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1
MOREL, Nathalie, and Jean MASSOULIÉ. "Expression and processing of vertebrate acetylcholinesterase in the yeast Pichia pastoris." Biochemical Journal 328, no. 1 (November 15, 1997): 121–29. http://dx.doi.org/10.1042/bj3280121.
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In the methylotrophic yeast Pichia pastoris, we expressed the rat acetylcholinesterase H and T subunits (AChEH and AChET respectively), as well as truncated subunits from rat (W553stop or AChETΔ, from which most of the T-peptide was removed) and from Bungarus (V536stop, or AChENAT, or AChEΔ, reduced to the catalytic domain). We show that AChEH and AChET subunits are processed into the same molecular forms as in vivo or in transfected mammalian cells, but that lytic processes converting amphiphilic forms into non-amphiphilic derivatives appear to be more active in yeast. The production of glycophosphatidylinositol (GPI)-anchored molecules (dimers, with a small proportion of monomers) demonstrates that P. pastoris can correctly process a mammalian C-terminal GPI-addition signal. Truncated rat and Bungarus AChE molecules, which exclusively generated non-amphiphilic monomers, were released more efficiently and thus produced more AChE activity. In the hope of increasing the production of AChE, we replaced the endogenous signal peptide by yeast prepeptides, with or without a propeptide. We found that the presence of a propeptide, which does not exist in AChE, does not prevent the proper folding of the enzyme, and that it may either increase or decrease the yield of secreted AChE, depending on the signal peptide. Surprisingly, the highest yield was obtained with the endogenous signal peptide. For all combinations, the yield was 2-3 times higher for Bungarus than for rat AChE, probably reflecting differences in the folding efficiency or stability of the polypeptides. The Michaelis constant (Km), the constant of inhibition by excess substrate (Kss) and the catalytic constant (kcat) values of the recombinant AChEs obtained both in P. pastoris and in COS cells, were essentially identical with those of the corresponding natural enzymes, and the Ki values of active-site and peripheral-site inhibitors (edrophonium, decamethonium, propidium) were similar.
2
Hout, Michael. "The Statistical Analysis of Quasi-Experiments.Christopher H. Achen." American Journal of Sociology 95, no. 2 (September 1989): 468–70. http://dx.doi.org/10.1086/229285.
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King, Gary, and Curtis S. Signorino. "The Generalization in the Generalized Event Count Model, with Comments on Achen, Amato, and Londregan." Political Analysis 6 (1996): 225–52. http://dx.doi.org/10.1093/pan/6.1.225.
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We use an analogy with the normal distribution and linear regression to demonstrate the need for the Generalized Event Count (GEC) model. We then show how the GEC provides a unified framework within which to understand a diversity of distributions used to model event counts, and how to express the model in one simple equation. Finally, we address the points made by Christopher Achen, Timothy Amato, and John Londregan. Amato's and Londregan's arguments are consistent with ours and provide additional interesting information and explanations. Unfortunately, the foundation on which Achen built his paper turns out to be incorrect, rendering all his novel claims about the GEC false (or in some cases irrelevant).
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Batto, Nathan F. "The Taiwan Voter, edited by Christopher H. Achen and T.Y. Wang (2017)." International Journal of Taiwan Studies 3, no. 2 (August 20, 2020): 363–66. http://dx.doi.org/10.1163/24688800-00302010.
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Heersink, Boris, Brenton D. Peterson, and Jeffery A. Jenkins. "Disasters and Elections: Estimating the Net Effect of Damage and Relief in Historical Perspective." Political Analysis 25, no. 2 (April 2017): 260–68. http://dx.doi.org/10.1017/pan.2017.7.
