-infected humans might facilitate identification of initial immune responses to the virus and an understanding of pathogenic mechanisms in HTLV-I-related disease. Previously, we showed that infection of pig-tailed macaques with HTLV-I(ACH) is associated with multiple signs of disease characteristic of both HAM/TSP and ATL. We report here that within the first few weeks after HTLV-I(ACH) infection of pig-tailed macaques, serum concentrations of interferon (IFN)-alpha increased and interleukin-12 decreased transiently, levels of nitric oxide were elevated, and activation of CD4(+) and CD8(+) lymphocytes and CD16(+) natural killer cells in peripheral blood were observed. HTLV-I(ACH) infection elicited virus-specific antibodies in all four animals within 4 to 6 weeks; however, Tax-specific lymphoproliferative responses were not detected until 25-29 weeks after infection in all four macaques. IFN-gamma production by peripheral blood cells stimulated with a Tax or Gag peptide was detected to varying degrees in all four animals by ELISPOT assay. Peripheral blood lymphocytes from one animal that developed only a marginal antigen-specific cellular response were unresponsive to mitogen stimulation during the last few weeks preceding its death from a rapidly progressive disease syndrome associated with HTLV-I(ACH) infection of pig-tailed macaques. The results show that during the first few months after HTLV-I(ACH) infection, activation of both innate and adaptive immunity, limited virus-specific cellular responses, sustained immune system activation, and, in some cases, immunodeficiency were evident. Thus, this animal model might be valuable for understanding early stages of infection and causes of immune system dysregulation in HTLV-I-infected humans. PMID:15157363

McGinn, Therese M; Wei, Qing; Stallworth, Jackie; Fultz, Patricia N

2004-04-01

150

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

PubMed

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

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

2011-11-01

151

In vitro screening assays to identify natural or synthetic acetylcholinesterase inhibitors: thin layer chromatography versus microplate methods.  

PubMed

Acetylcholinesterase inhibitors (AChEI) are currently still the best available pharmacotherapy for Alzheimer patients. Successful screening for new AChEI relies on effective and fast assays. Two colorimetric screening assays frequently used to search for new AChEI, namely a thin layer chromatography (TLC) assay with Fast Blue B salt as reagent and a 96-well plate assay based on Ellman's method, were compared. For the majority (83%) of the 138 test compounds of natural and synthetic origin, the results obtained with the two assays converged and both screening assays were considered suitable for the generation of new hits. Fifteen percent of investigated compounds were classified as active with the microplate assay but were shown to be inactive by TLC and about 2% were measured active by TLC but showed to be inactive with the microplate assay. These divergences were not due to the main differences between the experimental protocols of the two screening assays, namely the different colorimetric methods and pre-incubation of test compounds with acetylcholinesterase (AChE). They might be explained by the interaction of either AChE or test compounds with the silica of the TLC plates, resulting in an altered affinity of the enzyme for the compounds. PMID:18082383

Di Giovanni, Saviana; Borloz, Aline; Urbain, Aurélie; Marston, Andrew; Hostettmann, Kurt; Carrupt, Pierre-Alain; Reist, Marianne

2008-02-01

152

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

PubMed

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

2014-09-01

153

Nicotinic ACh receptor subtypes on gastrointestinally projecting neurones in the dorsal motor vagal nucleus of the rat.  

PubMed

To determine the predominant nicotinic ACh receptor (nAChR) located on neurones in the dorsal motor nucleus of the vagus (DMV) that project to the gastrointestinal tract, we used the rat brainstem slice preparation and whole-cell recordings of DMV neurones identified by retrograde DiI tracing to pharmacologically characterize nAChRs. Pressure ejection of acetylcholine (ACh, 250 microM for 200 ms) from a patch pipette placed approximately 10-20 microm from the surface of the recorded cell produced an inward current in most DMV neurones sampled. The average currents for neurones projecting to the fundus, antrum and caecum were 149 +/- 38 (n = 25), 115 +/- 18 (n = 29) and 117 +/- 23 pA (n = 6), respectively. Blockade of the alpha7 subtype of nAChR with either alpha-bungarotoxin (alpha-BGT) or methyllycaconitine (MLA) counteracted 60-75 % of the ACh-evoked current in DMV neurones projecting to the fundus, antrum and caecum. In neurones projecting to the fundus and the antrum, currents resistant to alpha-BGT were significantly blocked by dihydro-beta-erythroidine (10-20 nM), an antagonist of the alpha4beta2 subtype of nAChR. In neurones projecting to the caecum, currents resistant to alpha-BGT were significantly depressed by a low concentration of mecamylamine (1 microM). Cytisine (100 microM), an agonist of nAChRs that contain the alpha7 or the beta4 subunit, evoked significant currents in caecum-projecting neurones that were previously exposed to alpha-BGT. In contrast, cytisine had no effect on DMV neurones previously exposed to alpha-BGT that project to the fundus or antrum. Our data indicate that the prevailing nAChR subtype in DMV neurones projecting to the GI tract is the alpha7 subtype. In addition, we obtained evidence for the co-expression of the alpha4beta2 nAChR subtype on DMV neurones projecting to the fundus and antrum, and the alpha3beta4 nAChR subtype on DMV neurones projecting to the caecum. PMID:12482903

Sahibzada, Niaz; Ferreira, Manuel; Williams, Bernice; Wasserman, Adam; Vicini, Stefano; Gillis, Richard A

2002-12-15

154

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

E-print Network

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

Adler, Joan

155

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

PubMed Central

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

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

2014-01-01

156

Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, A? aggregation, and ?-secretase.  

PubMed

Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with K(i) of 6.47nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, A? aggregation, and ?-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD. PMID:23041347

Peng, Da-Yong; Sun, Qi; Zhu, Xiao-Lei; Lin, Hong-Yan; Chen, Qiong; Yu, Ning-Xi; Yang, Wen-Chao; Yang, Guang-Fu

2012-11-15

157

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

2014-01-01

158

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

PubMed

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

2014-02-01

159

Late quaternary sequence stratigraphy, South Florida margin  

SciTech Connect

Late Quaternary sea-level change and the Florida Current have combined to produce a progradational shelf-slope margin along the western portion of the south Florida Platform facing the Straits of Florida. Analysis of high resolution seismic reflection profiles suggest at least eight 5th order late Quaternary sequences downlap onto the Pourtales Terrace at 250 m water depth. Along most of the south Florida margin, this Late Quaternary section is very thin, and only where significant accumulations occur can the stratigraphic patterns produced by sea-level change be clearly observed. Recognition of systems tracts and their boundaries from high-resolution seismic data is important for prediction of sedimentary facies and stratigraphic development of margins. Many south Florida seismic boundaries can be fit to the Exxon sequence stratigraphy model. Others appear to reflect the added effect of bottom-current erosion that complicates the signal produced by sea-level change. Overall, the sea-level signal appears to dominate the stratigraphic record, especially from the 2-dimensional perspective of dip-oriented seismic profiles. However, the 3-dimensional geometry of deposits are strongly influenced by along slope accumulation patterns controlled by the Florida Current. This study provides new insight on the importance of both geostrophic boundary currents and sea-level change in controlling stratigraphic development of a carbonate platform margin. Similar anomalously thick slope deposits in ancient sequences may indicate similar controls on accumulation and could lend to predictions of related paleo-platform configurations.

Locker, S.D.; Hine, A.C. [Univ. of South Florida, St. Petersburg, FL (United States). Dept. of Marine Science

1995-12-01

160

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

PubMed

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

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

2011-06-01

161

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

2011-01-01

162

Neural factors regulate AChR subunit mRNAs at rat neuromuscular synapses  

PubMed Central

To elucidate the nature of signals that control the level and spatial distribution of mRNAs encoding acetylcholine receptor (AChR), alpha-, beta-, gamma-, delta- and epsilon-subunits in muscle fibers chronic paralysis was induced in rat leg muscles either by surgical denervation or by different neurotoxins that cause disuse of the muscle or selectively block neuromuscular transmission pre- or postsynaptically and cause an increase of AChRs in muscle membrane. After paralysis, the levels and the spatial distributions of the different subunit-specific mRNAs change discoordinately and seem to follow one of three different patterns depending on the subunit mRNA examined. The level of epsilon- subunit mRNA and its accumulation at the end-plate are largely independent on the presence of the nerve or electrical muscle activity. In contrast, the gamma-subunit mRNA level is tightly coupled to innervation. It is undetectable or low in innervated normally active muscle and in innervated but disused muscle, whereas it is abundant along the whole fiber length in denervated muscle or in muscle in which the neuromuscular contact is intact but the release of transmitter is blocked. The alpha-, beta-, and delta-subunit mRNA levels show a different pattern. Highest amounts are always found at end-plate nuclei irrespective of whether the muscle is innervated, denervated, active, or inactive, whereas in extrasynaptic regions they are tightly controlled by innervation partially through electrical muscle activity. The changes in the levels and distribution of gamma- and epsilon- subunit-specific mRNAs in toxin-paralyzed muscle correlate well with the spatial appearance of functional fetal and adult AChR channel subtypes along the muscle fiber. The results suggest that the focal accumulation at the synaptic region of mRNAs encoding the alpha-, beta- , delta-, and epsilon-subunits, which constitute the adult type end- plate channel, is largely determined by at least two different neural factors that act on AChR subunit gene expression of subsynaptic nuclei. PMID:1646821

1991-01-01

163

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

PubMed Central

In this work, we describe the activity of ACH-702 against clinical isolates of Mycobacterium tuberculosis and six different nontuberculous mycobacteria. The MIC50 and MIC90 of both susceptible and drug-resistant M. tuberculosis strains tested were 0.0625 and 0.125 ?g/ml, respectively. The MIC50 and MIC90 values for Mycobacterium fortuitum isolates were 0.0625 ?g/ml in both cases; Mycobacterium avium complex isolates showed MIC50 and MIC90 values of 0.25 and 4 ?g/ml, respectively. PMID:20231398

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

2010-01-01

164

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

Microsoft Academic Search

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

ANA A. ?U?ULOVI?

165

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.

2005-01-01

166

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

Code of Federal Regulations, 2012 CFR

... false Quaternary ammonium salt of fluorinated alkylaryl amide...9075 Quaternary ammonium salt of fluorinated alkylaryl amide...generically as quaternary ammonium salt of fluorinated alkylaryl...f). (ii) Release to water. Requirements as...

2012-07-01

167

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

Code of Federal Regulations, 2013 CFR

... false Quaternary ammonium salt of fluorinated alkylaryl amide...9075 Quaternary ammonium salt of fluorinated alkylaryl amide...generically as quaternary ammonium salt of fluorinated alkylaryl...f). (ii) Release to water. Requirements as...

2013-07-01

168

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

PubMed

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

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

2013-01-25

169

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

PubMed

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

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

2014-06-01

170

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

PubMed

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of ?7 and ?2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in ?7?2nAChR(-/-) mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. ?7?2nAChR(-/-) mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in ?7?2nAChR(-/-) mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to ?7nAChR(-/-) mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of ?7?2nAChR(-/-) mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central ?2nAChR deficiency. PMID:24685552

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

2014-05-01

171

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

PubMed Central

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

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

2012-01-01

172

Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia.  

PubMed

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

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

2014-01-01

173

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

PubMed

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

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

2013-12-01

174

Scaffold Ranking and Positional Scanning Utilized in the Discovery of nAChR-Selective Compounds Suitable for Optimization Studies  

PubMed Central

Nicotine binds to nicotinic acetylcholine receptors (nAChR), which can exist as many different subtypes. The ?4?2 nAChR is the most prevalent subtype in the brain and possesses the most evidence linking it to nicotine seeking behavior. Herein we report the use of mixture based combinatorial libraries for the rapid discovery of a series of ?4?2 nAChR selective compounds. Further chemistry optimization provided compound 301, which was characterized as a selective ?4?2 nAChR antagonist. This compound displayed no agonist activity but blocked nicotine-induced depolarization of HEK cells with an IC50 of approximately 430 nM. 301 demonstrated nearly 500-fold selectivity for binding and 40-fold functional selectivity for ?4?2 over ?3?4 nAChR. In total over 5 million compounds were assessed through the use of just 170 samples in order to identify a series of structural analogues suitable for future optimization toward the goal of developing clinically relevant smoking cessation medications. PMID:24274400

Wu, Jinhua; Zhang, Yaohong; Maida, Laura E.; Santos, Radleigh G.; Welmaker, Gregory S.; LaVoi, Travis M.; Nefzi, Adel; Yu, Yongping; Houghten, Richard A.; Toll, Lawrence; Giulianotti, Marc A.

2014-01-01

175

Antibacterial activity of gemini quaternary ammonium salts.  

PubMed

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

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

2014-01-01

176

Activation of volume-regulated Cl? channels by ACh and ATP in Xenopus follicles  

PubMed Central

Osmolarity-dependent ionic currents from follicle-enclosed Xenopus oocytes (follicles) were studied using electrophysiological techniques. Whole follicle currents were monitored using a two-electrode voltage clamp and single-channel activity was measured using the patch-clamp technique.In follicles held at -60 mV two chloride currents were activated in external hyposmotic solutions. One was the habitual volume-regulated current elicited by external hyposmolarity (ICl,swell), and the second was a slow and smooth current (Sin) generated by ACh or ATP application.In follicles, the permeability ratios for different anions with respect to Cl? were similar for both ICl,swell and Sin, with a sequence of: SCN? > I? > Br?? NO3?? Cl? > gluconate ? cyclamate > acetate > SO42?.Extracellular ATP blocked the outward component of Sin. Also, extracellular pH modulated the inactivation kinetics of Sin elicited by ACh; e.g. inactivation at +80 mV was ?100% slower at pH 8.0 compared with that at pH 6.0.Lanthanides inhibited ICl,swell and Sin. La3+ completely inhibited ICl,swell with a half-maximal inhibitory concentration (IC50) of 17 ± 1.9 ?m, while Sin was blocked up to 55% with an apparent IC50 of 36 ± 2.6 ?m.Patch-clamp recordings in follicular cells showed that hyposmotic challenge opened inward single-channel currents. The single channel conductance (4.7 ± 0.4 pS) had a linear current-voltage relationship with a reversal membrane potential close to ?20 mV. This single-channel activity was increased by application of ACh or ATP.The ICl,swell generation was not affected by pirenzepine or metoctramine, and did not affect the purinergic activation of the chloride current named Fin. Thus, ICl,swell was not generated via neurotransmitters released during cellular swelling.All together, equal discrimination for different anions, similar modulatory effects by extracellular pH, the blocking effects by ATP and La3+, and the same single-channel activity, strongly suggest that ICl,swell and Sin currents depend on the opening of the same type or a closely related class of volume-regulated chloride channels. PMID:10856124

Perez-Samartin, Alberto L; Miledi, Ricardo; Arellano, Rogelio O

2000-01-01

177

Quaternary glacial and climate history of Antarctica lafur Inglfsson  

E-print Network

climate changes. A good un- derstanding of the Late Quaternary glacial and climate history of AntarcticaQuaternary glacial and climate history of Antarctica �lafur Ingólfsson University of Iceland, and is important for understanding the relative timing of climate changes between the polar hemispheres (Denton et

Ingólfsson, �lafur

178

Nonlinear drift-diffusion model of gating in K and nACh ion channels  

NASA Astrophysics Data System (ADS)

The configuration of a sensor regulates the transition between the closed and open states of both voltage and ligand gated channels. The closed state dwell-time distribution f(t) derived from a Fokker Planck equation with a nonlinear diffusion coefficient is in good agreement with experimental data and can account for the power law approximation to f(t) for a delayed rectifier K channel and a nicotinic acetylcholine (nACh) ion channel. The solution of a master equation which approximates the Fokker Planck equation provides a better description of the small time behaviour of the dwell-time distribution and can account for the empirical rate-amplitude correlation for these ion channels.

Vaccaro, S. R.

2007-09-01

179

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

PubMed

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

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

2014-05-01

180

Survival of Listeria monocytogenes on sliced cooked sausage after treatment with pediocin AcH.  

PubMed

A preparation with pediocin AcH bound to its heat-killed producer cells Lactobacillus plantarum WHE 92 (starter culture ALC01, Wisby, Denmark) by adjusting the pH of the preparation to 6.0 was studied for its effects against Listeria monocytogenes ATCC 7644 and (spoilage) lactic acid bacteria on sliced cooked sausage. The pediocin AcH preparation or 0.9% (w/w) NaCl dilution (as a control) were randomly distributed dropwise on the surface of the slices. Treated slices were vacuum-packed and stored at 6 degrees C. Microbiological analysis and determination of pH values were performed after 3, 6, 9, 14 and 21 days of storage. Flavour of the sausages was evaluated after 7 and 11 days of storage. The pediocin preparation had effect (p > 0.05) neither on the growth of lactic acid bacteria, on the pH value nor on the flavour of vacuum-packed sliced sausage during 21 days of storage compared to control. However, during 6 days of storage, the number of L. monocytogenes decreased from the initial level of 2.7 log cfu/g sausage to < 2 log cfu/g, while on the control sausages the number of L. monocytogenes remained at the inoculated level. The numbers of L. monocytogenes remained at those levels to the end of storage period (21 days). However, the treated samples were determined to be Listeria positive, which indicates that the pediocin preparation was not efficient enough to kill all L. monocytogenes. PMID:14623394

Mattila, Kirsi; Saris, Per; Työppönen, Susanna

2003-12-31

181

Acetaldehyde metabolism by liver mitochondrial ALDH from UChA and UChB rats: effect of inhibitors.  

PubMed

We have observed that blood acetaldehyde (AcH) levels after an ethanol dose were significantly higher in disulfiram-pre-treated UChA (low ethanol consumer) than in UChB (high ethanol consumer) rats. In order to explore these results further, we studied the effect of disulfiram (300 mg/kg i.p.) and chlorpropamide (80) mg/kg i.p.) pre-treatment on blood AcH levels after oral ethanol (60 mmol/kg) and on AcH metabolism by liver mitochondrial aldehyde(s) dehydrogenase(s) from UChA and UChB rats. AcH metabolism by liver mitochondrial aldehyde dehydrogenase (ALDH) was studied by following AcH disappearance rate and the formation of NADH at 340 nm in the incubation medium. The results showed that chlorpropamide, like disulfiram, produced a higher blood AcH level consistent with a greater inhibition of the low-Km mitochondrial ALDH in the UChA rats than in the UChB rats. These drugs did not inhibit the high Km mitochondrial ALDH. Kinetic studies of mitochondrial ALDH show that low-Km mitochondrial ALDH from UChB rats exhibits a higher affinity for NAD than UChA rats. This observation could explain the different inhibition of ALDH by both drugs, assuming that the inhibitors reduce NAD availability, the rate limiting step in the mitochondrial ALDH oxidation. PMID:12893455

Tampier, L; Sánchez, E; Quintanilla, M E

1996-01-01

182

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

PubMed

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

2014-07-23

183

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

PubMed Central

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

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

2013-01-01

184

Blockade of Neuronal alpha7-nAChR by alpha-Conotoxin ImI Explained by Computational Scanning and Energy Calculations  

Microsoft Academic Search

?-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin\\/nAChR complexes. However, the structural determinants

Rilei Yu; David J. Craik; Quentin Kaas; James Briggs

2011-01-01

185

Recombinant human receptors and functional assays in the discovery of altinicline (SIB1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist  

Microsoft Academic Search

Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia,

Nicholas D. P. Cosford; Leo Bleicher; Jean-Michel Vernier; Laura Chavez-Noriega; Tadimeti S. Rao; Robert S. Siegel; Carla Suto; Mark Washburn; G. Kenneth Lloyd; Ian A. McDonald

2000-01-01

186

Blockade of nicotinic responses by physostigmine, tacrine and other cholinesterase inhibitors in rat striatum.  