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Do natural disasters help or hurt politicians’ electoral fortunes? Research on this question has produced conflicting results. Achen and Bartels (2002, 2016) find that voters punish incumbent politicians indiscriminately after such disasters. Other studies find that voters incorporate the quality of relief efforts by elected officials. We argue that results in this literature may be driven, in part, by a focus on contemporary cases of disaster and relief. In contrast, we study a case of catastrophic flooding in the American South in 1927, in which disaster aid was broadly and fairly distributed and Herbert Hoover (the 1928 Republican presidential candidate) was personally responsible for overseeing the relief efforts. Despite the distribution of unprecedented levels of disaster aid, we find that voters punished Hoover at the polls: in affected counties, Hoover’s vote share decreased by more than 10 percentage points. Our results are robust to the use of synthetic control methods and suggest that—even if voters distinguish between low- and high-quality responses—the aggregate effect of this disaster remains broadly negative. Our findings provide some support for Achen and Bartels’ idea of blind retrospection, but also generate questions about the precise mechanisms by which damage and relief affect vote choice.
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Achen, Marc, and Steven Stacker. "Editorial [Hot Topic:Targeting Tumor Stroma (Guest Editors: Marc G. Achen and Steven A. Stacker)]." Current Cancer Drug Targets 8, no. 6 (September 1, 2008): 446. http://dx.doi.org/10.2174/156800908785699397.
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Parvin, Phil. "Representing the People: British Democracy in an Age of Political Ignorance." Political Studies Review 16, no. 4 (March 14, 2018): 265–78. http://dx.doi.org/10.1177/1478929918758572.
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The article evaluates the arguments presented in Jason Brennan’s Against Democracy, Ilya Somin’s Democracy and Political Ignorance and Achen and Bartels’ Democracy for Realists and their implications for democratic theory and practice. The article uses their work to shine a light on ongoing and contradictory trajectories of democratic reform in Britain at the local and national levels, and to argue against the widespread view that British democracy should be reformed in ways that give citizens more control over political decisions. These books point to ways in which democracy might be salvaged, rather than replaced, and in which British democracy in particular might be reformed in order to better meet the challenges of the twenty-first century, by focusing less on participation and more on representation. This requires a two-pronged strategy. First, that we reform liberal democratic institutions in ways which better harness the power of non-majoritarian institutions, strengthen formal epistocratic checks and balances, and embrace the move towards greater political elitism in order to appropriately constrain the popular will and to ensure rigorous scrutiny within a traditionally configured representative democratic system. Second, that we explore ways of incorporating citizens’ voices at different points in the democratic system in order to circumvent some of the problems these authors describe and to ensure that the strengthening of representative institutions does not unfairly marginalise citizens. Achen CH and Bartels LM (2016) Democracy for Realists: Why Elections Do Not Produce Responsive Government. Princeton, NJ: Princeton University Press. Brennan J (2016) Against Democracy. Princeton, NJ: Princeton University Press. Somin I (2016) Democracy and Political Ignorance: Why Smaller Government Is Smarter, 2nd edn. Palo Alto, CA: Stanford University Press.
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Galston, William A. "Getting Real about Realism: Voters Are More Reasonable, and Democracies More Responsive, than Achen and Bartels Suggest." Critical Review 30, no. 1-2 (April 3, 2018): 57–70. http://dx.doi.org/10.1080/08913811.2018.1466853.
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Chen, Maohua, and Zhaojun Han. "Cloning and sequence analysis of 2 different acetylcholinesterase genes in Rhopalosiphum padi and Sitobion avenae." Genome 49, no. 3 (March 1, 2006): 239–43. http://dx.doi.org/10.1139/g05-104.