PubMed Central

1. The acetylcholinesterase inhibitors physostigmine, neostigmine, tetrahydroaminoacridine (tacrine; THA) and diisopropylfluorophosphate (DFP) were tested for possible direct nicotinic actions in rat striatal synaptosomes preloaded with [3H]-dopamine. In this preparation, nicotinic cholinoceptor activation evoked [3H]-dopamine release. 2. Antagonist activity was examined by giving a brief nicotine (1 microM) challenge after 30 min superfusion with an acetylcholinesterase (AChE) inhibitor (0.3-300 microM). Physostigmine, neostigmine and tacrine produced a concentration-dependent blockade. Physostigmine and tacrine were particularly potent (IC50S approx. 10 microM and 1 microM, respectively). DFP reduced nicotinic responses only at the highest concentration tested (300 microM). 3. Nicotinic blockade produced by superfusion with physostigmine (30 microM) was insurmountable when tested against nicotine (0.1-100 microM). 4. Physostigmine (30 microM) also reduced responses to the nicotinic agonists 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and cytisine, but did not alter responses to high K+ or (+)-amphetamine. A higher concentration of physostigmine (300 microM) completely blocked responses to nicotine, somewhat reduced responses to amphetamine, and did not alter responses to high K+. Tacrine (3 microM) reduced responses to nicotine and to high K+ but did not affect responses to amphetamine. 5. Physostigmine (0.3-300 microM), given as a brief pulse, did not produce a nicotinic agonist-like effect. 6. Physostigmine, neostigmine, tacrine and DFP (all at 30 microM) each produced near-total (> 96%) inhibition of AChE activity. However, DFP at a concentration (60 microM) that produced a degree of AChE inhibition equal to that of physostigmine 30 microM, did not significantly reduce nicotine-induced dopamine release.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8019748

Clarke, P. B.; Reuben, M.; el-Bizri, H.

1994-01-01

187

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

PubMed Central

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

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

2014-01-01

188

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

PubMed

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

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

2012-10-20

189

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

PubMed

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

2014-02-15

190

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

2013-01-01

191

Exposure of differentiated airway smooth muscle cells to serum stimulates both induction of hypoxia-inducible factor-1{alpha} and airway responsiveness to ACh.  

PubMed

Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch between differentiated and proliferative phenotypes. In rabbit tracheal ASM cells that had been differentiated in vitro by serum starvation, readdition of FBS caused initiation of proliferation and induction of nuclear and transcriptionally active hypoxia-inducible factor (HIF)-1alpha. In addition, FBS stimulated the induction of HIF-1alpha by the hypoxia mimetic cobalt. Treatment with actinomycin D, cycloheximide, the phosphatidylinositol 3-kinase inhibitors LY-294002 and wortmannin or the reactive oxygen species scavenger diphenyleneiodonium inhibited the FBS-dependent induction of HIF-1alpha. These data indicate that, in differentiated ASM cells, FBS upregulates HIF-1alpha by a transcription-, translation-, phosphatidylinositol 3-kinase-, and reactive oxygen species-dependent mechanism. Interestingly, addition of FBS and cobalt also induced HIF-1alpha in organ cultures of rabbit trachea strips and synergistically increased their contractile response to ACh, suggesting that HIF-1alpha might be implicated in airway hypercontractility. PMID:17660326

Chachami, Georgia; Hatziefthimiou, Apostolia; Liakos, Panagiotis; Ioannou, Maria G; Koukoulis, Georgios K; Bonanou, Sofia; Molyvdas, Paschalis-Adam; Simos, George; Paraskeva, Efrosyni

2007-10-01

192

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

Microsoft Academic Search

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

Katherine J. Willis; Karl J. Niklas

2004-01-01

193

Antifungal activity of gemini quaternary ammonium salts.  

PubMed

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

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

2013-12-14

194

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

PubMed

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

2014-09-01

195

Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of human acetylcholinesterase and butyrylcholinesterase  

PubMed Central

Background Alzheimer’s disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD. Findings A series of lycorine derivatives (1–10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 ± 0.66 ?M and 4.17 ± 0.29 ?M, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity. Conclusion Acylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary. PMID:22958411

2012-01-01

196

Late Quaternary temperature change velocity in Mesoamerica  

NASA Astrophysics Data System (ADS)

Quaternary climate has been highly variable, and yet few quantitative continental reconstructions are available for tropical areas. Quantitative records of temperature change during the Quaternary are especially relevant for putting modern climate change into a historic context. Within this perspective, two aspects are of singular relevance: i) Identifying and quantifying past climatic variability, and ii) Providing a means to estimate the seed at which climate change happened in the past. Here we show temperature reconstructions and temperature change velocity calculations for two locations in northern tropical America. Temperature reconstruction was based on two sedimentary records form Lake Chalco (30,000 years), central Mexican highlands, and Lake Petén-Itzá, Guatemalan lowlands (86,000 years). Temperature reconstruction was based on the analysis of fossil pollen on the light of pollen-temperature transfer functions. These functions were calibrated through an extensive survey of modern pollen samples covering an elevational gradient from 0 to 4,218 m asl. Derived temperature profiles show a parallel long-term trend and a similar cooling of approximately 5 oC during the Last Glacial Maximum in the lowlands and highlands of Mexico and Guatemala. Using a digital elevation model, we ere able to reconstruct the velocity at which isotherms displaced to produce the observed temperature anomalies. Spatial velocities of temperature change in the studied areas were at least four times slower than values reported for the last 50 years, but also at least twice as fast as those obtained from recent models. This study demonstrates that modern temperature change has no precedent within the last 86,000 years, but also that tropical climate has been more variable than it has been assumed to date.

Correa-Metrio, A.; Lozano, S.; Sosa-Nájera, S.; Bush, M. B.

2013-05-01

197

PANIC ATTACKS QUICK! Your heart is pounding, your chest aches, you can't catch a breath or swallow, your  

E-print Network

PANIC ATTACKS QUICK! Your heart is pounding, your chest aches, you can't catch a breath or swallow, maybe. But what you may be experiencing is a panic attack. What is a panic attack? You may have had a panic attack if you experienced a bunch of the symptoms listed above coming on abruptly and peaking

Kasman, Alex

198

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

Microsoft Academic Search

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

Andrew Paterson

199

A quaternary temperament model and defense cluster preferences.  

PubMed

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

Kelly, Kathryn E; Tobacyk, Jerome J

2003-10-01

200

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

PubMed

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

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

2014-04-21

201

[Syk inhibitors].  

PubMed

Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk. PMID:23961675

Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

2013-07-01

202

Syk inhibitors.  

PubMed

Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation. PMID:23994797

Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

2013-01-01

203

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

ERIC Educational Resources Information Center

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

Barrineau, Irene T., Ed.

2003-01-01

204

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

PubMed Central

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. Reduced HsPBGS activity is implicated in toxicities associated with lead poisoning and 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 twelve 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.

2011-01-01

205

The newsletter of the CAMBRIDGE QUATERNARY ISSUE 36 LENT 2007  

E-print Network

entitled `The History of Quaternary Glaciations'. The work is also available online via ScienceDirect. #12 enjoys sport, especially floorball (which is played in Cambridge!) and ice hockey. Seminar Dates QDG

de Gispert, Adrià

206

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

PubMed

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

Satya; Upreti, Dalip K; Patel, D K

2012-01-01

207

Quaternary extension in southern Tibet: Field observations and tectonic implications  

Microsoft Academic Search

We summarize evidence for Quaternary and active faulting collected in the field during three Sino-French expeditions to southeastern Tibet (1980-1982). Detailed mapping of Quaternary and active faults as well as microtectonic measurements indicate that normal faulting has been the dominant tectonic regime north of the Himalayas in the last 2+\\/-0.5 m.y. The maximum horizontal principal stress in south Tibet appears

Rolando Armijo; Paul Tapponnier; J. L. Mercier; Han Tong-Lin

1986-01-01

208

The tempo of avian diversification during the Quaternary  

Microsoft Academic Search

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

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

2004-01-01

209

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

2012-06-07

210

?7 nicotinic acetylcholine receptor (?7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex.  

PubMed

The immune response to infection or injury coordinates host defense and tissue repair, but also has the capacity to damage host tissues. Recent advances in understanding protective mechanisms have found neural circuits that suppress release of damaging cytokines. Stimulation of the vagus nerve protects from excessive cytokine production and ameliorates experimental inflammatory disease. This mechanism, the inflammatory reflex, requires the ?7 nicotinic acetylcholine receptor (?7nAChR), a ligand-gated ion channel expressed on macrophages, lymphocytes, neurons and other cells. To investigate cell-specific function of ?7nAChR in the inflammatory reflex, we created chimeric mice by cross-transferring bone marrow between wild-type (WT) and ?7nAChR-deficient mice. Deficiency of ?7nAChR in bone marrow-derived cells significantly impaired vagus nerve-mediated regulation of tumor necrosis factor (TNF), whereas ?7nAChR deficiency in neurons and other cells had no significant effect. In agreement with recent work, the inflammatory reflex was not functional in nude mice, because functional T cells are required for the integrity of the pathway. To investigate the role of T-cell ?7nAChR, we adoptively transferred ?7nAChR-deficient or WT T cells to nude mice. Transfer of WT and ?7nAChR-deficient T cells restored function, indicating that ?7nAChR expression on T cells is not necessary for this pathway. Together, these results indicate that ?7nAChR expression in bone marrow-derived non-T cells is required for the integrity of the inflammatory reflex. PMID:22183893

Olofsson, Peder S; Katz, David A; Rosas-Ballina, Mauricio; Levine, Yaakov A; Ochani, Mahendar; Valdés-Ferrer, Sergio I; Pavlov, Valentin A; Tracey, Kevin J; Chavan, Sangeeta S

2012-01-01

211

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.

2013-12-01

212

Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model  

Microsoft Academic Search

Our recent studies have indicated that acetylcholine (ACh) protects cardiomyocytes from prolonged hypoxia through activation of the PI3K\\/Akt\\/HIF-1?\\/VEGF pathway and that cardiomyocyte-derived VEGF promotes angiogenesis in a paracrine fashion. These results suggest that a cholinergic system plays a role in modulating angiogenesis. Therefore, we assessed the hypothesis that the cholinergic modulator donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, exhibits

Yoshihiko Kakinuma; Mutsuo Furihata; Tsuyoshi Akiyama; Mikihiko Arikawa; Takemi Handa; Rajesh G. Katare; Takayuki Sato

2010-01-01

213

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.

2013-01-01

214

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

SciTech Connect

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

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

1993-05-13

215

Nitric oxide, cAMP and the biphasic muscarinic modulation of ACh release at the lizard neuromuscular junction  

PubMed Central

In this study, we characterized the pharmacology and physiology of the automodulation of ACh release at the lizard neuromuscular junction (NMJ). The activation of muscarinic ACh receptors generated a biphasic modulation of synaptic transmission. Muscarine-induced activation of M3 receptors (0–12 min) decreased release, whereas M1 activation (> 12 min) enhanced release. Both phases of the biphasic effect are dependent on nitric oxide. However, cAMP acting via protein kinase A is also necessary for the M1 effect. In summary, we present a novel biphasic role for muscarine and implicate M3 receptors in the inhibition and M1 receptors in the enhancement of transmitter releaseat the cholinergic lizard NMJ. PMID:15235096

Graves, Austin R; Lewin, Katherine A; Lindgren, Clark A

2004-01-01

216

Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and A?-aggregation inhibitors: Synthesis and biological evaluation.  

PubMed

A group of 2-substituted N-(naphth-1-ylmethyl)pyrimidin-4-amines (6a-k) and N-benzhydrylpyrimidin-4-amines (7a-k) in conjunction with varying steric and electronic properties at the C-2 position were designed, synthesized and evaluated as dual cholinesterase and amyloid-? (A?)-aggregation inhibitors. The naphth-1-ylmethyl compound 6f (2-(4-cyclohexylpiperazin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine) exhibited optimum dual ChE (AChE IC(50)=8.0 ?M, BuChE IC(50)=3.9 ?M) and hAChE-promoted A?-aggregation inhibition (30.8% at 100 ?M), whereas in the N-benzhydryl series, compound 7f (N-benzhydryl-2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-amine) exhibited optimum combination of dual ChE (AChE IC(50)=10.0 ?M, BuChE IC(50)=7.6?M) and hAChE-promoted A?-aggregation inhibition (32% at 100 ?M). These results demonstrate that a 2,4-disubstituted pyrimidine ring serves as a suitable template to target multiple pathological routes in AD, with a C-2 cyclohexylpiperazine substituent providing dual ChE inhibition and potency whereas a C-4 diphenylmethane substituent provides A?-aggregation inhibition. PMID:21873056

Mohamed, Tarek; Yeung, Jacky C K; Rao, Praveen P N

2011-10-01

217

Chemical structure of silicon-, oxygen- and nitrogen-containing aC:H films prepared by RF plasma beam CVD  

Microsoft Academic Search

Si-, SiOx- and SiNx-containing a-C:H films (denoted as DLCSi, DLCSiO and DLCSiN) were deposited respectively from tetramethylsilane, hexamethyldisiloxane and hexamethyldisilazane precursors onto silicon wafer and aluminium substrates by electron cyclotron wave resonance (ECWR) RF plasma beam CVD. The chemical composition and the bonding states of the constituent elements were characterised by X-ray photoelectron spectroscopy and X-ray induced Auger electron spectroscopy.Compared

A. Toth; M. Mohai; T. Ujvari; I. Bertóti

2005-01-01

218

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

Microsoft Academic Search

The climatic control of productivity for two populations of the lichen Cetraria cucullata (Bell.) Ach. growing in the arctic tundra of northern Alaska (70°28'N, 157°23'W) was examined. Respiratory losses of carbon vary with tissue temperature, tissue water content, and time since wetting. Potential net photosynthetic gains of carbon are affected by photon flux density, tissue temperature, and water content. The

Martin J. Lechowicz

1981-01-01

219

Effects of inert gas dilution of 1,3 butadiene on plasma deposition of aC:H films  

Microsoft Academic Search

Amorphous hydrogenated carbon films (a-C:H) were deposited by the plasma decomposition of mixtures of 1,3 butadiene with different inert gas diluents (Ar, Ne, and He). Several characteristics of the plasma and the deposited films were investigated for deposition gas mixtures ranging in concentration from 0% to 90% of the diluent. Measurement of the optical emission from the plasma indicated the

Jayshree Seth; S. V. Babu

1993-01-01

220

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

2013-01-01

221

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

PubMed

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

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

2014-04-01

222

Pyridostigmine-induced inhibition of blood acetylcholinesterase (AChE) and resulting effects on manual ocular tracking performance in the trained baboon.  

PubMed

A method was developed to determine the effects of pyridostigmine on sensory-motor control in baboons trained to perform visuo-oculo-manual tracking tasks. The performance was evaluated in terms of accuracy, maximum smooth pursuit velocity, and gain. Administration of pyridostigmine (0.4-0.7 mg/kg intramuscularly) induced a dose-related decrease in smooth pursuit performance which appeared 10 to 30 min after injection and lasted about 1 h. If the animal was allowed to track the target with its hand or to move the target itself, the smooth pursuit performance increased significantly, returning to near normal values. The movement of the hand was not altered. The effect of intramuscular injections of pyridostigmine (0.5 mg/kg) was studied on blood acetylcholinesterase activity in alert baboons. Maximum inhibition of about 60% of baseline activity was observed 10 min after pyridostigmine injection. Subsequently the activity slowly tended to return to control level. Three hours after drug administration, acetylcholinesterase activity inhibition was still 34.1% of control value. In the baboon, the time-course of acetylcholinesterase activity recovery after injection is similar to that recorded in human. The similarity of the time-course of blood acetylcholinesterase activity and changes in smooth pursuit performance suggests a causal relationship between the two factors. A further experiment showed that pyridostigmine administered per os at a dose normally used as a prophylactic against organophosphates does not significantly alter sensorimotor performance as evaluated at the oculomanual tracking system level. When compared to the literature, our results suggest that the baboon can be used as a human experimental analog for pharmacological studies such as the action of acetylcholinesterase inhibitors. PMID:2350325

Vercher, J L; Dusticier, N; Ebihara, Y; Nieoullon, A; Gauthier, G M

1990-05-01

223

Recombinant expression of the AChR-alpha1 subunit for the detection of conformation-dependent epitopes in Myasthenia Gravis  

PubMed Central

Detection of autoantibodies associated with neurological disease typically involves immunoprecipitation of radioactively labeled native proteins. We explored whether single receptor subunits, fused to Renilla luciferase (Ruc), could detect patient autoantibodies in Luciferase Immunoprecipitation Systems. Myasthenia Gravis patient sera were tested for conformational autoantibodies to only the ?1-subunit of the nicotinic acetylcholine receptor (AChR). Using a panel of 10 AChR-?1 fragments, AChR-?1-?5-Ruc demonstrated the highest immunoreactivity with a conformational-specific antibody and the highest sensitivity in a pilot cohort. Testing a larger cohort with AChR-?1-?5-Ruc demonstrated 21% sensitivity and 97% specificity. A point mutation within Ruc increased the diagnostic performance of AChR-?1-?5 (32% sensitivity, 97% specificity). The 125I-?-bungarotoxin multi-subunit AChR assay demonstrated 63% sensitivity and 97% specificity. These findings highlight the difficulty in detecting Myasthenia Gravis conformational epitopes across assay formats and lay the foundation for detecting autoantibodies to defined recombinant chains of the AChR and potentially other neurotransmitter receptors. PMID:21195619

Ching, Kathryn H.; Burbelo, Peter D.; Kimball, Richard M.; Clawson, Lora L.; Corse, Andrea M.; Iadarola, Michael J.

2011-01-01

224

Simultaneous determination of nine acetylcholinesterase inhibitors using micellar electrokinetic chromatography.  