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Two genes encoding different acetylcholinesterases (AChE) were successfully cloned from 2 species of aphid, Rhopalosiphum padi (L.) and Sitobion avenae (F.). They were named Rp.AChE1 (GenBank accession No. AY707318), Rp.AChE2 (AY667435), Sa.AChE1 (AY707319), and Sa.AChE2 (AY819704), and were 2133, 2363, 2131, and 2362 bp in length and encoded 664, 676, 664, and 676 amino acids, respectively. All of them shared the characteristics of the AChE family: catalytic tiads, 3 intra-chain disulfide bridges, an acyl pocket, and the conservative aromatic residues for the active site of the gorge. Sequence analysis revealed that Rp.AChE1 and Sa.AChE1 showed higher identity to the reported orthologous genes of Drosophila AChE, and Rp.AChE2 and Sa.AChE2 to paralogous genes. However, in each of the aphids, the 2 genes from the same species shared only 29% identity between one another. It was therefore concluded that each of the aphids has 2 different AChE genes, which are either orthologous or paralogous to Drosophila AChE. The high conservation of AChE1 and AChE2 indicated that 2 acetylcholinesterases exist popularly and that both might function in aphids.Key words: Rhopalosiphum padi (L.), Sitobion avenae (F.), aphids, acetylcholinesterase.
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Li, Fei, and Zhao-Jun Han. "Two different genes encoding acetylcholinesterase existing in cotton aphid (Aphis gossypii)." Genome 45, no. 6 (December 1, 2002): 1134–41. http://dx.doi.org/10.1139/g02-085.
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Two acetylcholinesterase (AChE) genes, Ace1 and Ace2, have been cloned from cotton aphid, Aphis gossypii Glover, using the rapid amplification of cDNA ends (RACE) technique. To the best of our knowledge, this should be the first direct molecular evidence that multiple AChE genes exist in insects. The Ace1 gene was successfully amplified along its full length of 2371 bp. The open reading frame is 2031 bp long and encodes 676 amino acids (GenBank accession No. AF502082). The Ace2 gene was amplified as a mega-fragment of 2130 bp lacking part of 5'-end untranslated region (UTR). The open reading frame is 1992 bp long and ecodes a protein of 664 amino acids (GenBank accession No. AF502081). Both genes have the conserved amino acids and features shared by the AChE family, but share only 35% identity in amino acid sequence. The Ace1 gene is highly homologous to the AChE gene of Schizaphis graminum (AF321574) with 95% identity, and Ace2 to that of Myzus persicae (AF287291) with 92% identity. Phylogenetic analysis showed that the two cloned AChEs of A. gossypii are different in evolution. The phylogenetic tree generated by the PHYLIP program package inferred that AChE2 of A. gossypii is a more ancestral form of AChE. Homology modeling of structures using Torpedo californica (2ACE_) andDrosophila melanogaster (1Q09:A) native acetylcholinesterase structure as main template indicated that the two AChEs ofAphis gossypii might have different three-dimensional structures. Alternative splicing of Ace1 near the 5'-end resulting in two proteins differing by the presence or absence of a fragment of four amino acids is also reported.Key words: Aphis gossypii Glover, acetylcholinesterase, gene clone, homology modeling, alternative splicing, phylogenetic analysis.
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Roberts, Neil. "A Discussion of Christopher H. Achen and Larry M. Bartels'Democracy for Realists: Why Elections Do Not Produce Responsive Government." Perspectives on Politics 15, no. 1 (March 2017): 154–56. http://dx.doi.org/10.1017/s1537592716004242.
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Liberal democracy is often viewed by its supporters as a system of government that responds to the informed and rational preferences of the public organized as voters. And liberal democracy is often viewed by its critics as a system that fails to respond to the informed and rational preferences of its citizens. In this book Larry Bartels and Chris Achen draw on decades of research to argue that a “realistic” conception of democracy cannot be centered on the idea of a “rational voter,” and that the ills of contemporary democracies, and especially democracy in the U.S., must be sought in the dynamics that link voters, political parties and public policy in ways that reproduce inequality. “We believe,” write the authors, “that abandoning the folk theory of democracy is a prerequisite to both greater intellectual clarity and real political change. Too many democratic reformers have squandered their energy on misguided or quixotic ideas.”