PubMed

MEKC was used for the separation of nine acetylcholinesterase inhibitors (AChEIs). AChEIs are an important group of drug compounds that are used medicinally to treat Alzheimer's disease and Myasthenia Gravis. At the time of the experiment, this is the first time that nine AChEIs are used simultaneously in a study. Several chromatographic parameters, such as buffer concentration, pH, surfactants and their concentration, background electrolyte composition, etc., were evaluated to optimize the separation. The optimum separation of the nine AChEIs was achieved in less than 15 min by using 12.5 mM Na(2)HPO(4), 12.5 mM Na(2)B(4)O(7) and 20 mM SDS at pH 10, an applied voltage of 30 kV and a temperature of 25 °C. The reproducibility of the method was also evaluated by computing the RSDs of the migration times and the areas of the nine analyte-peaks, and the migration time and the area of the peak that corresponds to rivastigmine added in the blood sample. The RSD values of the migration times and the peak areas were less than 2% and 6%, respectively, in most cases. The limits of detection and quantification were 0.5 ?g/mL and 1.7 ?g/mL, respectively. The MEKC method developed was applied to a real blood sample that was obtained from a patient who was not under any of this medication. The sample was spiked with rivastigmine in order to establish the ability of the method to separate the drug from other components that might exist in the blood sample. PMID:21439115

Nicolaou, Irene N; Kapnissi-Christodoulou, Constantina P

2011-04-01

225

Synthesis and Biological Evaluation of Novel Carbon-11 Labeled Pyridyl Ethers: Candidate Ligands for In Vivo Imaging of ?4?2 Nicotinic Acetylcholine Receptors (?4?2-nAChRs) in the brain with Positron Emission Tomography  

PubMed Central

The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), ?4?2, plays a critical role in various brain functions and pathological states. Imaging agents suitable for visualization and quantification of ?4?2 nAChRs by positron emission tomography (PET) would present unique opportunities to define the function and pharmacology of the nAChRs in the living human brain. In this study, we report the synthesis, nAChR binding affinity, and pharmacological properties of several novel 3-pyridyl ether compounds. Most of these derivatives displayed a high affinity to the nAChR and a high subtype selectivity for ?4?2-nAChR. Three of these novel nAChR ligands were radiolabeled with the positron-emitting isotope 11C and evaluated in animal studies as potential PET radiotracers for imaging of cerebral nAChRs with improved brain kinetics. PMID:19481945

Gao, Yongjun; Ravert, Hayden T.; Kuwabara, Hiroto; Xiao, Yingxian; Endres, Christopher J.; Hilton, John; Holt, Daniel P.; Kumar, Anil; Alexander, Mohab; Wong, Dean F.; Dannals, Robert F.; Horti, Andrew G.

2009-01-01

226

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

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

2010-01-01

227

Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.  

PubMed

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic ?-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 ?M; MAO B (IC50 = 10.2 ± 0.9 ?M); AChE (IC50 = 1.8 ± 0.1 ?M); BuChE (IC50 = 1.6 ± 0.25 ?M)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice. PMID:24813882

Wang, Li; Esteban, Gerard; Ojima, Masaki; Bautista-Aguilera, Oscar M; Inokuchi, Tsutomu; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid; Youdim, Moussa B H; Romero, Alejandro; Soriano, Elena; Herrero, Raquel; Fernández Fernández, Ana Patricia; Ricardo-Martínez-Murillo; Marco-Contelles, José; Unzeta, Mercedes

2014-06-10

228

Polygenetic Quaternary volcanism at Crater Flat, Nevada  

NASA Astrophysics Data System (ADS)

Alkali basalts erupted during the Quaternary at Crater Flat, Nevada, record a complex history of polycyclic and polygenetic volcanism. Magmas from the two main centers (Black Cone and Red Cone) are petrographically and geochemically similar, although field evidence suggests a number of separate eruptive events. High incompatible element concentrations, low Nb/La and high Zr/Y indicate that the magmas were derived by small degrees of partial melting from the lithospheric mantle. At Red Cone, a significant range of Sr, La, Ce, Ba and Th concentrations is observed with time (e.g., Sr range 1308-1848 ppm): the youngest samples having the more elevated values. However, there is only limited variation in the compatible trace elements (e.g., Sc and Ni). The array of compositions at Red Cone could not have been produced by changes in the degree of partial melting, or by fractional crystallization. Rather, a model of magma mixing is proposed between relatively enriched and depleted end-members. The cluster of Black Cone data falls consistently at the least-enriched end of the Red Cone sample arrays, suggesting that the Black Cone magma represents one of the mixing end-members. The modeling indicates that the magmatic plumbing systems of the two centers were linked, at least during the early stages of volcanism. Moreover, volcanic activity may have occurred at a number of sites along the length of the magmatic feeder zone during a single eruptive phase. This could have significant implications for volcanic hazard assessment in the region around Yucca Mountain, and the proposed nuclear waste repository.

Bradshaw, T. K.; Smith, Eugene I.

1994-11-01

229

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

NASA Astrophysics Data System (ADS)

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

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

2004-12-01

230

Hepatitis C virus NS5A inhibitors and drug resistance mutations  

PubMed Central

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

2014-01-01

231

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

232

The tempo of avian diversification during the Quaternary.  

PubMed Central

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

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

2004-01-01

233

Tertiary and Quaternary Research with Remote Sensing Methods  

NASA Technical Reports Server (NTRS)

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

Conel, J. E.

1985-01-01

234

Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity  

SciTech Connect

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

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

1984-04-01

235

FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer's disease  

PubMed Central

Objective Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer’s disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD. Methods In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion. Results A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510–70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups. Conclusion FOXO1 may influence the clinical response to AChEIs in AD patients. PMID:25364236

Paroni, Giulia; Seripa, Davide; Fontana, Andrea; D'Onofrio, Grazia; Gravina, Carolina; Urbano, Maria; Cascavilla, Leandro; Pellegrini, Fabio; Greco, Antonio; Pilotto, Alberto

2014-01-01

236

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

SciTech Connect

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

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

1995-12-31

237

Ice Age Earth: Late Quaternary geology and climate  

SciTech Connect

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

Dawson, A.G.

1992-01-01

238

Quaternary glaciation of the Himalayan-Tibetan orogen  

Microsoft Academic Search

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

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

2008-01-01

239

Interaction with mycorrhiza helper bacterium Streptomyces sp. AcH 505 modifies organisation of actin cytoskeleton in the ectomycorrhizal fungus Amanita muscaria (fly agaric)  

Microsoft Academic Search

The actin cytoskeleton (AC) of fungal hyphae is a major determinant of hyphal shape and morphogenesis, implicated in controlling\\u000a tip structure and secretory vesicle delivery. Hyphal growth of the ectomycorrhizal fungus Amanita muscaria and symbiosis formation with spruce are promoted by the mycorrhiza helper bacterium Streptomyces sp. AcH 505 (AcH 505). To investigate structural requirements of growth promotion, the effect

Silvia D. Schrey; Vanamo Salo; Marjatta Raudaskoski; Rüdiger Hampp; Uwe Nehls; Mika T. Tarkka

2007-01-01

240

Monitoring enzyme reaction and screening of inhibitors of acetylcholinesterase by quantitative matrix-assisted laser desorption\\/ionization fourier transform mass spectrometry  

Microsoft Academic Search

A matrix-assisted laser desorption\\/ionization Fourier transform mass spectrometry (MALDI-FTMS)-based assay was developed for\\u000a kinetic measurements and inhibitor screening of acetylcholinesterase. Here, FTMS coupled to MALDI was applied to quantitative\\u000a analysis of choline using the ratio of choline\\/acetylcholine without the use of additional internal standard, which simplified\\u000a the experiment. The Michaelis constant (K\\u000a m) of acetylcholinesterase (AChE) was determined to be

Zhe Xu; Shengjun Yao; Yuanlong Wei; Jing Zhou; Li Zhang; Cuihong Wang; Yinlong Guo

2008-01-01

241

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

Code of Federal Regulations, 2011 CFR

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

2011-07-01

242

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

Code of Federal Regulations, 2010 CFR

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

2010-07-01

243

Multifunctional corrosion inhibitors for protective coatings  

SciTech Connect

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

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

1994-12-31

244

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

USGS Publications Warehouse

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

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

2000-01-01

245

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

Microsoft Academic Search

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

ANA A. ?U?ULOVI?

2009-01-01

246

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.

2013-01-01

247

Community inertia of Quaternary small mammal assemblages in North America  

E-print Network

Community inertia of Quaternary small mammal assemblages in North America Brian J. Mc is often studied by looking for the presence or absence of community inertia (lack of change) over time reference points for the amount of inertia in random biological systems, and (iii) using a robust approach

Hadly, Elizabeth

248

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.

2013-01-01

249

Quantitation and Purification of Quaternary Ammonium Compounds From Halophyte Tissue  

PubMed Central

A simple and sensitive spectrophotometric assay for quaternary ammonium compounds (QACs) based on Dragendorff's reagent is described. Although not specific for a particular QAC, the assay allows for rapid survey of tissue for QAC content. A separation method for QACs in halophyte tissue containing high levels of cations was developed using ion exchange resins and ninhydrin to remove the amino acid fraction. PMID:16663593

Stumpf, David K.

1984-01-01

250

Synthesis and immobilization of quaternary ammonium cations in acidic zeolites  

Microsoft Academic Search

A general method for the synthesis of quaternary ammo- nium cations in acidic zeolites by a direct reaction of tertiary amines and alcohols is described. Zeolites and zeolite-related porous solids are ideal inorganic hosts for accommodating a large variety of guest species. 1 Bulky carbon-centered ionic intermediates, such as triar- ylmethyl cations, can be encapsulated within zeolite supercages via a

Wei Wang; Andreas Buchholz; Irina I. Ivanova; Jens Weitkampa; Michael Hunger

2003-01-01

251

Pliocene - Quaternary Faults and Potential Seismic Hazards in Southern Nevada  

Microsoft Academic Search

Known Quaternary faults in the Central Basin & Range Province (CBR) have a southern limit at about 35 degrees 30' N latitude, south of Las Vegas, NV. The boundary is generally aligned with the southern end of the Sierra Nevada and strike-slip faults, such as those in Death Valley, that accommodate the right-lateral motion transferred from the plate boundary to

W. J. Taylor; J. Wagoner; C. M. Depolo; B. Luke; J. Louie

2005-01-01

252

The newsletter of the CAMBRIDGE QUATERNARY ISSUE 32 MICHAELMAS 2005  

E-print Network

Research Institute and the British Antarctic Survey. The research environment at all levels is fostered in a wide range of Quaternary fields. This environment is unique in Britain, offering opportunities Antarctic Survey and Geography), Professor Roy Switsur (Godwin Lab), Professor Martin Jones (Archaeology

de Gispert, Adrià

253

Quaternary Paleoecology and Climate Change, Bladen County, NC  

NSDL National Science Digital Library

Students analyze a Quaternary pollen diagram from lakes in Bladen County, NC. This diagram contains (from the top down) the current deglaciation, the last glacial, and the previous interglacial. Students These lakes occur in Carolina Bays and students also evaluate a proposal that meteorite impact created the Bays.

Farley, Martin

254

The Quaternary Structure of the Saccharomyces cerevisiae Succinate Dehydrogenase  

Microsoft Academic Search

Succinate dehydrogenases and fumarate reductases are complex mitochondrial or bacterial respiratory chain proteins with remarkably similar structures and functions. Succinate dehydrogenase oxidizes succinate and reduces ubiquinone using a flavin adenine dinucle- otide cofactor and iron-sulfur clusters to transport elec- trons. A model of the quaternary structure of the tetrameric Saccharomyces cerevisiae succinate dehydrogenase was constructed based on the crystal structures

Kayode S. Oyedotun; Bernard D. Lemire

255

Quaternary fossil fish from the Kibish Formation, Omo Valley, Ethiopia  

Microsoft Academic Search

The late Quaternary Kibish Formation of the Omo Valley, southwestern Ethiopia, preserves environments reflecting a history of fluctuations in the level of nearby Lake Turkana over the past 200,000 years. The Kibish Formation has yielded a diverse mammalian fauna (as well as birds and crocodiles), stone tools, and the oldest anatomically modern Homo sapiens. Fish, the most common vertebrate fossils

Josh Trapani

2008-01-01

256

Recent dolomitization of quaternary biocalcarenites from fuerteventura (Canary Islands)  

Microsoft Academic Search

Quaternary marine and eolian biocalcarenites in the supratidal breaker and spray zone along the Barlovento coast of the peninsula Jandía, Fuerteventura (Canary Islands) are dolomitized by percolating brines with a high Mg\\/Ca ratio resulting from evaporation of seawater on the sediment's surface. Only fragments of calcareous algae primarily consisting of high-magnesian calcite are replaced by a cryptocrystalline variety of dolomite.

German Müller; Rerd Tietz

1966-01-01

257

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

2014-03-01

258

Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents.  

PubMed

A series of backbone modified and sulfonic acid replacement analogs of our topical, clinical candidate (iii) were synthesized. Their antimicrobial activities and aqueous stabilities at pH 4 and pH 7 were determined, and has led us to identify quaternary ammonium N,N-dichloroamines as a new class of topical antimicrobial agents. PMID:19362467

Francavilla, Charles; Low, Eddy; Nair, Satheesh; Kim, Bum; Shiau, Timothy P; Debabov, Dmitri; Celeri, Chris; Alvarez, Nichole; Houchin, Ashley; Xu, Ping; Najafi, Ron; Jain, Rakesh

2009-05-15

259

Quaternary glaciation in Africa: key chronologies and climatic implications  

Microsoft Academic Search

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

Bryan G. Mark; Henry A. Osmaston

2008-01-01

260

Journal of Theoretical and Computational Chemistry, Vol. 1, No. 1 (2002) 8192 c World Scientific Publishing Company  

E-print Network

acetylcholinesterase (AChE) and its inhibitor, with the view of designing new AChE inhibitors. The predicted), acetylcholinesterase (AChE) plays a key role in both central and peripheral nervous systems in the transmission

Sussman, Joel L.

261

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

PubMed

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

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

2006-01-01

262

The influence of motor nerve tetanization on the effect of organophosphorus cholinesterase inhibitors on neuromuscular transmission.  

PubMed Central

1. The changes in the activity of synaptic cholinesterases (ChE) of the ant. tibial muscle in the anaesthetized cat were detected by recording the changes of the blocking activity of acetylcholine (ACh) and comparing them with the blocking activity of carbaminoylcholine (carbachol) injected intra-arterially or intravenously. After the administration of organophosphorus inhibitors (OPI) of ChE the ACh blocking dose diminished 500 to 2000-fold but the carbachol blocking dose did not change. In 4-6 h after the injection of OPI the ACh blocking dose increased again 8 to 15-fold, but the dose of carbachol still remained unchanged. The transmission of high frequency impulses improved after OPI in parallel with the decrease of the ACh blocking activity. Thus the synaptic ChE is partly restored in a few hours after its irreversible inhibition with OPI. 2. Tetanization of the motor nerve (50-60 Hz, 10 min), started simultaneously with the intravenous injection of OPI (armine Gd-42), diminished the impairment of neuromuscular transmission. On the side of tetanization the ACh blocking action was less pronounced and the transmission of high frequency impulses better than on the control side. Thus the tetanization produced some protection of synaptic ChE against inhibition by OPI. The protective effect of tetanization was absent when the tetanization was performed before the injection of OPI or was started 10-20 min after the injection of OPI. 3. The protective effect of tetanization was also observed on the isolated phrenic nerve diaphragm preparation of the rat. 4. The possible mechanisms of the protective effect of tetanization are discussed. PMID:175873

Danilov, A F; Ivanov, Y J; Michelson, M J

1976-01-01

263

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

SciTech Connect

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

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

1995-12-31

264

Quaternary and pre-Quaternary( ) materials and processes of southeast Ohio: Overview, speculations, and recommendations  

SciTech Connect

Investigations and mapping of surficial deposits in Ohio have focused largely on the glacial deposits which cover nearly two-thirds of the state. Research on Quaternary deposits beyond the glacial border has been done by Foster, Hildreth, Andrews, Leverett, Tight, Stout, Goldthwait, Forsyth, Lessig, White, Totten, Hoyer, and Noltimier. However, growing human interaction with surficial materials of southeast Ohio now requires much more detailed mapping and characterization of these deposits. Recognition of periglacial, proglacial, and preglacial processes and materials in eastern and southern states has led to the search for similar processes and materials in southeast Ohio. Evidence for gelifraction, gelifluction, cryoturbation, and considerable periglacial colluviation is more extensive than previously thought. Proglacial deposits are also much more extensive, outwash and glaciolacustrine deposits cover large areas in southeast Ohio and are poorly mapped and characterized, or not mapped at all. Preglacial processes including a long span of profound weathering and formation of saprolite have been given little or no attention in southeast Ohio. The signature of protracted preglacial weathering still remains in this part of the state, and should change prevailing views of the terrain upon which periglacial processes worked. Mapping and characterization of these materials are urgently needed as citizens make important land-use decisions such as locating landfills and new developments.

Berg, T.M. (Ohio Geological Survey, Columbus, OH (United States))

1992-01-01

265

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

PubMed

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

2013-12-28

266

Automated Docking with Protein Flexibility in the Design of Femtomolar "Click Chemistry" Inhibitors of Acetylcholinesterase  

PubMed Central

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

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

2013-01-01

267

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

PubMed

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

2011-12-01

268

Molecular Basis of Downregulation of G-Protein-Coupled Inward Rectifying K+ Current (IK,ACh) in Chronic Human Atrial Fibrillation: Decrease in GIRK4 mRNA Correlates With Reduced IK,ACh and Muscarinic Receptor-Mediated Shortening of Action Potentials  

Microsoft Academic Search

Background—Clinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K current (IK,ACh) contribute to chronic AF. Methods and Results—In the present study, we used electrophysiological recordings and competitive reverse-transcription polymerase chain reaction to study changes in IK,ACh and the level

D. Dobrev; E. Graf; E. Wettwer; H. M. Himmel; O. Hala; C. Doerfel; T. Christ; S. Schuler; U. Ravens

2001-01-01

269

Unexpected primitive rodents in the Quaternary of Argentina  

NASA Astrophysics Data System (ADS)

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

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

2005-10-01

270

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

SciTech Connect

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

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

2008-11-18

271

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

2013-04-01

272

Activity of an insoluble antimicrobial quaternary amine complex in plastics  

Microsoft Academic Search

Summary Growth and survival ofStaphylococcus aureus, Pseudomonas aeruginosa., Klebsiella pneumoniae andAspergillus niger were reduced by a low-solubility polysubstituted.-quaternary amine complex (InterseptR) processed into the matrices of ethylene vinyl acetate, polystyrene and polyethylene., Recoveries of challenge microorganisms from agar film overlays and determination of the effects of the complex on radiolabelled-leucine transport by adhered cells and bacterial biofilms were more suitable

D. L. Price; A. D. Sawant; D. G. Ahearn

1991-01-01

273

The impact of Quaternary Ice Ages on mammalian evolution.  

PubMed Central

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

Lister, Adrian M

2004-01-01

274

Quaternary freshwater Ostracoda from the Great Salt Lake Basin  

E-print Network

THE UNIVERSITY OF KANSAS PALEONTOLOGICAL CONTRIBUTIONS October 23, 1975 Paper 78 QUATERNARY FRESHWATER OSTRACODA FROM THE GREAT SALT LAKE BASIN, UTAH' KENNETH H. LISTER Department of Geology, The University of Kansas, Lawrence; present address: 317... Via Anita, Redondo Beach, California ABSTRACT Ostracodes are described from two cores, each more than 200 m long taken in Quater- nary sediments of the Great Salt Lake Basin, Utah. Thirty-one species of Ostracoda in thirteen genera have been identified...

Lister, K. H.

1975-10-23

275

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

2003-01-01

276

Composite aromatic boxes for enzymatic transformations of quaternary ammonium substrates.  

PubMed

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

2014-12-01

277

Vegetation ecotone dynamics in Southwest Alaska during the Late Quaternary  

Microsoft Academic Search

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

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

2001-01-01

278

Changes in the regulatory effects of cell-cell interactions on neuronal AChR subunit transcript levels after synapse formation.  