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Schwennicke, Antje. "A Discussion of Christopher H. Achen and Larry M. Bartels' Democracy for Realists: Why Elections Do Not Produce Responsive Government." Perspectives on Politics 15, no. 1 (March 2017): 148–51. http://dx.doi.org/10.1017/s1537592716004229.
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Liberal democracy is often viewed by its supporters as a system of government that responds to the informed and rational preferences of the public organized as voters. And liberal democracy is often viewed by its critics as a system that fails to respond to the informed and rational preferences of its citizens. In this book Larry Bartels and Chris Achen draw on decades of research to argue that a “realistic” conception of democracy cannot be centered on the idea of a “rational voter,” and that the ills of contemporary democracies, and especially democracy in the U.S., must be sought in the dynamics that link voters, political parties and public policy in ways that reproduce inequality. “We believe,” write the authors, “that abandoning the folk theory of democracy is a prerequisite to both greater intellectual clarity and real political change. Too many democratic reformers have squandered their energy on misguided or quixotic ideas.”
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Cohen, Elizabeth F. "A Discussion of Christopher H. Achen and Larry M. Bartels Democracy for Realists: Why Elections Do Not Produce Responsive Government." Perspectives on Politics 15, no. 1 (March 2017): 152–53. http://dx.doi.org/10.1017/s1537592716004230.
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Liberal democracy is often viewed by its supporters as a system of government that responds to the informed and rational preferences of the public organized as voters. And liberal democracy is often viewed by its critics as a system that fails to respond to the informed and rational preferences of its citizens. In this book Larry Bartels and Chris Achen draw on decades of research to argue that a “realistic” conception of democracy cannot be centered on the idea of a “rational voter,” and that the ills of contemporary democracies, and especially democracy in the U.S., must be sought in the dynamics that link voters, political parties and public policy in ways that reproduce inequality. “We believe,” write the authors, “that abandoning the folk theory of democracy is a prerequisite to both greater intellectual clarity and real political change. Too many democratic reformers have squandered their energy on misguided or quixotic ideas.”
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Sabl, Andrew. "A Discussion of Christopher H. Achen and Larry M. Bartels' Democracy for Realists: Why Elections Do Not Produce Responsive Government." Perspectives on Politics 15, no. 1 (March 2017): 157–58. http://dx.doi.org/10.1017/s1537592716004254.
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Liberal democracy is often viewed by its supporters as a system of government that responds to the informed and rational preferences of the public organized as voters. And liberal democracy is often viewed by its critics as a system that fails to respond to the informed and rational preferences of its citizens. In this book Larry Bartels and Chris Achen draw on decades of research to argue that a “realistic” conception of democracy cannot be centered on the idea of a “rational voter,” and that the ills of contemporary democracies, and especially democracy in the U.S., must be sought in the dynamics that link voters, political parties and public policy in ways that reproduce inequality. “We believe,” write the authors, “that abandoning the folk theory of democracy is a prerequisite to both greater intellectual clarity and real political change. Too many democratic reformers have squandered their energy on misguided or quixotic ideas.”
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Mares, Isabela. "A Discussion of Christopher H. Achen and Larry M. Bartels' Democracy for Realists: Why Elections Do Not Produce Responsive Government." Perspectives on Politics 15, no. 1 (March 2017): 159–60. http://dx.doi.org/10.1017/s1537592716004266.
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Liberal democracy is often viewed by its supporters as a system of government that responds to the informed and rational preferences of the public organized as voters. And liberal democracy is often viewed by its critics as a system that fails to respond to the informed and rational preferences of its citizens. In this book Larry Bartels and Chris Achen draw on decades of research to argue that a “realistic” conception of democracy cannot be centered on the idea of a “rational voter,” and that the ills of contemporary democracies, and especially democracy in the U.S., must be sought in the dynamics that link voters, political parties and public policy in ways that reproduce inequality. “We believe,” write the authors, “that abandoning the folk theory of democracy is a prerequisite to both greater intellectual clarity and real political change. Too many democratic reformers have squandered their energy on misguided or quixotic ideas.”