PubMed

Nicotinic acetylcholine receptors (AChRs) mediate excitatory synaptic transmission in the chick ciliary ganglion. AChR protein and mRNA levels are increased by both innervation and retrograde signals from target tissues during synapse formation. We now show that AChR alpha3, beta4, and alpha5 subunit transcript levels stop increasing after synaptogenesis. Moreover, maintenance of these mRNA levels requires the continued presence of regulatory signals from both pre- and postganglionic tissues. Unilateral preganglionic denervation or postganglionic axotomy causes declines in alpha3, beta4, and alpha5 transcript levels, ranging from twofold to 3. 5-fold, relative to contralateral control neuron values in newly hatched chicks. The reductions are not merely an injury response; cbeta4-tubulin mRNA levels are not affected by either axotomy or denervation. Further, similar decreases in AChR mRNA levels are observed after local application of colchicine to the postganglionic nerves, which blocks fast transport without disturbing axonal integrity. These results also demonstrate a developmental change in the regulatory effects of target tissues. Reductions in alpha5 mRNA levels caused by axotomy or colchicine treatment after peripheral synapse formation contrast with the lack of an effect on alpha5 when synapse formation with the target tissue is prevented. The ability of the target tissue to regulate alpha5 mRNA levels after synaptogenesis is interesting, because this subunit may be necessary for the formation of high-conductance AChRs. The specific regulatory effects of target tissues and inputs at different developmental stages demonstrate that neurons continually depend on signals from their pre- and postsynaptic tissues to accomplish mature levels of AChR subunit expression and optimal functioning of that neuronal circuit. PMID:8824326

Levey, M S; Jacob, M H

1996-11-01

279

Potentiation by tonic A2a-adenosine receptor activation of CGRP-facilitated [3H]-ACh release from rat motor nerve endings.  

PubMed Central

1. The effect of calcitonin gene-related peptide (CGRP) on [3H]-acetylcholine ([3H]-ACh) release from motor nerve endings and its interaction with presynaptic facilitatory A2a-adenosine and nicotinic acetylcholine receptors was studied on rat phrenic nerve-hemidiaphragm preparations loaded with [3H]-choline. 2. CGRP (100-400 nM) increased electrically evoked [3H]-ACh release from phrenic nerve endings in a concentration-dependent manner. 3. The magnitude of CGRP excitation increased with the increase of the stimulation pulse duration from 40 microseconds to 1 ms, keeping the frequency, the amplitude and the train length constants. With 1 ms pulses, the evoked [3H]-ACh release was more intense than with 40 microseconds pulse duration. 4. Both the nicotinic acetylcholine receptor agonist, 1,1-dimethyl-4-phenylpiperazinium, and the A2a adenosine receptor agonist, CGS 21680C, increased evoked [3H]-ACh release, but only CGS 21680C potentiated the facilitatory effect of CGRP. This potentiation was prevented by the A2a adenosine receptor antagonist, PD 115,199. 5. Adenosine deaminase prevented the excitatory effect of CGRP (400 nM) on [3H]-ACh release. This effect was reversed by the non-hydrolysable A2a-adenosine receptor agonist, CGS 21680C. 6. The nicotinic antagonist, tubocurarine, did not significantly change, whereas the A2-adenosine receptor antagonist, PD 115,199, blocked the CGRP facilitation. The A1-adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine, potentiated the CGRP excitatory effect. 7. The results suggest that the facilitatory effect of CGRP on evoked [3H]-ACh release from rat phrenic motor nerve endings depends on the presence of endogenous adenosine which tonically activates A2a-adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8004402

Correia-de-Sa, P.; Ribeiro, J. A.

1994-01-01

280

Modulation of Na+-channels by neurotoxins produces different effects on [3H]ACh release with mobilization of distinct Ca2+-channels.  

PubMed

1. Voltage-gated Na+ channels are responsible for initiation and conduction of action potentials. The arrival of an action potential at nerve terminal increases intracellular Na+ and Ca2+ concentrations. Calcium entry into neurons through voltage-dependent calcium channels is associated with a variety of intracellular processes. Scorpion neurotoxins have been used as tools to investigate mechanisms involved in neurotransmitter release. Tityustoxin (TsTX) is an alpha-type toxin that delays Na+-channel inactivation. Toxin-gamma (TiTX-gamma) is a beta-type toxin that induces Na+-channel activation at resting potentials. 2. In the present work, we describe the effects of both toxins on [3H]acetylcholine ([3H]ACh) release from rat cerebrocortical synaptosomes, in the presence or absence of the calcium channels blockers: omega-conotoxin-GVIA (omega-CgTx), 1 microM; omega-agatoxin-IVA (omega-Aga), 30 nM; omega-conotoxin-MVIIC (omega-MVIIC), 1 microM; or verapamil, 1 microM. 3. TsTX evokes [3H]ACh release in a concentration-dependent manner with a gradual increase up to saturation at concentrations of 500 nM. However, release of ACh evoked by TiTX-gamma was not linear regarding the toxin concentration. The [3H]-ACh release evoked by TsTX or TiTX-gamma was partially inhibited by omega-CgTx or omega-Aga, and blocked with omega-MVIIC. Verapamil (1 microM) had no effect. Tetrodotoxin blocked [3H]ACh release evoked by both toxins. 4. These results show that different actions on Na+-channels produce different effects on [3H]ACh release with involvement of distinct presynaptic Ca2+-channels, which supports the idea that sodium channels may modulate neurotransmitter release. PMID:12585699

Falqueto, Eduardo Belisário; Massensini, André Ricardo; Moraes-Santos, Tasso; Gomez, Marcus Vinícius; Romano-Silva, Marco A

2002-12-01

281

Up-scaling the production of modified a-C:H coatings in the framework of plasma polymerization processes  

NASA Astrophysics Data System (ADS)

Hydrogenated amorphous carbon (a-C:H) films with silicon and oxygen additions, which exhibit mechanical, tribological and wetting properties adequate for protective coating performance, have been synthesized at room temperature in a small- (0.1 m 3) and a large-scale (1 m 3) coaters by low-pressure Plasma-Activated Chemical Vapour Deposition (PACVD). Hence, a-C:H:Si and a-C:H:Si:O coatings were produced in atmospheres of tetramethylsilane (TMS) and hexamethyldisiloxane (HMDSO), respectively, excited either by radiofrequency (RF - small scale) or by pulsed-DC power (large scale). Argon was employed as a carrier gas to stabilize the glow discharge. Several series of 2-5 ?m thick coatings have been prepared at different mass deposition rates, Rm, by varying total gas flow, F, and input power, W. Arrhenius-type plots of Rm/ F vs. ( W/ F) -1 show linear behaviours for both plasma reactors, as expected for plasma polymerization processes at moderated energies. The calculation of apparent activation energy, Ea, in each series permitted us to define the regimes of energy-deficient and monomer-deficient PACVD processes as a function of the key parameter W/ F. Moreover, surface properties of the modified a-C:H coatings, such as contact angle, abrasive wear rate and hardness, appear also correlated to this parameter. This work shows an efficient methodology to scale up PACVD processes from small, lab-scale plasma machines to industrial plants by the unique evaluation of macroscopic parameters of deposition.

Corbella, C.; Bialuch, I.; Kleinschmidt, M.; Bewilogua, K.

2009-10-01

282

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.

1987-01-01

283

Ecological impacts of the late Quaternary megaherbivore extinctions.  

PubMed

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

2014-03-01

284

Simulation of Quaternary glacial cycles with fully interactive carbon cycle  

NASA Astrophysics Data System (ADS)

Although it is generally accepted that, as postulated by the Milankovitch theory, Earth's orbital variations play an important role in Quaternary climate dynamics, the mechanism of glacial cycles still not fully understood. Among major scientific challenges remains the understanding of the nature of 100 kyr cycles that dominated climate variability over the late part of Quaternary and a strong link between ice volume and atmospheric CO2 concentration. Here using the Earth system model of intermediate complexity CLIMBER-2 which includes all major components of the Earth system - atmosphere, ocean, land surface, northern hemisphere ice sheets, terrestrial biota and soil carbon, aeolian dust and marine biogeochemistry - we performed simulations of the Quaternary climate cycles using variations in the Earth's orbital parameters as the only prescribed climate forcing. Thanks to high computational efficiency of the CLIMBER-2 model we performed a large suite of model simulations aimed on better understanding the role of individual processes. We found that the main drivers of atmospheric CO2 evolve with time: changes in sea surface temperature and volume of bottom water of southern origin exert CO2 control during glacial inception and deglaciation, while changes in carbonate chemistry and marine biology are dominant during the first and second parts of the glacial cycles, respectively. Changes in terrestrial carbon pool play significant role during deglaciation. We also discus how paleoclimate records, such as atmospheric and deep oceanic d13C, can help to constrain model parameters and test hypotheses on the mechanism of glacial-interglacial CO2 variations.

Ganopolski, Andrey; Brovkin, Victor

2014-05-01

285

Genetic ages for Quaternary topographic evolution: A new dating tool  

NASA Astrophysics Data System (ADS)

All eukaryote populations accumulate mutations in their mitochondrialDNA (mtDNA) over time, so reproductively isolated populationsbecome characterized by distinct mtDNA lineages. In addition,the degree of genetic differentiation among distinct populationscan be used to estimate time elapsed since their isolation.We have identified an informative system for calibrating themtDNA "clock" by genetically comparing freshwater galaxiid fishpopulations isolated in different river drainages. Calibrationusing a range of Quaternary geological events in southern NewZealand shows that the mtDNA divergence rate in galaxiid fishesis between 1% and 2%/100 k.y. up to 250 k.y., with the ratedecreasing with increasing age. The estimated divergence rateslows to around 4%/m.y. for the middle Quaternary, althoughcalibration is poor. A calibration curve has been fitted toall data: divergence (%) = -2.2e-9t + 2.5t + 2.2,where t is isolation age (in m.y.). This molecular clock haspotential as a dating tool for glacially related and activetectonic events that have caused river drainage changes in thelate Quaternary in the Southern Hemisphere, where galaxiidsare widespread. An application of this dating tool to an examplein northern South Island uses three different species of freshwater-limitedfish, and all three data sets imply formation of a drainagedivide at 320 ± 110 ka, at about the time of a majorglacial advance though the divide (oxygen isotope stage 8).

Craw, Dave; Burridge, Chris; Norris, Richard; Waters, Jon

2008-01-01

286

Quaternary diversification in European alpine plants: pattern and process.  

PubMed Central

Molecular clock approaches applied previously to European alpine plants suggest that Primula sect. Auricula, Gentiana sect. Ciminalis and Soldanella diversified at the beginning of the Quaternary or well within this period, whereas Globularia had already started diversifying in the (Late-)Tertiary. In the first part of this paper we present evidence that, in contrast to Globularia and Soldanella, the branching patterns of the molecular internal transcribed spacer phylogenies of both Primula and Gentiana are incompatible with a constant-rates birth-death model. In both of these last two taxa, speciation probably decreased through Quaternary times, perhaps because of some niche-filling process and/or a decrease in specific range size. In the second part, we apply nonlinear regression analyses to the lineage-through-time plots of P. sect. Auricula to test a range of capacity-dependent models of diversification, and the effect of Quaternary climatic oscillations on diversification and extinction. At least for one major clade of sect. Auricula there is firm evidence that both diversification and extinction are a function of temperature. Intriguingly, temperature appears to be correlated positively with extinction, but negatively with diversification. This suggests that diversification did not take place, as previously assumed, in geographical isolation in high-altitude interglacial refugia, but rather at low altitudes in geographically isolated glacial refugia. PMID:15101582

Kadereit, Joachim W; Griebeler, Eva Maria; Comes, Hans Peter

2004-01-01

287

Quaternary extension in southern Tibet: Field observations and tectonic implications  

NASA Astrophysics Data System (ADS)

We summarize evidence for Quaternary and active faulting collected in the field during three Sino-French expeditions to southeastern Tibet (1980-1982). Detailed mapping of Quaternary and active faults as well as microtectonic measurements indicate that normal faulting has been the dominant tectonic regime north of the Himalayas in the last 2 ± 0.5 m.y. The maximum horizontal principal stress in south Tibet appears to be only the intermediate principal stress ?2, ?1 being vertical. South of the "chord" joining the eastern and western syntaxes of the Himalayan arc, extensional strains are principally localized within seven regularly spaced rift zones, three of which have been studied in some detail. The extension direction is determined to be N96° E ± 7° mainly from statistical averaging of strikes of newly formed normal faults. Throw rates on normal faults are evaluated for different time spans (2 ± 0.5 m.y., 60 ± 40 kyr, and 10 ± 2 kyr B.P.), using structural and topographic reliefs, as well as synglacial and postglacial vertical offsets. The rate of Quaternary extension is about 1% m.y.-1 along an 1100-km-long ESE traverse across south Tibet. This corresponds to a "spreading" rate of 1 ± 0.6 cm/yr. This rate and the divergent horizontal projections of slip vectors of earthquakes along the Himalayan front constrain the rate at which rigid India underthrusts southern Tibet to be 2 ± 1 cm/yr. Although most of the normal faults appear to be independent of, and nearly orthogonal to, the ?E-W Mesozoic-Tertiary tectonic fabric, the Yadong-Gulu rift appears to be guided for over 130 km by the older, oblique (?NE-SW) Nyainqentanglha range and fault zones along it. This reactivated zone is the most prominent left-lateral strike-slip fault system in SE Tibet. Excepting this zone, and the vicinity of the SE extremity of the Karakorum fault, Quaternary strike-slip faulting is rare in south Tibet, i.e., south of the chord between the syntaxes of the Himalayan arc. North of the chord, the tectonic style is different. There minor conjugate strike-slip faulting is widespread and appears to control Quaternary normal faulting, which is more diffuse and subdued than in south Tibet. Along the chord, the presence of a major zone of active right-lateral, en échelon strike-slip faults (Karakorum-Jiali fault zone) probably reflects the greater facility of eastward extrusion in north central Tibet, in response to the northward push of India. The eastern Himalayan syntaxis may be an obstacle to such extrusion movements south of the chord.

Armijo, Rolando; Tapponnier, Paul; Mercier, J. L.; Han, Tong-Lin

1986-12-01

288

Digital release of the Alaska Quaternary fault and fold database  

NASA Astrophysics Data System (ADS)

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

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

2011-12-01

289

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.

2003-01-01

290

QUATERNARY RESEARCH 29, 93-112 (1988) Lithospheric Thickness, Antarctic Deglaciation History, and Ocean  

E-print Network

QUATERNARY RESEARCH 29, 93- 112 (1988) Lithospheric Thickness, Antarctic Deglaciation History the delay of West Antarctic melting and the thickness of the lithosphere required to reconcile the observed

Peltier, W. Richard

291

Population diversity and distinct haplotype frequencies associated with ACHE and BCHE genes of Israeli Jews from trans-caucasian Georgia and from Europe  

SciTech Connect

Variant alleles of the butyrylcholinesterase gene, BCHE, have often been used to trace the genetic histories of populations. The D70G substitution in BCHE causes prolonged postanesthesia apnea ({open_quotes}atypical{close_quotes} phenotype); H322N substitution in the closely related acetylcholinesterase gene, ACHE, is the basis of the mutually incompatible YT blood groups. In both genes, additional point mutations were reported to be linked to these phenotypically evident ones. To examine whether the intragenic linkage reported for the ACHE and BCHE mutations in Americans is universal, the authors studied frequencies of these mutations in trans-Caucasian Georgian Jews, a population that has remained relatively isolated for 1500 years. To this end they employed PCR amplification followed by DNA sequencing and enzymatic restriction and compared the frequencies found to corresponding reported phenotype data. Georgian Jews` N322 ACHE was a rather low 7.0% and was totally linked to a P446 mutation, in agreement with a recent report. In BCHE, however, G70 was a relatively high 5.8%, and the V497 and T539 mutations were not found, either in Georgian or in Ashkenazi Jews, in contrast to reported findings in Americans. The findings reveal distinct displays of ACHE and BCHE haplotypes in Georgian Jews and suggest different founder effects, genetic drifts, and/or selection pressures in the evolution of each of these genes. 29 refs., 3 figs., 2 tabs.

Ehrlich, G.; Ginzberg, D.; Loewenstein, Y. [Hebrew Univ., Jerusalem (Israel)] [and others] [Hebrew Univ., Jerusalem (Israel); and others

1994-07-15

292

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

NASA Astrophysics Data System (ADS)

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

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

2007-09-01

293

Comparisons of G and its Stability The combination of some data and an aching desire for an answer does not ensure  

E-print Network

36 Comparisons of G and its Stability The combination of some data and an aching desire (1986) Version 26 June 2014 As shown in the previous chapter, theory offers some hints that parts of G (its orientation) may be somewhat stable over modest amounts of time, but also suggests the G can dra

Walsh, Bruce

294

Comparisons of G and its Stability The combination of some data and an aching desire for an answer does not ensure  

E-print Network

32 Comparisons of G and its Stability The combination of some data and an aching desire of G (its orientation) may be somewhat stable over modest amounts of time, but also suggests the G can dra- matically change over short periods of time. Hence, the stability of G remains foremost

Walsh, Bruce

295

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.

296

The Emergence And Development Of The Action Committee For Higher Education (ache): From Crisis To Institutionalization (joint Venture, Associations, Public Relations, Grassroots)  

Microsoft Academic Search

The purpose of the study is to trace, describe and analyze the creation, development, motivation and impact of the Action Committee for Higher Education (ACHE) as an organizational instrument influencing higher education legislation in the 1980s. Concepts from organizational analysis and communication theory are used to assist in explaining and interpreting the findings of the study.This is a case study

Frances Rose Matera

1986-01-01

297

Electrical coupling and release of K+ from endothelial cells co-mediate ACh-induced smooth muscle hyperpolarization in guinea-pig inner ear artery  

PubMed Central

The physiological basis of ACh-elicited hyperpolarization in guinea-pig in vitro cochlear spiral modiolar artery (SMA) was investigated by intracellular recording combined with dye labelling of recorded cells and immunocytochemistry. We found the following. (1) The ACh-hyperpolarization was prominent only in cells that had a low resting potential (less negative than ?60 mV). ACh-hyperpolarization was reversibly blocked by 4-DAMP, charybdotoxin or BAPTA-AM, but not by N?-nitro-l-arginine methyl ester, glipizide, indomethacin or 17-octadecynoic acid. (2) Ba2+ (100 ?m) and ouabain (1 ?m) each attenuated ACh-hyperpolarization by ? 30% in smooth muscle cells (SMCs) but had only slight or no inhibition in endothelial cells (ECs). A combination of Ba2+ and 18?-glycyrrhetinic acid near completely blocked the ACh-hyperpolarization in SMCs. (3) High K+ (10 mm) induced a smaller hyperpolarization in ECs than in SMCs, with an amplitude ratio of 0.49: 1. Ba2+ blocked the K+-induced hyperpolarization by ? 85% in both cell types, whereas ouabain inhibited K+-hyperpolarization differently in SMCs (19%) and ECs (35%) and increased input resistance. 18?-Glycyrrhetinic acid blocked the high K+-hyperpolarization in ECs only. (4) Weak myoendothelial dye coupling was detected by confocal microscopy in cells recorded with a propidium iodide-containing electrode for longer than 30 min. A sparse plexus of choline acetyltransferase-immunoreactive (ChAT) fibres was observed around the SMA and its up-stream arteries. (5) Evoked excitatory junction potentials (EJP) were partially blocked by 4-DAMP in half of the cells tested. We conclude that ACh-induced hyperpolarization originates from ECs via activation of Ca2+-activated potassium channels, and is independent of the release of NO, cyclo-oxygenase or cytochrome P450 products. ACh-induced hyperpolarization in smooth muscle cells involves two mechanisms: (a) electrical spread of the hyperpolarization from the endothelium, and (b) activation of inward rectifier K+ channels (Kir) and Na+–K+ pump current by elevated interstitial K+ released from the endothelial cells, these being responsible for about 60% and 40% of the hyperpolarization, respectively. The role ratio of Kir and pump current activation is at 8 : 1 or less. PMID:15731195

Jiang, Zhi-Gen; Nuttall, Alfred L; Zhao, Hui; Dai, Chun-Fu; Guan, Bing-Cai; Si, Jun-Qiang; Yang, Yu-Qin

2005-01-01

298

ACE Inhibitors: Pharmacology  

Microsoft Academic Search

\\u000a More than IS inhibitors of the angiotensin-converting enzyme (ACE) are now clinically available worldwide. ACE inhibitors\\u000a can be divided into three chemical classes according to their zinc ligand. They mainly differ in their elimination half-life,\\u000a potency, lipophilicity and the route of elimination. ACE inhibitors act by blocking the systemic and local generation of angiotensin\\u000a II (Ang II) from angiotensin I

P. Gohlke

299

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)

2011-01-01

300

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

NASA Astrophysics Data System (ADS)

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; Wang, Liping; Hu, Litian; Hu, Tianchang; Wang, Yunfeng; Zhang, Yaonan

2011-01-01

301

Investigation of acetylcholine receptor diversity in a nematode parasite leads to characterization of tribendimidine- and derquantel-sensitive nAChRs.  

PubMed

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

Buxton, Samuel K; Charvet, Claude L; Neveu, Cedric; Cabaret, Jacques; Cortet, Jacques; Peineau, Nicolas; Abongwa, Melanie; Courtot, Elise; Robertson, Alan P; Martin, Richard J

2014-01-01

302

Role of ?7- and ?4?2-nAChRs in the neuroprotective effect of nicotine in stress-induced impairment of hippocampus-dependent memory.  

PubMed

We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of ?7- and ?4?2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either ?7-nAChRs [methyllycaconitine (MLA)] or ?4?2-nAChRs [dihydro-?-erythroidine (DH?E)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 ?g/side.d and 41 ?g/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DH?E infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of ?7-nAChRs, but not ?4?2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions. PMID:23067572

Alzoubi, Karem H; Srivareerat, Marisa; Tran, Trinh T; Alkadhi, Karim A

2013-06-01

303

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

2014-01-01

304

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.

2013-01-01

305

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.

306

Arctic-alpine blockfields in northern Sweden: Quaternary not Neogene  

NASA Astrophysics Data System (ADS)

Slowly-eroding, blockfield-mantled, non-glacial surface remnants may serve as markers against which to determine Quaternary glacial erosion volumes in high latitude mountain settings. To investigate this potential utility of these surfaces, chemical weathering, erosion rates, and origins of mountain blockfields are investigated in northern Sweden. This is done, firstly, by assessing the intensity of regolith chemical weathering along altitudinal transects descending from three blockfield-mantled summits. Clay/silt ratios, secondary mineral assemblages determined through X-ray diffraction, and the presence of chemically weathered grains visible on scanning electron microscopy, in fine matrix samples collected from pits excavated along the transects are each used for this purpose. Secondly, erosion rates and total surface histories of two of the summits are inferred from concentrations of in situ-produced cosmogenic 10Be and 26Al in quartz at the blockfield surface. An interpretative model is adopted that includes temporal variations in nuclide production rates through surface burial by glacial ice and glacial isostasy-induced elevation changes of the blockfield surfaces. Together, our data indicate that these blockfields are not derived from remnants of intensely weathered Neogene weathering profiles, as is commonly considered. Evidence for this interpretation includes minor chemical weathering in each of the three examined blockfields, despite some differences according to slope position. In addition, average erosion rates of ∼16.2 mm ka-1 and ∼6.7 mm ka-1, calculated for two blockfield-mantled summits, are low but of sufficient magnitude to remove present blockfield mantles, of up to a few meters in thickness, within a late-Quaternary timeframe. Hence, blockfield mantles appear to be replenished by regolith formation through, primarily physical, weathering processes that have operated during the Quaternary. Erosion rates remain low enough, however, for blockfield-mantled, non-glacial surface remnants to provide reasonable landscape markers against which to contrast Quaternary erosion volumes in surrounding glacial landscape elements. The persistence of blockfield mantles over a number of glacial-interglacial cycles and an apparently low likelihood that they can re-establish on glacially eroded bedrock, also discounts the operation of a "glacial buzz-saw" on surface remnants that are presently perceived as non-glacial. These interpretations are tempered though by outstanding questions concerning the composition of preceding Neogene regoliths and why they have apparently been comprehensively removed from these remnant non-glacial surfaces. It remains possible that periglacial erosion of perhaps more intensely weathered Neogene regoliths was high during the Pliocene-Pleistocene transition to colder conditions and that periglacial processes reshaped non-glacial surface remnants largely before the formation of blockfield armours.

Goodfellow, B. W.; Stroeven, A. P.; Fabel, D.; Fredin, O.; Derron, M.-H.; Bintanja, R.; Caffee, M. W.

2014-02-01

307

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.

308

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

2014-03-01

309

Late Quaternary incised-valley fill of the Yangtze delta (China): its stratigraphic framework and evolution  

Microsoft Academic Search

A Late Quaternary stratigraphic framework of the Yangtze delta, China, has been established based on the analysis and correlation of over 600 cores. Thirty cores were drilled and analyzed during this study, and the rest were collected from numerous publications. The Late Quaternary stratigraphic framework of the Yangtze delta consists of incised-valley fill and two interfluvial sequences. The incised valley

Congxian Li; Ping Wang; Heping Sun; Jiaqiang Zhang; Daidu Fan; Bing Deng

2002-01-01

310

Quaternary Diffusion Coefficients in a Protein-Polymer-Salt-Water System Determined by Rayleigh Interferometry  

E-print Network

Quaternary Diffusion Coefficients in a Protein-Polymer-Salt-Water System Determined by Rayleigh in a protein-polymer-salt-water quaternary system. Specifically, we have measured the nine multicomponent diffusion coefficients, Dij, for the lysozyme-poly(ethylene glycol)-NaCl-water system at pH 4.5 and 25 °C

Annunziata, Onofrio

311

Late Quaternary vegetation and climate history near Little Lake, central Coast Range, Oregon  

E-print Network

­25 000 yr B.P.), the Fraser glaciation (ca. 25 000­ 10 000 yr B.P.), and the Holocene. Little Lake (latLate Quaternary vegetation and climate history near Little Lake, central Coast Range, Oregon Marc A recovered from Little Lake, Oregon, provide the first record of late Quaternary climate and veg- etation

Whitlock, Cathy L.

312

Dating late Quaternary planktonic foraminifer Neogloboquadrina pachyderma from the Arctic Ocean by using amino acid racemization  

E-print Network

Dating late Quaternary planktonic foraminifer Neogloboquadrina pachyderma from the Arctic Ocean was determined by using independently dated sediment cores from the Arctic Ocean. The racemization rates calibrated for the last 150 ka using 14 C ages and the emerging Quaternary chronostratigraphy of Arctic Ocean

Howat, Ian M.

313

Late Quaternary slip rates across the central Tien Shan, Kyrgyzstan, central Asia  

Microsoft Academic Search

(1) Slip rates across active faults and folds show that late Quaternary faulting is distributed across the central Tien Shan, not concentrated at its margins. Nearly every intermontane basin contains Neogene and Quaternary syntectonic strata deformed by Holocene north-south shortening on thrust or reverse faults. In a region that spans two thirds of the north-south width of the central Tien

Stephen C. Thompson; Ray J. Weldon; Charles M. Rubin; Kanatbek Abdrakhmatov; Peter Molnar; Glenn W. Berger

2002-01-01

314

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

E-print Network

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

St-Ong, Guillaume

315

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

E-print Network

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

Long, Bernard

316

Late Quaternary stratigraphy and sedimentation patterns in the western Arctic Ocean Leonid Polyak a,  

E-print Network

Late Quaternary stratigraphy and sedimentation patterns in the western Arctic Ocean Leonid Polyak a Article history: Accepted 17 March 2009 Available online xxxx Keywords: Arctic Ocean sediment stratigraphy sedimentary environments Late Quaternary glaciations Sediment cores from the western Arctic Ocean obtained

Howat, Ian M.

317

LATE-QUATERNARY VEGETATION DYNAMICS IN NORTH AMERICA: SCALING FROM TAXA TO BIOMES  

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

2004-01-01

318

Flightless ducks, giant mice and pygmy mammoths: Late Quaternary extinctions on California's Channel Islands  

Microsoft Academic Search

Explanations for the extinction of Late Quaternary megafauna are heavily debated, ranging from human overkill to climate change, disease and extraterrestrial impacts. Synthesis and analysis of Late Quaternary animal extinctions on California's Channel Islands suggest that, despite supporting Native American populations for some 13,000 years, few mammal, bird or other species are known to have gone extinct during the prehistoric

Torben C. Rick; Courtney A. Hofman; Todd J. Braje; Jesús E. Maldonado; T Scott Sillett; Kevin Danchisko; Jon M. Erlandson

2012-01-01

319

Diatoms from the Quaternary sediments of the Nile Delta, Egypt, and their palaeoecological significance  

Microsoft Academic Search

This study represents the first contribution describing diatom taxa from the Quaternary sediments of the Nile Delta, Egypt. A total of 99 diatom species and varieties belonging to 28 genera were identified. The palaeoecological conditions during the time of deposition (pH salinity, eutrophication and dissolved silica concentration) are discussed. Deposition of the Quaternary Nile Delta sediments occurred in slightly alkaline,

Abdelfattah A. Zalat

1995-01-01

320

Espizua, L. (2004). Pleistocene glaciations in the Mendoza Andes, Argentina. In Quaternary Glaciations Extent  

E-print Network

Quaternary glaciations of Ecuador, Peru and Bolivia. In Quaternary Glaciations ­ Extent and Chronology, Part III (J. Ehlers and P. Gibbard, Eds.), pp. 151­163. Elsevier. Meglioli, A. (1992). Glacial geology-Ar chronology of Pleistocene glaciations in Patagonia. Geological Society of America Bulletin 116, 434

Sheldon, Nathan D.

321

A comparison of lignin and stable carbon isotope compositions in quaternary marine sediments  

Microsoft Academic Search

Heges, J.I. and van Geen, A., 1982. A comparison of lignin and stable carbon isotope compositions in quaternary marine sediments. Mar. Chem., 11: 43--53. Organic matter in four Quaternary sediment cores from the Gulf of Mexico and one core from the Washington State coast have been analyzed for lignin and stable carbon isotope compositions. Holocene sequences of all five cores

JOHN I. HEDGES; ALEXANDER VAN GEEN

1982-01-01

322

Late Quaternary marginal marine deposits and palaeoenvironments from northeastern Buenos Aires Province, Argentina: A review  

Microsoft Academic Search

The late Quaternary marginal marine deposits along eastern Argentina (Southwestern Atlantic) are reviewed according to our present knowledge. In the northeastern coastal area of Buenos Aires Province they have been assigned to a series of transgressions and regressions ranging from the late Pliocene to the late Quaternary. The most widely accepted model is Frenguelli's (1957) classical chronostratigraphical scheme of: ‘Belgranense’,

M. L. Aguirre; R. C. Whatley

1995-01-01

323

Quaternary Addition Circuits Based on SUSLOC Voltage-Mode Cells and Modeling with SystemVerilog  

E-print Network

Quaternary Addition Circuits Based on SUSLOC Voltage-Mode Cells and Modeling with System] are modeled and used for our adder circuit structures. Several different adder configurations are designed offers efficient modeling capabilities to model and simulate large MVL circuits [3]. The quaternary

Thornton, Mitchell

324

Cholinesterase inhibitors from the roots of Harpagophytum procumbens.  

PubMed

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

2014-09-01

325

Morphological Change in Quaternary Mammals of North America  

NASA Astrophysics Data System (ADS)

This book examines case studies of North American Quaternary mammalian evolution within the larger domain of modern evolutionary theory. It presents previously unpublished studies of a variety of taxa (xenarthrans, rodents, carnivores, ungulates) examined over several temporal scales, from a few thousand years during the Holocene to millions of years of late Pliocene and Pleistocene time. Different organizational levels are represented, from mosaic population variation, to a synopsis of Quaternary evolution of an entire order (Rodentia). In addition to specific case histories, the book includes purely theoretical and methodological contributions, for example, on the statistical recognition of stasis in the fossil record, new ways to calculate evolutionary rates, and the use of digital image analysis in the study of dental ontogeny. Perhaps the most important aspect of the studies reported in this book is that they span the time between the "ecological moment" and "deep time". Modern taxa can be traced back into the fossil record, and variation among extant taxa can be used as a control against which variation in the extinct ones can be understood.

Martin, Robert A.; Barnosky, Anthony D.

1993-09-01

326

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.

1993-05-01

327

Late Quaternary sediment fluxes from tropical watersheds [review article  

NASA Astrophysics Data System (ADS)

Inherited saprolite stores and continued weathering in Quaternary time juxtapose abundant clay and fresh rock in tropical landscapes. This influences sediment fluxes and affects the interpretation of sediment sequences derived from tropical watersheds. Detrital kaolinites derive from inherited saprolite sources as well as from soil clays and appear in delta and ocean sediments. These sediments appear to correspond with sub-Milankovitch, millennial-scale cycles of climate change, but may also record century-scale episodes of rapid warming (Dansgaard-Oeschger events). Destabilisation of sediment sources and increased sediment fluxes in the Late Quaternary followed millennia of climatic deterioration (cooling/aridity) and vegetation change and led to altered patterns of sedimentation during the Last Glacial Maximum (LGM). Sediment yield from slopes increased 10× around the LGM, when rainfall was reduced by 30-60% and led to fan building and braided channels. Rainfall increased 40-80% from the LGM to the Early Holocene maximum and this led to channel cutting and major sediment fluxes to delta and ocean sinks. Vegetation recovery lagged the rapid warming by several millennia and was interrupted by (Younger Dryas) YD aridity, influencing slope and stream behaviour. Holocene sedimentation has been by both vertical and lateral accretion, increasing floodplain sediment stores.

Thomas, Michael F.

2003-11-01

328

Radiosensitization by quaternary salts of 5-nitroimidazole derivatives.  

PubMed

The radiosensitizing effects of five newly synthesized quaternary salts of 5-nitroimidazole derivatives on the survival of TC-SV40 mammalian cells have been measured. A toxicity study was carried out in order to determine the concentrations to be used in the radiosensitizing experiments. The oxygen enhancement ratio (OER) for TC-SV40 cells was 2.74. None of the five 5-nitroimidazole derivatives showed radiosensitizing activity in aerobic conditions, while in hypoxia their dose-modifying factors (DMF) at the concentration of 0.2 mmol dm-3 range from 1.52 to 1.03 in this order: unsubstituted pyridinium greater than carbamoyl pyridinium greater than trimethyl pyridinium greater than t-butyl pyridinium greater than imidazolium. This latter product at the concentration of 2 mmol dm-3 has a DMF of 1.64. As comparison, metronidazole was also tested on this cell line and its DMF at 0.2 mmol dm-3 was 1.35. The response-concentration dependences for the unsubstituted pyridinium 5-nitroimidazole derivative and for metronidazole (comparing charged and uncharged structures) showed the flattening response-concentration curve of quaternary compounds. The electron affinity was evaluated through the CNDO/S theoretical method, and an exponential relationship between these values and the DMFs of the pyridinium derivatives was demonstrated. PMID:2567335

Santos, L; Lopez Zumel, M C; Alvarez, M V; Izquierdo, M C

1989-06-01

329

Latest Quaternary stratigraphic framework of the Mississippi River delta region  

USGS Publications Warehouse

Previous researchers separated the uppermost Quaternary stratigraphy of the Mississippi River delta region into two major lithofacies. The stratigraphically lower of these, "substratum," primarily consists of coarse-grained sediment deposited within lowstand-incised stream valleys. Relatively finer-grained "topstratum" overlies substratum; above interfluves, topstratum directly overlies weathered late Pleistocene sediments. However, the onshore to offshore distribution and architecture of these lithofacies was not well constrained. This study integrates published and unpublished lithostratigraphic data with high-resolution seismic profiles from the continental shelf to aid in mapping the regional distribution of major substratum deposits and thickness of topstratum sediments. A transgressive sand sheet commonly marks the base of the topstratum deposits, providing a stratigraphic marker to aid in regional lithostratigraphic correlations. Radiocarbondated deposits and boreholes tied to oxygen isotope chronologies provide chronostratigraphic control. Excellent correlation between these multiple datasets has been found to exist, enabling construction of regional isopachous and structural elevation maps and cross sections detailing elements of the Late Quaternary stratigraphy.

Kulp, Mark; Howell, Paul; Adiau, Sandra; Penland, Shea; Kindinger, Jack; Williams, S. Jeffress

2002-01-01

330

ACHS Conference 2009 PROCEEDINGS  

E-print Network

, 1998). 2 A. Markus, `Labour and immigration 1946-9: the displaced persons program', Labour History 47 few immigrants from anywhere except Britain and Ireland. On a wave of "populate or perish" sentiment driven by the Japanese near-invasion five years earlier, it had its first Minister for Immigration

Franklin, James

331

Generalized Body Aches  

MedlinePLUS

... Schueler, MD How it Works Testimonials FAQ for Consumers FAQ for Physicians News Advertising Terms of Use Contact Us Site Map How ... yourself? About Stephen J. Schueler, M.D News Advertising How It Works FAQ for Consumers FAQ for Physicians Testimonials Site Map Terms of ...

332

Oooh, Your Aching Head!  

MedlinePLUS

... odors , such as perfume, smoke, fumes, or the smell of a new car or carpet, can start a headache. Some foods can cause headaches in some kids, such as bacon, bologna, and hot dogs. The caffeine in sodas, chocolate, coffee, and tea ...