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Brady, Henry E. "Cross-Level Inference. By Christopher H. Achen and W. Phillips Shively. Chicago: University of Chicago Press, 1995. 248p. $55.00." American Political Science Review 90, no. 2 (June 1996): 399–400. http://dx.doi.org/10.2307/2082893.
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Metaxas, Spiro. "Book Review: Christopher H Achen and Larry M Bartels, Democracy for Realists: Why Elections Do Not Produce Responsive Government." Political Studies Review 15, no. 3 (June 1, 2017): 437. http://dx.doi.org/10.1177/1478929917708110.
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Ohno, Kinji, Joan Brengman, Akira Tsujino, and Andrew G. Engel. "Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme." Proceedings of the National Academy of Sciences 95, no. 16 (August 4, 1998): 9654–59. http://dx.doi.org/10.1073/pnas.95.16.9654.
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In skeletal muscle, acetylcholinesterase (AChE) exists in homomeric globular forms of type T catalytic subunits (ACHET) and heteromeric asymmetric forms composed of 1, 2, or 3 tetrameric ACHET attached to a collagenic tail (ColQ). Asymmetric AChE is concentrated at the endplate (EP), where its collagenic tail anchors it into the basal lamina. The ACHET gene has been cloned in humans; COLQ cDNA has been cloned in Torpedo and rodents but not in humans. In a disabling congenital myasthenic syndrome, EP AChE deficiency (EAD), the normal asymmetric species of AChE are absent from muscle. EAD could stem from a defect that prevents binding of ColQ to ACHET or the insertion of ColQ into the basal lamina. In six EAD patients, we found no mutations in ACHET. We therefore cloned human COLQ cDNA, determined the genomic structure and chromosomal localization of COLQ, and then searched for mutations in this gene. We identified six recessive truncation mutations of COLQ in six patients. Coexpression of each COLQ mutant with wild-type ACHET in SV40-transformed monkey kidney fibroblast (COS) cells reveals that a mutation proximal to the ColQ attachment domain for ACHET prevents association of ColQ with ACHET; mutations distal to the attachment domain generate a mutant ≈10.5S species of AChE composed of one ACHET tetramer and a truncated ColQ strand. The ≈10.5S species lack part of the collagen domain and the entire C-terminal domain of ColQ, or they lack only the C-terminal domain, which is required for formation of the triple collagen helix, and this likely prevents their insertion into the basal lamina.
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Martinez-Pena y Valenzuela, Isabel, and Mohammed Akaaboune. "Acetylcholinesterase Mobility and Stability at the Neuromuscular Junction of Living Mice." Molecular Biology of the Cell 18, no. 8 (August 2007): 2904–11. http://dx.doi.org/10.1091/mbc.e07-02-0093.
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Acetylcholinesterase (AChE) is an enzyme that terminates acetylcholine neurotransmitter function at the synaptic cleft of cholinergic synapses. However, the mechanism by which AChE number and density are maintained at the synaptic cleft is poorly understood. In this work, we used fluorescence recovery after photobleaching, photo-unbinding, and quantitative fluorescence imaging to investigate the surface mobility and stability of AChE at the adult innervated neuromuscular junction of living mice. In wild-type synapses, we found that nonsynaptic (perisynaptic and extrasynaptic) AChEs are mobile and gradually recruited into synaptic sites and that most of the trapped AChEs come from the perijunctional pool. Selective labeling of a subset of synaptic AChEs within the synapse by using sequential unbinding and relabeling with different colors of streptavidin followed by time-lapse imaging showed that synaptic AChEs are nearly immobile. At neuromuscular junctions of mice deficient in α-dystrobrevin, a component of the dystrophin glycoprotein complex, we found that the density and distribution of synaptic AChEs are profoundly altered and that the loss rate of AChE significantly increased. These results demonstrate that nonsynaptic AChEs are mobile, whereas synaptic AChEs are more stable, and that α-dystrobrevin is important for controlling the density and stability of AChEs at neuromuscular synapses.