333

Adapted J6/JFH1-Based Hepatitis C Virus Recombinants with Genotype-Specific NS4A Show Similar Efficacies against Lead Protease Inhibitors, Alpha Interferon, and a Putative NS4A Inhibitor  

PubMed Central

To facilitate studies of hepatitis C virus (HCV) NS4A, we aimed at developing J6/JFH1-based recombinants with genotype 1- to 7-specific NS4A proteins. We developed efficient culture systems expressing NS4A proteins of genotypes (isolates) 1a (H77 and TN), 1b (J4), 2a (J6), 4a (ED43), 5a (SA13), 6a (HK6a), and 7a (QC69), with peak infectivity titers of ?3.5 to 4.5 log10 focus-forming units per ml. Except for genotype 2a (J6), growth depended on adaptive mutations identified in long-term culture. Genotype 1a, 1b, and 4a recombinants were adapted by amino acid substitutions F772S (p7) and V1663A (NS4A), while 5a, 6a, and 7a recombinants required additional substitutions in the NS3 protease and/or NS4A. We demonstrated applicability of the developed recombinants for study of antivirals. Genotype 1 to 7 NS4A recombinants showed similar responses to the protease inhibitors telaprevir (VX-950), boceprevir (Sch503034), simeprevir (TMC435350), danoprevir (ITMN-191), and vaniprevir (MK-7009), to alpha interferon 2b, and to the putative NS4A inhibitor ACH-806. The efficacy of ACH-806 was lower than that of protease inhibitors and was not influenced by changes at amino acids 1042 and 1065 (in the NS3 protease), which have been suggested to mediate resistance to ACH-806 in replicons. Genotype 1a, 1b, and 2a recombinants showed viral spread under long-term treatment with ACH-806, without acquisition of resistance mutations in the NS3-NS4A region. Relatively high concentrations of ACH-806 inhibited viral assembly, but not replication, in a single-cycle production assay. The developed HCV culture systems will facilitate studies benefitting from expression of genotype-specific NS4A in a constant backbone in the context of the complete viral replication cycle, including functional studies and evaluations of the efficacy of antivirals. PMID:24060868

Gottwein, Judith M.; Jensen, Sanne B.; Serre, Stephanie B. N.; Ghanem, Lubna; Scheel, Troels K. H.; Jensen, Tanja B.; Krarup, Henrik; Uzcategui, Nathalie; Mikkelsen, Lotte S.

2013-01-01

334

[Tissue factor pathway inhibitors].  

PubMed

Activation of the extrinsic pathway of blood coagulation plays the key role in the process of blood coagulation. The hemostasis is influenced by the activity of procoagulant factors and its inhibitors. In this work we summarize existing data on tissue factor pathway inhibitors: TFPI and TFPI-2. Despite structural similarity between them, they exhibit many differences in synthesis, distribution and mechanism of action. TFPI inhibits the activity of factor Xa and the complex of tissue factor and factor VIIa (TF/VIIa). Conversely, TFPI-2 does not inhibits factor Xa, but it is a strong inhibitor of factor XIa, plasma kallikrein, plasmin and trypsin. PMID:12362512

Sierko, Ewa; Zawadzki, Roman J; Wojtukiewicz, Marek Z

2002-07-01

335

Curr. Med. Chem. Central Nervous System Agents, 2005, 5, 259-269 259 1568-0150/05 $50.00+.00 2005 Bentham Science Publishers Ltd.  

E-print Network

antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs, as well as other ACh of molecules: acetylcho- linesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase

Suslick, Kenneth S.

336

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

2009-01-01

337

Multiple lumbar transverse process stress fractures as a cause of chronic low back ache in a young fast bowler - a case report  

Microsoft Academic Search

A rare case of multilevel transverse process stress fractures as a cause of low back ache in a professional cricket player\\u000a has been presented. The report discusses the possible mechanism of such an injury in a cricket player and also highlights\\u000a the preventive and therapeutic aspects of management in such patients. The report also stresses upon the need for early

Kamal Bali; Vishal Kumar; Vibhu Krishnan; Dharm Meena; Saurabh Rawall

2011-01-01

338

Multiple lumbar transverse process stress fractures as a cause of chronic low back ache in a young fast bowler - a case report  

PubMed Central

A rare case of multilevel transverse process stress fractures as a cause of low back ache in a professional cricket player has been presented. The report discusses the possible mechanism of such an injury in a cricket player and also highlights the preventive and therapeutic aspects of management in such patients. The report also stresses upon the need for early identification of such sports related injuries to prevent long term morbidity in the athletes. PMID:21477351

2011-01-01

339

Multiple lumbar transverse process stress fractures as a cause of chronic low back ache in a young fast bowler - a case report.  

PubMed

A rare case of multilevel transverse process stress fractures as a cause of low back ache in a professional cricket player has been presented. The report discusses the possible mechanism of such an injury in a cricket player and also highlights the preventive and therapeutic aspects of management in such patients. The report also stresses upon the need for early identification of such sports related injuries to prevent long term morbidity in the athletes. PMID:21477351

Bali, Kamal; Kumar, Vishal; Krishnan, Vibhu; Meena, Dharm; Rawall, Saurabh

2011-01-01

340

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

Microsoft Academic Search

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

Qi Ding; Liping Wang; Litian Hu; Tianchang Hu; Yunfeng Wang; Yaonan Zhang

2011-01-01

341

Separation of a mixture of paraconic acids from Cetraria islandica (L.) Ach. employing a fluorous tag—catch and release strategy  

Microsoft Academic Search

A light-fluorous catch and release approach application has been designed to the separation of a mixture of three paraconic acids extracted from the Island moss (Cetraria islandica (L.) Ach.). The (+)-protolichesterinic acid was caught and released via a Michaël\\/retro-Michaël addition sequence with a fluorous thiol, while the resulting two other compounds were classically separated, allowing the isolation of (+)-roccellaric acid

David Horhant; Anne-Cécile Le Lamer; Joël Boustie; Philippe Uriac; Nicolas Gouault

2007-01-01

342

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

343

Tricks of perspective: insights and limitations to the study of macroscopic currents for the analysis of nAChR activation and desensitization.  

PubMed

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

2010-01-01

344

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

SciTech Connect

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

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

1997-08-01

345

Syntheses and structure-activity relationships in cytotoxicities of 13-substituted quaternary coptisine derivatives.  

PubMed

Twenty five 13-substituted quaternary coptisine derivatives were synthesized to test their cytotoxicities against several cancer cell-lines and on intestinal epithelial cell-6 (IEC-6) in vitro to evaluate structure-activity relationship (SAR). Introduction of the alkyl groups into the C-13 position of quaternary coptisine (1) led to significant increase of the cytotoxic activity, while the substitution of arylmethyl groups and others at the same position showed no effect on improving cytotoxicities against the same cancer cell-lines. The cytotoxicities of quaternary 13-alkylcoptisines was significantly reinforced as the length of the aliphatic chain increased, with quaternary 13-n-undecylcoptisine (4l) showing 7, 23, 12, and 9 times, respectively, more active than quaternary coptisine (1) against HCT, A549, Bel7402, and C33A, and being 4, 11, 2, and 3 times, respectively, more active than the positive control, fluorouracil (5-FU), against the same cell-lines, by IC50 values. In comparison to quaternary 13-n-undecylcoptisine (4l) and the above references, quaternary 13-n-dodecylcoptisine (4m) almost showed the same cytotoxicities. In contrast with the n-alkyl chains, the arylmethyl substituents at C-13 displayed low cytotoxicity, except for naphthyl rings or phenyl rings with CF3 or methyl substituents. However, their low cytotoxicity could make them useful as drug candidates for other diseases (bowel, etc). PMID:25203783

Zhang, Zhi-Hui; Deng, An-Jun; Wu, Lian-Qiu; Fang, Lian-Hua; Yu, Jin-Qian; Li, Zhi-Hong; Yuan, Tian-Yi; Wang, Wen-Jie; Du, Guan-Hua; Qin, Hai-Lin

2014-10-30

346

Effects of CH4 gas and substrate temperature on hydrogenated amorphous carbon (a-C:H) films fabricated using DC facing target sputtering  

NASA Astrophysics Data System (ADS)

Hydrogenated amorphous carbon (a-C:H) films were deposited on soda-lime glass substrates by using a DC facing target sputtering system. The effects of the CH4 gas and the substrate temperature on the deposition rate and the properties of the film were investigated. We found that the deposition rate of the film grown under an Ar-CH4 plasma was about three times larger than that of the film grown under an Ar plasma. The CH4 gas played a role as an additional carbon precursor to increase the deposition rate, which could be seen as a CH* peak at 431 nm in the optical emission spectra of the Ar-CH4 plasma. The sp 3 fraction in the film increased gradually from 32 to 37% as the substrate temperature was increased from 100 °C to 400 °C. The optical band-gap energy of the a-C:H films varied from 3.9 to 3.98 eV, and this variation was closely related to changes in the sp3 fraction. Overall, these results indicate that the addition of CH4 gas to a-C:H film deposition enhanced the deposition rate by changing the deposition mechanism from physical to reactive.

Bhak, JongGoo; Kim, Chan; Rhee, Ilsu; Kim, Hong Tak

2013-01-01

347

Drug-like leads for steric discrimination between substrate and inhibitors of human acetylcholinesterase.  

PubMed

Protection of the enzyme acetylcholinesterase (AChE) from the toxic effects of organophosphate insecticides and chemical warfare agents (OPs) may be provided by inhibitors that bind at the peripheral binding site (P-site) near the mouth of the active-site gorge. Compounds that bind to this site may selectively block access to the acylation site (A-site) catalytic serine for OPs, but not acetylcholine itself. To identify such compounds, we employed a virtual screening approach using AutoDock 4.2 and AutoDock Vina, confirmed using compounds experimentally known to bind specifically to either the A-site or P-site. Both programs demonstrated the ability to correctly predict the binding site. Virtual screening of the NCI Diversity Set II was conducted using the apo form of the enzyme, and with acetylcholine bound at the crystallographic locations in the A-site only and in both and A- and P-sites. The docking identified 32 compounds that were obtained for testing, and one was demonstrated to bind specifically to the P-site in an inhibitor competition assay. PMID:21668653

Wildman, Scott A; Zheng, Xiange; Sept, David; Auletta, Jeffrey T; Rosenberry, Terrone L; Marshall, Garland R

2011-10-01

348

New metal corrosion inhibitors  

Microsoft Academic Search

A new highly effective inhibitor has been developed, designated IKB-2-2, with improved handling properties. The IKB-2-2 gives 90-98% protection; the inhibitor remains fluid down to -45 C so that it can be used in any area of the country. IKB-2 has been successfully applied in commercial tests in crude oil distillation units, in oil fields and in atmospheric vacuum pipestills.

V. N. Umutbaev; V. V. Fryazinov; T. P. Kamalova; E. A. Sapozhnikova

1986-01-01

349

Expanded record of Quaternary oceanographic change: Amerasian Arctic Ocean  

USGS Publications Warehouse

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

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

1996-01-01

350

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

PubMed

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

2012-12-01

351

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.

2014-11-01

352

REFUGIA AND MIGRATION IN THE QUATERNARY HISTORY OF THE NEW ENGLAND FLORA  

E-print Network

REFUGIA AND MIGRATION IN THE QUATERNARY HISTORY OF THE NEW ENGLAND FLORA DAVID S. BARRINGTON, biogeography, genetic diversity, plant migration, refugia One of the prominent themes in the first century

Lintilhac, Philip M.

353

Enantioselective synthesis of benzazepinoindoles bearing trifluoromethylated quaternary stereocenters catalyzed by chiral spirocyclic phosphoric acids.  

PubMed

The first highly enantioselective iso-Pictet-Spengler reaction of C-2-linked o-aminobenzylindoles with trifluoromethyl ketones was developed using chiral spirocyclic phosphoric acids as organocatalysts, which afforded optically active benzazepinoindoles bearing trifluoromethylated quaternary stereocenters. PMID:24890313

Li, Xuejian; Chen, Di; Gu, Haorui; Lin, Xufeng

2014-07-18

354

A multiple quantum well integrated with a selectively grown quaternary layer  

NASA Astrophysics Data System (ADS)

The multiple quantum well is an important backbone to a number of advanced III-V optoelectronic devices. These include semiconductor lasers, detectors and modulators. Increased device functionality can be achieved by monolithically integrating a multiple quantum well with a selectively grown bulk quaternary. We report on a method for fabricating a selectively deposited quaternary film integrated with a multiple quantum well in an MOCVD reactor. Selective area epitaxy is known to cause a composition shift in the deposited quaternary. Quantitative modelling of the selective area epitaxy process is used to determine the nominal group-III composition required to deposit a quaternary film such that the peak strain induced by the composition shift is minimized. Measurements using spatially resolved photoluminescence and surface profiling are reported to demonstrate the validity and usefulness of the model.

Greenspan, J. E.; Campbell, S.; Shih, I.

2006-07-01

355

Quaternary Science Reviews 24 (2005) 23752391 Saginaw Lobe tunnel channels (Laurentide Ice Sheet) and  

E-print Network

Quaternary Science Reviews 24 (2005) 2375­2391 Saginaw Lobe tunnel channels (Laurentide Ice Sheet meltwater activity beneath the Saginaw Lobe of the Laurentide Ice Sheet. The channels are incompletely

Fisher, Timothy G.

356

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.

HAN,JUNG; FIGIEL,JEFFREY J.; PETERSEN,GARY A.; MYERS JR.,SAMUEL M.; CRAWFORD,MARY H.; BANAS,MICHAEL ANTHONY; HEARNE,SEAN JOSEPH

2000-01-18

357

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"

358

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

2004-01-01

359

THE NORWEGIAN–GREENLAND SEA CONTINENTAL MARGINS: MORPHOLOGY AND LATE QUATERNARY SEDIMENTARY PROCESSES AND ENVIRONMENT  

Microsoft Academic Search

The continental margins surrounding the Norwegian–Greenland Sea are to a large degree shaped by processes during the late Quaternary. The paper gives an overview of the morphology and the processes responsible for the formation of three main groups of morphological features: slides, trough mouth fans and channels.Several large late Quaternary slides have been identified on the eastern Norwegian–Greenland Sea continental

TORE O. VORREN; JAN SVERRE LABERG; FRANK BLAUME; JULIAN A. DOWDESWELL; NEIL H. KENYON; JÜRGEN MIENERT; JAN RUMOHR; FRIEDRICH WERNER

1998-01-01

360

Effect of alkyl quaternary ammonium on processing discoloration of melt-intercalated PVC-montmorillonite composites  

Microsoft Academic Search

The effects of alkyl quaternary ammonium on the processing thermal stability of poly (vinyl chloride)\\/alkyl quaternary ammonium modified montmorillonite (PVC\\/OMMT) composites were investigated. PVC\\/sodium montmorillonite (MMT) composites were prepared for comparison. The intercalated PVC\\/OMMT composites exhibited a non-terminal rheological behavior, and showed better mechanical properties and higher thermal degradation stability than the PVC\\/MMT composites. However, under identical melt processing conditions,

Chaoying Wan; Yong Zhang; Yinxi Zhang

2004-01-01

361

Catalytic performance of quaternary ammonium salts in the reaction of butyl glycidyl ether and carbon dioxide  

Microsoft Academic Search

The synthesis of cyclic carbonate from butyl glycidyl ether (BGE) and carbon dioxide was performed in the presence of quaternary ammonium salt catalysts. Quaternary ammonium salts of different alkyl group (C3, C4, C6 and C8) and anions (Cl?, Br? and I?) were used for this reaction carried out in a batch autoclave reactor at 60–120°C. The catalytic activity increased with

Hye-Young Ju; Mamparambath-Dharman Manju; Kyung-Hoon Kim; Sang-Wook Park; Dae-Won Park

2008-01-01

362

Synergistic chiral ion pair catalysts for asymmetric catalytic synthesis of quaternary ?,?-diamino acids.  

PubMed

The combination of a chiral phosphate anion with a silver ion has been demonstrated as a powerful and synergistic ion pair catalyst for the aza-Mannich reaction. A series of valuable quaternary ?,?-diamino acid derivatives was obtained in high yield, and with excellent diastereo- (up to 25:1 dr) and enantioselectivity (up to 99% ee). The adducts can be smoothly transformed into the corresponding protected chiral quaternary ?,?-diamino acids by a one-pot hydrolysis reaction. PMID:22472066

Shi, Shi-Hui; Huang, Fu-Ping; Zhu, Ping; Dong, Zhen-Wen; Hui, Xin-Ping

2012-04-20

363

Band Edge Energies and Band Gaps of Quaternary GaInAsSb Alloys  

Microsoft Academic Search

Quaternary alloys without a common atom such as (Ga,In)-(As,Sb) pose a difficult combinatorially design problem in that there are many different atomic configurations even when the system is constrained to be lattice-matched on a substrate. Using an atomistic pseudopotential approach we have calculated the band edge energies of this quaternary random alloys as a function of Ga\\/In (x) and As\\/Sb

Rita Magri; Alex Zunger; Herbert Kroemer

2007-01-01

364

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

2014-01-01

365

Acetylcholine Receptor (AChR) Clustering Is Regulated Both by Glycogen Synthase Kinase 3? (GSK3?)-dependent Phosphorylation and the Level of CLIP-associated Protein 2 (CLASP2) Mediating the Capture of Microtubule Plus-ends.  

PubMed

The postsynaptic apparatus of the neuromuscular junction (NMJ) traps and anchors acetylcholine receptors (AChRs) at high density at the synapse. We have previously shown that microtubule (MT) capture by CLASP2, a MT plus-end-tracking protein (+TIP), increases the size and receptor density of AChR clusters at the NMJ through the delivery of AChRs and that this is regulated by a pathway involving neuronal agrin and several postsynaptic kinases, including GSK3. Phosphorylation by GSK3 has been shown to cause CLASP2 dissociation from MT ends, and nine potential phosphorylation sites for GSK3 have been mapped on CLASP2. How CLASP2 phosphorylation regulates MT capture at the NMJ and how this controls the size of AChR clusters are not yet understood. To examine this, we used myotubes cultured on agrin patches that induce AChR clustering in a two-dimensional manner. We show that expression of a CLASP2 mutant, in which the nine GSK3 target serines are mutated to alanine (CLASP2-9XS/9XA) and are resistant to GSK3?-dependent phosphorylation, promotes MT capture at clusters and increases AChR cluster size, compared with myotubes that express similar levels of wild type CLASP2 or that are noninfected. Conversely, myotubes expressing a phosphomimetic form of CLASP2 (CLASP2-8XS/D) show enrichment of immobile mutant CLASP2 in clusters, but MT capture and AChR cluster size are reduced. Taken together, our data suggest that both GSK3?-dependent phosphorylation and the level of CLASP2 play a role in the maintenance of AChR cluster size through the regulated capture and release of MT plus-ends. PMID:25231989

Basu, Sreya; Sladecek, Stefan; Pemble, Hayley; Wittmann, Torsten; Slotman, Johan A; van Cappellen, Wiggert; Brenner, Hans-Rudolf; Galjart, Niels

2014-10-31

366

Using ACE inhibitors appropriately.  

PubMed

When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction. altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and nonfatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications. (Am Fam Physician 2002;66:473.) PMID:12182524

Bicket, Daphne P

2002-08-01

367

Direct thrombin inhibitors.  

PubMed

Direct thrombin inhibitors interact with thrombin and block its catalytic activity on a wide range of substrates. Their action is in contrast to heparin and its derivatives, which inhibit thrombin and other coagulation serine proteases via antithrombin, and to the warfarin-type drugs that interfere with synthesis of the precursors of the coagulation serine proteases. There are three direct thrombin inhibitors approved for clinical use at present (lepirudin, bivalirudin, argatroban) and another in advanced clinical testing (melagatran/ximelagatran). The chemical structure, kinetics of thrombin inhibition, pharmacokinetics, and clinical use of each of these agents are discussed. PMID:12124681

Kaplan, Karen L; Francis, Charles W

2002-07-01

368

The first trimester human trophoblast cell line ACH-3P: A novel tool to study autocrine/paracrine regulatory loops of human trophoblast subpopulations - TNF-? stimulates MMP15 expression  

PubMed Central

Background The trophoblast compartment of the placenta comprises various subpopulations with distinct functions. They interact among each other by secreted signals thus forming autocrine or paracrine regulatory loops. We established a first trimester trophoblast cell line (ACH-3P) by fusion of primary human first trimester trophoblasts (week 12 of gestation) with a human choriocarcinoma cell line (AC1-1). Results Expression of trophoblast markers (cytokeratin-7, integrins, matrix metalloproteinases), invasion abilities and transcriptome of ACH-3P closely resembled primary trophoblasts. Morphology, cytogenetics and doubling time was similar to the parental AC1-1 cells. The different subpopulations of trophoblasts e.g., villous and extravillous trophoblasts also exist in ACH-3P cells and can be immuno-separated by HLA-G surface expression. HLA-G positive ACH-3P display pseudopodia and a stronger expression of extravillous trophoblast markers. Higher expression of insulin-like growth factor II receptor and human chorionic gonadotropin represents the basis for the known autocrine stimulation of extravillous trophoblasts. Conclusion We conclude that ACH-3P represent a tool to investigate interaction of syngeneic trophoblast subpopulations. These cells are particularly suited for studies into autocrine and paracrine regulation of various aspects of trophoblast function. As an example a novel effect of TNF-? on matrix metalloproteinase 15 in HLA-G positive ACH-3P and explants was found. PMID:18093301

Hiden, Ursula; Wadsack, Christian; Prutsch, Nicole; Gauster, Martin; Weiss, Ursula; Frank, Hans-Georg; Schmitz, Ulrike; Fast-Hirsch, Christa; Hengstschlager, Markus; Potgens, Andy; Ruben, Angela; Knofler, Martin; Haslinger, Peter; Huppertz, Berthold; Bilban, Martin; Kaufmann, Peter; Desoye, Gernot

2007-01-01

369

Pliocene - Quaternary Faults and Potential Seismic Hazards in Southern Nevada  

NASA Astrophysics Data System (ADS)

Known Quaternary faults in the Central Basin & Range Province (CBR) have a southern limit at about 35 degrees 30' N latitude, south of Las Vegas, NV. The boundary is generally aligned with the southern end of the Sierra Nevada and strike-slip faults, such as those in Death Valley, that accommodate the right-lateral motion transferred from the plate boundary to east of the Sierra Nevada. Between ~8-4 Ma, the time range when the right-lateral motion was transferred to the east, CBR tectonism changed from rapid extension, low-angle normal faulting, and strike-slip faulting in the center to strike-slip faulting in the west and slower extension along normal faults in the middle and eastern CBR. Timing data from known <6-4 Ma CBR normal faults near the southern limit of Quaternary faulting show synchronicity with strike-slip faults in the southern Walker Lane and Eastern California shear zone on the west. Excellent examples of young faults in southern Nevada lie in Las Vegas basin and eastward to Mesquite. Our detailed stratigraphic and fault model of Las Vegas basin combined with shear-wave data shows significant ground shaking would occur there as a result of large magnitude earthquakes on almost any CBR fault. Faults in southern Nevada with documented Holocene activity include the normal-slip California Wash and Black Hills faults, and the strike-slip Mead Slope, Rock Valley, Pahrump Valley and Amargosa Valley faults / fault zones. The latter two faults aid in accommodating the step-over of some plate boundary slip from the San Andreas fault to faults east of the Sierra Nevada. Potential earthquake magnitudes for these faults range from ~M6.5-7.2 based on surface rupture lengths and documented single-event offsets. The <6-4 Ma central CBR faults appear to accommodate a change in shape of the rock volume between the strike-slip faults on the west and the Colorado Plateau to the east. We suggest that the shape change results from NW-motion of strike-slip fault blocks in the west and deformation on long segmented normal faults in the east.

Taylor, W. J.; Wagoner, J.; Depolo, C. M.; Luke, B.; Louie, J.

2005-12-01

370

Late Quaternary carbonate deposition at the bottom of the world  

NASA Astrophysics Data System (ADS)

Carbonate sediments on polar shelves hold great potential for improving understanding of climate and oceanography in regions of the globe that are particularly sensitive to global change. Such deposits have, however, not received much attention from sedimentologists and thus remain poorly understood. This study investigates the distribution, composition, diagenesis, and stratigraphic context of Late Quaternary calcareous sediments recovered in 15 piston cores from the Ross Sea shelf, Antarctica. Results are used to develop a depositional model for carbonate deposition on glaciated, polar shelves. The utility of the deposits as analogs for the ancient record is explored. In the Ross Sea, carbonate-rich lithofacies, consisting of poorly sorted skeletal sand and gravel, are concentrated in the west and along the outer reaches of the continental shelf and upper slope. Analysis of fossil assemblages shows that deposits were produced by numerous low-diversity benthic communities dominated locally by stylasterine hydrocorals, barnacles, or bryozoans. Radiocarbon dating indicates that carbonate sedimentation was episodic, corresponding to times of reduced siliciclastic deposition. Most accumulation occurred during a time of glacial expansion in the lead-up to the Last Glacial Maximum. A more recent interval of carbonate accumulation postdates the early Holocene sea level rise and the establishment of the modern grounding line for the Ross Ice Shelf. When carbonate factories were inactive, fossil debris was subjected to infestation by bioeroders, dissolution, fragmentation, and physical reworking. This study reveals the episodic nature of carbonate deposition in polar settings and a reciprocal relationship with processes that deliver and redistribute siliciclastic debris. Carbonate production is most active during colder periods of the glacial-interglacial cycle, a potential new sedimentological paradigm for polar carbonate systems. Low accumulation rates and long residence times on the seafloor leave sediments vulnerable to significant post-depositional modification, processes that profoundly affect the appearance of deposits as they enter the rock record. Comparison with other examples of polar carbonates highlights the utility of these Late Quaternary deposits as a well-constrained analog that can aid in the recognition and interpretation of similar deposits from the ancient record.

Frank, Tracy D.; James, Noel P.; Bone, Yvonne; Malcolm, Isabelle; Bobak, Lindsey E.

2014-05-01

371

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

PubMed

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

2014-10-01

372

Caspases and caspase inhibitors  

Microsoft Academic Search

Five years ago, little was known about mechanisms of apoptotic execution. Now, one class of cell-death gene, the cysteine aspartases (caspases) has come under intensive study. This review discusses the two classes of caspases, the reasons why humans may have so many caspase genes, the growing list of caspase substrates, and viral and pharmacological caspase inhibitors.

Pascal Villa; Scott H. Kaufmann; William C. Earnshaw

1997-01-01

373

Quaternary heteroaromatic salts with prophylactic and antidotal activity towards soman  

SciTech Connect

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

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

1993-05-13

374

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

SciTech Connect

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

Millings, V.T. III; Green, J.D.; Nusbaum, R.L. (Coll. of Charleston, SC (United States). Dept. of Geology)

1993-03-01

375

Antibacterial nanocomposite with calcium phosphate and quaternary ammonium.  

PubMed

Secondary caries is a frequent reason for restoration failure, resulting from acidogenic bacteria and their biofilms. The objectives of this study were to: (1) develop a novel nanocomposite containing nanoparticles of amorphous calcium phosphate (NACP) and quaternary ammonium dimethacrylate (QADM); and (2) investigate its mechanical and antibacterial durability. A spray-drying technique yielded NACP with particle size of 116 nm. The nanocomposite contained NACP and reinforcement glass fillers, with QADM in the resin. Two commercial composites were tested as controls. Composites were inoculated with Streptococcus mutans. After 180-day water-aging, NACP+QADM nanocomposite had flexural strength and elastic modulus matching those of commercial controls (p > 0.1). NACP+QADM nanocomposite reduced the biofilm colony-forming units (CFU) by 3-fold, compared with commercial composites (p < 0.05). Metabolic activity and lactic acid production of biofilms on NACP+QADM were much less than those on commercial composites (p < 0.05). The antibacterial properties of NACP+QADM were maintained after water-aging for 30, 90, and 180 d (p > 0.05). In conclusion, the novel NACP-QADM nanocomposite greatly decreased biofilm metabolic activity, CFU, and lactic acid, while matching the load-bearing capability of commercial composites without antibacterial properties. The NACP-QADM nanocomposite with strong and durable antibacterial properties, together with its previously reported Ca-PO(4) release capability, may render it useful for caries-inhibiting restorations. PMID:22403412

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

2012-05-01

376

Mucoadhesive nanoparticles made of thiolated quaternary chitosan crosslinked with hyaluronan.  

PubMed

Mucoadhesive polymeric nanoparticles intended for drug transport across the gastrointestinal mucosa were prepared from quaternary ammonium-chitosan conjugates synthesised from reduced-MW chitosan (32 kDa). Conjugates contained pendant moieties of 2-4 adjacent diethyl-dimethylene-ammonium groups substituted on repeating units (26-55%). Conjugates were thiolated via amide bonds with thioglycolic acid to yield products with thiol content in the 35-87 ?mol/g range. Nanoparticles with mean size in the 270-370 nm range and positive zeta-potential (+3.7 to +12.5 mV) resulted from ionotropic gelation of the thiolated conjugates with de-polymerised hyaluronic acid (470 kDa). The nanoparticles were fairly stable in size and thiol content and showed a significant mucoadhesivity, matching and even exceeding that of the constituent polymers. Nanoparticles were internalised by endothelial progenitor cells in direct relation to their surface charge intensity. Nanoparticle uptake significantly improved cell viability and resistance to oxidation. The lyophilised nanoparticles were re-dispersible and could make a manageable formulation for oral use. PMID:23218262

Zambito, Ylenia; Felice, Francesca; Fabiano, Angela; Di Stefano, Rossella; Di Colo, Giacomo

2013-01-30

377

Effects of Quaternary Ammonium Chain Length on Antibacterial Bonding Agents  

PubMed Central

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

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

2013-01-01

378

Antibacterial Nanocomposite with Calcium Phosphate and Quaternary Ammonium  

PubMed Central

Secondary caries is a frequent reason for restoration failure, resulting from acidogenic bacteria and their biofilms. The objectives of this study were to: (1) develop a novel nanocomposite containing nanoparticles of amorphous calcium phosphate (NACP) and quaternary ammonium dimethacrylate (QADM); and (2) investigate its mechanical and antibacterial durability. A spray-drying technique yielded NACP with particle size of 116 nm. The nanocomposite contained NACP and reinforcement glass fillers, with QADM in the resin. Two commercial composites were tested as controls. Composites were inoculated with Streptococcus mutans. After 180-day water-aging, NACP+QADM nanocomposite had flexural strength and elastic modulus matching those of commercial controls (p > 0.1). NACP+QADM nanocomposite reduced the biofilm colony-forming units (CFU) by 3-fold, compared with commercial composites (p < 0.05). Metabolic activity and lactic acid production of biofilms on NACP+QADM were much less than those on commercial composites (p < 0.05). The antibacterial properties of NACP+QADM were maintained after water-aging for 30, 90, and 180 d (p > 0.05). In conclusion, the novel NACP-QADM nanocomposite greatly decreased biofilm metabolic activity, CFU, and lactic acid, while matching the load-bearing capability of commercial composites without antibacterial properties. The NACP-QADM nanocomposite with strong and durable antibacterial properties, together with its previously reported Ca-PO4 release capability, may render it useful for caries-inhibiting restorations. PMID:22403412

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

2012-01-01

379

Facilitating Progress on the Quaternary History of Sea Level Change  

NASA Astrophysics Data System (ADS)

Understanding Future Sea Level Rise: The Challenges of Dating Past Interglacials; Woods Hole, Massachusetts, 20-25 September 2009; Substantial uncertainty exists in projections of future sea level rise, due primarily to a lack of understanding about ice sheet dynamics. Paleo Constraints on Sea Level Rise (PALSEA) is a working group of the Past Global Changes (PAGES) project and the International Marine Global Change Studies (IMAGES) program that aims to extract information about ice sheet response to temperature change by examining the history of sea level over the Quaternary (spanning the past ˜2.5 million years). In particular, PALSEA focuses on the past 800,000 years, particularly interglacial periods, with a range of temperatures bracketing the modern. PALSEA recently held a workshop at Woods Hole Oceanographic Institution (WHOI). Funded by IMAGES, PAGES, and WHOI's Ocean and Climate Change Institute, the workshop focused on challenges in uranium-thorium (U-Th) coral dating. The meeting also included a public outreach event, “Where land and sea meet: Managing shoreline change over the next 100 years,” funded by WHOI's Morss Colloquium.

Thompson, W. G.; Andersen, M. B.

2010-04-01

380

Effects of quaternary ammonium chain length on antibacterial bonding agents.  

PubMed

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

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

2013-10-01

381

A Quaternary volcanic ash deposit in western Missouri  

SciTech Connect

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

Emerson, J.W. (Central Missouri State Univ., Warrensburg, MO (United States))

1993-03-01

382

Enhanced adsorption of quaternary amine using modified activated carbon.  

PubMed

This study examined different methodologies to modify activated carbon (AC) for the removal of quaternary amine, tetramethylammonium hydroxide (TMAH), from water. Commercial carbon (WAC) was treated by nitric acid oxidation (NA-WAC), silica impregnation (SM-WAC0.5), and oxygen plasma (P10-WAC), and their characteristics and adsorption capacity were compared. The Langmuir model fitted the equilibrium adsorption data well under different pH. The maximum adsorption capacity of WAC was 27.77 mg/g, while those of NA-WAC, SM-WAC 0.5, and P10-WAC were 37.46, 32.83 and 29.03 mg/g, respectively. Nitric acid oxidation was the most effective method for enhancing the adsorption capacity of TMAH. Higher pH was favorable for TMAH adsorption. Desorption study revealed that NA-WAC had no considerable reduction in performance even after five cycles of regeneration by 0.1 N hydrochloric acid. It was proposed that electrostatic interaction was the main mechanism of TMAH adsorption on activated carbon. PMID:24845325

Prahas, Devarly; Wang, M J; Ismadji, Suryadi; Liu, J C

2014-01-01

383

Quaternary modulation formats for 100-Gbps optical links  

NASA Astrophysics Data System (ADS)

The demand for 100 Gb/s optical links is rapidly spreading across all levels of the optical networking infrastructure. Many of the first deployments will be in the local area network (LAN) and metro-core and regional network environments. To address needs in LAN, the upcoming IEEE standard (IEEE P802.3ba) seeks 100 Gb/s over distances up to 40km. Furthermore metro-core/regional dense wavelength division multiplexing (DWDM) architectures require reach of several hundred km and the ability to pass through ten or more ROADMs. However, a number of fundamental challenges remain including the selection of appropriate modulation formats that are robust to a variety of nonlinearities, are sufficiently spectrally efficient, and able to withstand the strong optical filtering of cascaded ROADMs. Here we compare a variety of single-carrier quaternary modulation formats, each providing 2 bits/symbol/polarization and each likely to provide some advantages at 100Gb/s. Each format is presented with an appropriate MZM-based transmitter, and constrained by practical signal fidelity limitations that also enable comparison to experimental results from our 100G testbed. We primarily examine direct detection for cost-sensitive metro networks; however we also quantify the performance of coherent receivers, where applicable. Simulation results demonstrate the relative OSNR penalty (at a pre-FEC BER of 10-3) for a range of launch powers and adjacent channel formats.

Detwiler, Thomas F.; Searcy, Steven M.; Lingle, Robert, Jr.; Basch, E. Bert; Ralph, Stephen E.

2010-01-01

384

Late Quaternary tephrostratigraphy of southern Chile and Argentina  

NASA Astrophysics Data System (ADS)

The Southern and Austral Volcanic Zones of the Andes comprise 74 volcanic centres with known post-glacial activity. At least 21 of these have had one or more large explosive eruptions in the late Quaternary, dispersing tephra over vast areas. These tephra layers therefore have great potential as tephrochronological marker horizons in palaeoenvironmental studies in southern Chile and Argentina, a region that is particularly useful to study climate dynamics of the southern hemisphere. However, to date tephrochronology has rarely been fully utilised in this region as a correlation and dating tool. Here we review the existing post-glacial tephrostratigraphic record of the Southern and Austral Volcanic Zones, and compile a database of known occurrences of tephra from these volcanoes in ice and lacustrine, marine, peat, and cave sediment records. We address the inconsistencies in and revisions of the tephrostratigraphies presented in prior literature, and discuss the challenges in correlating tephras and the limitations of the tephrostratigraphic record in this area. This study highlights the many gaps that still exist in our knowledge of the eruptive histories of these volcanoes, but also reveals the largely under-utilised potential of tephra as a correlation tool in this region. This is exemplified by the severe lack of adequate geochemical analysis of tephra layers preserved in many lacustrine and peat sediment sections, which are particularly important tephrostratigraphic records in southern Chile and Argentina due to the paucity of surface preservation.

Fontijn, Karen; Lachowycz, Stefan M.; Rawson, Harriet; Pyle, David M.; Mather, Tamsin A.; Naranjo, José A.; Moreno-Roa, Hugo

2014-04-01

385

Liquid chromatography of hydrocarbonaeous quaternary amines on cyclodextrin bonded silica  

USGS Publications Warehouse

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

Abidi, S. L.

1986-01-01

386

Effects of late quaternary climate change on Palearctic shrews.  

PubMed

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

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

2013-06-01

387

Regulated assembly and disassembly of the yeast telomerase quaternary complex.  

PubMed

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

Tucey, Timothy M; Lundblad, Victoria

2014-10-01

388

Quaternary glaciation of the Tashkurgan Valley, Southeast Pamir  

NASA Astrophysics Data System (ADS)

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

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

2012-07-01

389

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.

2014-01-01

390

Micropaleontologic record of late Pliocene and Quaternary paleoenvironments in the northern Albemarle Embayment, North Carolina, U.S.A  

Microsoft Academic Search

Micropaleontological data provide a strong actualistic basis for detailed interpretations of Quaternary paleoenvironmental change. The 90 m-thick Quaternary record of the Albemarle Embayment in the mid-Atlantic coastal plain of the USA provides an excellent opportunity to use such an approach in a region where the details of Quaternary environmental change are poorly known.The foraminiferal record in nine cores from the northern

Stephen J. Culver; Kathleen M. Farrell; David J. Mallinson; Benjamin P. Horton; Debra A. Willard; E. Robert Thieler; Stanley R. Riggs; Scott W. Snyder; John F. Wehmiller; Christopher E. Bernhardt; Caroline Hillier

2008-01-01

391

Angiotensin-Converting Enzyme Inhibitors  

Microsoft Academic Search

ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active

Nancy J. Brown; Douglas E. Vaughan

2010-01-01

392

Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model.  

PubMed

Our recent studies have indicated that acetylcholine (ACh) protects cardiomyocytes from prolonged hypoxia through activation of the PI3K/Akt/HIF-1alpha/VEGF pathway and that cardiomyocyte-derived VEGF promotes angiogenesis in a paracrine fashion. These results suggest that a cholinergic system plays a role in modulating angiogenesis. Therefore, we assessed the hypothesis that the cholinergic modulator donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, exhibits beneficial effects, especially on the acceleration of angiogenesis. We evaluated the effects of donepezil on angiogenic properties in vitro and in vivo, using an ischemic hindlimb model of alpha7 nicotinic receptor-deleted mice (alpha7 KO) and wild-type mice (WT). Donepezil activated angiogenic signals, i.e., HIF-1alpha and VEGF expression, and accelerated tube formation in human umbilical vein endothelial cells (HUVECs). ACh and nicotine upregulated signal transduction with acceleration of tube formation, suggesting that donepezil promotes a common angiogenesis pathway. Moreover, donepezil-treated WT exhibited rich capillaries with enhanced VEGF and PCNA endothelial expression, recovery from impaired tissue perfusion, prevention of ischemia-induced muscular atrophy with sustained surface skin temperature in the limb, and inhibition of apoptosis independent of the alpha7 receptor. Donepezil exerted comparably more effects in alpha7 KO in terms of angiogenesis, tissue perfusion, biochemical markers, and surface skin temperature. Donepezil concomitantly elevated VEGF expression in intracardiac endothelial cells of WT and alpha7 KO and further increased choline acetyltransferase (ChAT) protein expression, which is critical for ACh synthesis in endothelial cells. The present study concludes that donepezil can act as a therapeutic tool to accelerate angiogenesis in cardiovascular disease patients. PMID:19962381

Kakinuma, Yoshihiko; Furihata, Mutsuo; Akiyama, Tsuyoshi; Arikawa, Mikihiko; Handa, Takemi; Katare, Rajesh G; Sato, Takayuki

2010-04-01

393

Summary of Quaternary Stratigraphy and history, Eastern Canada  

NASA Astrophysics Data System (ADS)

Deposits of three Wisconsinan substages, Sangamonian Stage, and older Quaternary stratigraphic units are recognized in Eastern Canada. The age assignment of these units is based on radiocarbon dating and correlation of events. Quaternary deposits older than Sangamonian are recognized locally in Eastern Canada. In southern Ontario glacial deposits directly underlie Sangamonian sediments and are referred to as Illinoian in age. In other areas the ages of older sediments are largely unknown. Offshore core stratigraphy suggests that a major glaciation took place about 436 ka and that the Illinoian (oxygen isotope stage 6) was also a time of extensive glaciation. In this report Sangamonian is used as the name for the chronostratigraphic stage that includes all of deep-sea oxygen isotope stage 5 and consequently, on a regional basis, it includes warm interglacial deposits, glacial deposits and cool interglacial deposits. In southern Ontario the warm interglacial deposits are represented by the Don Formation, the stadial deposits by the Scarborough Formation and the cool interglacial deposits by the Pottery Road Formation. Warm interglacial deposits have not been recognized in Quebec (unless they are part of the pre-Johnville Sediments); the Bécancour Till is included as glacial Sangamonian sediments, and the St. Pierre Sediments are recognized as cool interglacial sediments. The Early Wisconsinan appears to have been the time of maximum Wisconsinan glaciation in Eastern Canada with ice moving south of the International Boundary and well out onto the continental shelf. The Middle Wisconsinan was primarily a nonglacial period in southern Ontario and a glacial stade elsewhere in Eastern Canada. In southern Ontario the Middle Wisconsinan record has been subdivided into two interstades (Port Talbot and Plum Point), separated by a stade (Cherrytree). The Port Talbot Interstade began before the limit of radiocarbon dating (before 48 ka) and ended about 40 ka; glacial or near glacial conditions of the Cherrytree Stage lasted from about 40 to 35 ka ago, and the Plum Point Interstade was from about 35 to 23 ka ago. Central St. Lawrence Lowland was occupied by ice throughout the Middle Wisconsinan, but southeastern Quebec and the Montreal area were briefly deglaciated. Scattered evidence in Atlantic Canada suggests local deglaciation of coastal areas during Middle Wisconsinan but extensive ice remained on the continental shelf and ice from centres located on the shelf flowed onto land in at least two areas. Glacial conditions predominated throughout Eastern Canada during the Late Wisconsinan. At the Late Wisconsinan maximum, through-moving ice deposited the Catfish Creek Drift in southern Ontario but ice lobes, which developed in the basins of the Great Lakes after 15.5 ka, controlled ice flow during a period of ice margin oscillation and retreat. A calving bay developed in lower St. Lawrence valley, after the Late Wisconsinan maximum, causing a reversal of flow on the south shore of the St. Lawrence and replacing ice in the valley with the Champlain Sea about 12 ka. Late Wisconsinan glaciers were largely limited to land areas in Atlantic Canada. Local ice caps dominated with complicated patterns of flow and retreat developing as centres of accumulation shifted and competing ice centres achieved dominance. The period of Late Wisconsinan retreat in Atlantic Canada appears to have lasted from about 14 to 10 ka.

Fulton, R. J.; Karrow, P. F.; LaSalle, P.; Grant, D. R.

394

Mapping the late Quaternary evolution of the lower Mississippi Valley  

NASA Astrophysics Data System (ADS)

The lower Mississippi Valley (LMV) extends from Cape Girardeau to Natchez and from Little Rock to Memphis. Extensive Quaternary terraces within the LMV have been considered to reflect downstream changes in base level (global sea level) and (or) upstream changes in water and sediment input because of glaciation. We suggest that the first-order control on terrace development was glacial-isostatic adjustment (GIA). Observed variation in heights of Quaternary alluvial surfaces at Memphis is 50 m (Rittenour et al., 2007). GIA modeling by Clark et al. (1994) predicted vertical displacement of as much as 130 m at Memphis over the last 18,000 years. ICE-5G models predict smaller displacement and reinforce the viability of GIA as the primary cause of LMV aggradation and incision. Existing analyses of LMV terraces are built on geomorphic maps by Saucier and colleagues (1974, 1994; Autin et al., 1991) that were interpreted from aerial photographs and inch-to-the-mile contour maps. Geomorphic mapping from high-resolution DEMs is more accurate, more rapid, and more reproducible than mapping from aerial photography and intermediate-resolution contours. Working from lidar DEMs (1-5 m XY resolution) and the 10 m National Elevation Dataset (NED) DEM largely derived from 1:24,000 scale contours, Haugerud is mapping the geomorphology of the LMV at ~1:500,000 scale. Goals are to explore the GIA-terrace hypothesis and improve the geomorphic and stratigraphic context for studies of New Madrid seismicity. Mapping leads to several observations: 1. The Holocene floodplain of the Mississippi River onlaps older surfaces. The river appears to be filling a hole created by collapse of the Laurentide forebulge. Continued filling of this accommodation space will, barring human intervention, enable the river to abandon its course through Thebes Gap in favor of a lower-elevation route through Oran Gap. 2. Within Holocene meander belts, younger levee crests are higher than older levee crests. The belts are aggrading, their substrates are compacting, or both. 3. Pleistocene braid plains step downward and merge downstream. Evidently there was up-to-the-north tilting as the braid plains formed. 4. Anomalous landforms suggest Holocene faulting or folding. Greater sinuosity and more-extensive wetlands along the St Francis River immediately upstream of Crowleys Ridge and pronounced incision where the river crosses the ridge indicate uplift of the ridge relative to the Western Lowlands. Unusual inset terraces along the L'Anguille River south of Forrest City, AR may record local uplift. Ten km southeast of Monroe, LA, N-S scarps dissect a meander belt; to the east, a subtle NE-SW scarp truncates braid plain. These are probably fault scarps. 5. Much of the LMV has been surveyed with lidar. Surveys have been at the behest of NRCS, FEMA, USACE, state agencies, and USGS-NEHRP. Improved coordination among survey efforts would reduce overlap and costs, could ease data access, and might lead to greater use of the data.

Haugerud, R. A.; Simon, K. M.; James, T. S.

2013-12-01

395

Alpha glucosidase inhibitors.  

PubMed

Alpha glucosidase inhibitors (AGIs) are a unique class of anti-diabetic drugs. Derived from bacteria, these oral drugs are enzyme inhibitors which do not have a pancreato -centred mechanism of action. Working to delay carbohydrate absorption in the gastrointestinal tract, they control postprandial hyperglycaemia and provide unquestioned cardiovascular benefit. Specially suited for a traditional Pakistani carbohydrate-rich diet, AGIs have been termed the 'untapped diamonds' of diabetology. The use of these oral antidiabetic drugs (OADs) that target pathophysiology in the early stages of type 2 diabetes, notably to reduce postprandial hyperglycaemia and hyperinsulinaemia will inevitably increase with time. This review describes the history of their development, mechanism of action, basic and clinical pharmacology, and suggests practical, evidence-based guidance for their optimal use. PMID:24864650

Kalra, Sanjay

2014-04-01

396

Gamma-irradiation synthesis of quaternary phosphonium cationic starch flocculants.  

PubMed

Quaternary phosphonium cationic starch (St-g-AM/ATPPB) flocculant was synthesized by using corn starch and acrylamide (AM), allyl triphenyl phosphonium bromide binary (ATPPB) through simultaneous gamma-irradiation. The chemical structure of the copolymer was characterized by FTIR (Fourier transform infrared spectroscopy) and (1)H NMR (nuclear magnetic resonance) technologies. The effects of the absorbed dose in the range of 1 to 6 kGy, AM/ATPPB ratio and starch/(AM + ATPPB) ratio on grafting and flocculation were investigated. At a starch:AM:ATPPB wt ratio of 1:1.4:0.93, the graft ratio of AM/ATPPB reached maximum values at 3 and 6 kGy, and the cationic degree of St-g-AM/ATPPB increased with absorbed dose, while the turbidity reduction reached a maximum value at 5 kGy. At 3 kGy using a starch:(AM + ATPPB) wt. ratio of 1:2.33, the graft ratio of AM and ATPPB increased with AM/ATPPB ratio, while the cationic degree and turbidity reduction reached maximum values at AM:ATPPB wt. ratios of 1:0.67 and 1:0.5, respectively. At a constant AM:ATPPB wt. ratio of 1:0.67 and 3 kGy, the grafting ratio increased with starch/(AM + ATPPB), while the cationic degree and turbidity reduction simultaneously reached maximum values at a starch:(AM + ATPPB) wt. ratio of 1:2.67. Further study revealed that the higher the absorbed dose or the lower the starch/(AM + ATPPB) ratio, the lower the optimal flocculant concentration. PMID:24185060

Song, Weiqiang; Zhao, Zhiwei; Zheng, Hongjuan; Wang, Gaimin

2013-01-01

397

Late Quaternary land-sea correlations, northern Labrador, Canada  

SciTech Connect

Late Quaternary glacial and postglacial units in the Torngat Mountains, northern Labrador, are correlated with units identified on the adjacent continental shelf. The late Wisconsinan Laurentide Ice Sheet drained through major valleys of the Torngat Mountains as outlet glaciers, depositing the Saglek Moraines. These are of regional extent and have been mapped from Saglek Fiord north to Noodleook Fiord. A C-14 date of 18,210 +/- 1900 BP on total organic matter (TOM) from lake sediment dammed by a segment of the Saglek Moraines is interpreted as a maximum date for deposition of the Saglek Moraine system because of possible contamination. Glacial sediments comprising the Saglek Moraines are correlated with upper till mapped in troughs and saddles on the continental shelf. Outlet glaciers depositing a late Wisconsinan unit flowed through Labrador fiords and onto the shelf at low basal shear stresses, particularly on the shelf where, although grounded, they were hydrostatically buoyed up and moved principally by sliding. A glaciomarine unit conformably overlies late Wisconsinan till on the shelf and on the land. This unit is a gravelly clayey silt, contains abundant foraminifera, and has up to 60% limestone in the pebble fraction. C-14 dates suggest deposition of this unit began ca. 10,000 BP on the shelf and 9000 BP on the land, an ended by 8000 BP. Limestone pebbles in this unit suggest a source in part from sediment-laden icebergs and pack-ice from the north. Marine deposition from ca. 8000-0 BP is characterize by basinal sedimentation.

Clark, P.; Josenhans, H.

1985-01-01

398

Quaternary landscape evolution of the Turkey River Valley, northeastern Iowa  

SciTech Connect

The Turkey River Valley, a major Mississippi tributary in northeastern Iowa, provides a more complete and accessible Quaternary record than the Upper Mississippi Valley. This project, using 3-dimensional reconstructions of both valley and upland deposits, revealed at least 13 important depositional, erosional, and soil-forming events. From oldest to youngest these events are: (1) deposition of pre-Illinoian till; (2) erosion of till and bedrock as the Turkey River cut down; (3) deposition of fluvial and colluvial sediments in the valley; (4) development of a Sangamon soil(s) on both the pre-Illinoian (upland) till and valley sediments; (5) truncation of the Sangamon soil(s) relatively high in the valley as bedrock entrenchment proceeded to its deepest point; (6) deposition of coarse fluvial and colluvial sediments in the valley prior to 32,000 yr. B.P.; (7) aggradation of mostly loess-derived alluvium until approximately 16,000 yr. B.P.; (8) large-scale colluviation between approximately 32,000 and 13,000 yr., B.P.; (9) major downcutting between 16,000 and 14,000 yr. B.P.; (10) aggradation of coarse to medium alluvium from approximately 14,000 to 13,000 yr. B.P.; (11) overall downcutting during several intervals of the late Wisconsinan and early Holocene; (12) aggradation of mid to late Holocene alluvium starting by 5000 yr. B.P.; (13) lateral erosion and deposition during the past 200 yr. B.P. Turkey River Valley deposits previously interpreted as pre-Illinoian are now recognized as late Wisconsinan or early Holocene, as indicated by /sup 14/C dates and molluscan fossils. The Paleozoic Plateau landform region (formerly part of the Driftless Area) is herein interpreted as a rugged, although complex, extension of the Iowan Erosion Surface.

Hudak, C.M.

1987-01-01

399

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

2009-01-01

400

Deformation and Quaternary Faulting in Southeast Missouri across the Commerce Geophysical Lineament  

USGS Publications Warehouse

High-resolution seismic-reflection data acquired at three sites along the surface projection of the Commerce geophysical lineament in southeast Missouri reveal a complex history of post-Cretaceous faulting that has continued into the Quaternary. Near Qulin, Missouri, approximately 20 m of apparent vertical fault displacement has occurred in the Quaternary. Reflection data collected at Idalia Hill, about 45 km to the northeast, reveal a series of reverse and possibly right-lateral strike-slip faults with Quaternary displacement. In the Benton Hills, 45 km northeast of Idalia Hill, seismic data image a complicated series of anticlinal and synclinal fault-bounded blocks immediately north of the Commerce fault. We infer that most of the deformation imaged in the upper 400 m of these three data sets occurred since post-Cretaceous time, and a significant portion of it occurred during Quaternary time. Collectively, these seismic data along with geomorphic and surface-geologic evidence suggest (1) the existence of at least one potential seismogenic structure in southeastern Missouri outside the main zones of New Madrid seismicity, and (2) these structures have been active during the Quaternary. The geographic location of the imaged deformation suggests it is related to structures along with the Commerce geophysical lineament.

Stephenson, W. J.; Odum, J. K.; Williams, R. A.; Pratt, T. L.; Harrison, R. W.; Hoffman, D.

1999-01-01

401

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.

2011-01-01

402

Classification of acetylcholinesterase inhibitors and decoys by a support vector machine.  

PubMed

Acetylcholinesterase has long been considered as a target for Alzheimer disease therapy. In this work, several classification models were built for the purpose of distinguishing acetylcholinesterase inhibitors (AChEIs) and decoys. Each molecule was initially represented by 211 ADRIANA.Code and 334 MOE descriptors. Correlation analysis, F-score and attribute selection methods in Weka were used to find the best reduced set of descriptors, respectively. Additionally, models were built using a Support Vector Machine and evaluated by 5-, 10-fold and leave-one-out cross-validation. The best model gave a Matthews Correlation Coefficient (MCC) of 0.99 and a prediction accuracy (Q) of 99.66% for the test set. The best model also gave good result on an external test set of 86 compounds (Q=96.51%, MCC=0.93). The descriptors selected by our models suggest that H-bond and hydrophobicity interactions are important for the classification of AChEIs and decoys. PMID:22263859

Wang, Kai; Hu, Xiaoying; Wang, Zhi; Yan, Aixia

2012-07-01

403

Droplet-based microfluidics for dose-response assay of enzyme inhibitors by electrochemical method.  

PubMed

A simple but robust droplet-based microfluidic system was developed for dose-response enzyme inhibition assay by combining concentration gradient generation method with electrochemical detection method. A slotted-vials array and a tapered tip capillary were used for reagents introduction and concentration gradient generation, and a polydimethylsiloxane (PDMS) microfluidic chip integrated with microelectrodes was used for droplet generation and electrochemical detection. Effects of oil flow rate and surfactant on electrochemical sensing were investigated. This system was validated by measuring dose-response curves of three types of acetylcholinesterase (AChE) inhibitors, including carbamate pesticide, organophosphorus pesticide, and therapeutic drugs regulating Alzheimer's disease. Carbaryl, chlorpyrifos, and tacrine were used as model analytes, respectively, and their IC50 (half maximal inhibitory concentration) values were determined. A whole enzyme inhibition assay was completed in 6 min, and the total consumption of reagents was less than 5 ?L. This microfluidic system is applicable to many biochemical reactions, such as drug screening and kinetic studies, as long as one of the reactants or products is electrochemically active. PMID:24016585

Gu, Shuqing; Lu, Youlan; Ding, Yaping; Li, Li; Zhang, Fenfen; Wu, Qingsheng

2013-09-24

404

The heat shock protein inhibitor KNK437 induces neurite outgrowth in PC12 cells.  

PubMed

The nervous system is highly sensitive to various environmental stresses, such as ischemia. Stress response mechanisms that result in neuroprotection, including the induction of heat shock proteins (HSP), are not well understood. We examined the effect of KNK437, a compound that inhibits the synthesis of inducible heat shock proteins, on neuronal differentiation in rat pheochromocytoma PC12 cells. KNK437 decreased the expression of HSP70, and induced the neurite outgrowth of PC12 cells in the absence of stress stimulation, although with lower efficacy than nerve growth factor (NGF). Neurite outgrowth stimulated by KNK437 and NGF was blocked by inhibitors of ERK mitogen-activated protein (MAP) kinase, p38 MAP kinase, and glycogen synthase kinase 3beta signaling pathways. NGF, and not KNK437, induced acetylcholine esterase (AChE) activity, a functional differentiation marker, indicating that KNK437 utilizes a mechanism distinct from that of NGF. KNK437 enhanced the activity of low dose NGF treatment on neurite outgrowth induction and ERK phosphorylation in PC12 cells, a finding that identifies KNK437 as a possible nerve regeneration agent. This compound may be a useful tool for the investigation of neuronal differentiation and neuroprotection against environmental stress. PMID:17055158

Koike, Tomoko; Uno, Shigeyuki; Ishizawa, Michiyasu; Takahashi, Hideo; Ikeda, Kazumasa; Yokota, Shinichi; Makishima, Makoto

2006-12-27

405

Characterisation of quaternary mixtures by the apparent content curves method: identification of tocopherols in vegetable oils.  

PubMed

A procedure for identification of the compounds in quaternary mixtures has been developed. The proposed procedure is based on the apparent content curves method. From these curves and using the Q parameter, work conditions are selected and quaternary mixtures treated as "pseudoternary" mixtures.A simple strategy to test matrix effects at working wavelengths has been developed, identification limits established and following the identification table quaternary mixtures were easily characterised. The procedure has been applied to the identification of phenols in mixtures by UV-visible spectrophotometry and tocopherols in edible oils by fluorimetry. Results obtained for edible oils are in agreement with the composition obtained by use of the reference method. PMID:12638048

Maurí-Aucejo, A R; Llobat-Estellés, M; Marín-Saez, R

2003-03-01

406