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Patterson, Leonard. "Youth Enfranchisement: A Case For A More Democratic Canada." Political Science Undergraduate Review 5, no. 1 (April 1, 2020): 34–37. http://dx.doi.org/10.29173/psur136.
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Despite granting its citizens universal suffrage, Canada continues to experience declining numbers in voter turnout (Achen, 2019). As fewer Canadians choose to participate in the electoral process, the very foundations of liberal democracy come into question as the legitimacy of a government elected by a dwindling number of supporters becomes increasingly unclear. While the topic of electoral reform is dominated by the debate over proportional representation versus the first-past-the-post system, this paper instead focuses on the legal voting age. I contend that lowering the voting age from 18 to 16 in Canada will create a more equitable, fair, and inclusive electoral system, thus strengthening fundamental democratic values. In this essay, I will discuss how the current system is unfairly excluding youth from participating in decisions that affect their future, why the argument for maintaining the current age is flawed, and how a lower voting age would increase political interest and create a more engaged electorate.
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George, Alexander L., and Richard Smoke. "Deterrence and Foreign Policy." World Politics 41, no. 2 (January 1989): 170–82. http://dx.doi.org/10.2307/2010406.
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Achen and Snidal's deductive theory of deterrence contributes very little to an understanding of the uses and limitations of deterrence strategy as an instrument of foreign policy. Lacking operationalization, their “rational deterrence theory” is incapable of predicting the outcome of individual cases. Furthermore, it has not yet addressed the need (i) to reconceptualize the problem of deterrence for different levels of conflict; (2) to refine the assumption of “rationality”; (3) to deal with the phenomenon of equifinality; (4) to develop a framework of strategic interaction between Initiator and Defender acknowledging that an Initiator often has multiple options for challenging the status quo from which to choose an action that meets his cost-benefit criteria; (5) to find a way of taking into account decision-making variables that, as case studies have demonstrated, often affect deterrence outcomes; and (6) to broaden the conceptualization of deterrence strategy to encompass the possible use of positive inducements as a means of discouraging challenges to a status quo situation.
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Wright, Gerald C. "A Discussion of Christopher H. Achen and Larry M. Bartels' Democracy for Realists: Why Elections Do Not Produce Responsive Government." Perspectives on Politics 15, no. 1 (March 2017): 161–62. http://dx.doi.org/10.1017/s1537592716004278.
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Maloy, J. S. "Book Review: Democracy for Realists: Why Elections Do Not Produce Responsive Government, by Christopher H. Achen & Larry M. Bartels." Political Theory 48, no. 2 (August 14, 2019): 255–60. http://dx.doi.org/10.1177/0090591719868432.
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MATTHEWS, J. B., O. LAZARI, A. J. DAVIDSON, S. WARREN, and M. E. SELKIRK. "A tryptophan amphiphilic tetramerization domain-containing acetylcholinesterase from the bovine lungworm, Dictyocaulus viviparus." Parasitology 133, no. 3 (May 24, 2006): 381–87. http://dx.doi.org/10.1017/s0031182006000345.
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Acetylcholine (ACh) is one of an array of neurotransmitters used by invertebrates and, analogous to vertebrate nervous systems, acetylcholinesterase (AChE) regulates synaptic levels of this transmitter. Similar to other invertebrates, nematodes possess several AChE genes. This is in contrast to vertebrates, which have a single AChE gene, transcripts of which are alternatively spliced to produce different types of the enzyme which vary at their C-termini. Parasitic nematodes have a repertoire of AChE genes which include those encoding neuromuscular AChEs and those genes which code for secreted AChEs. The latter proteins exist as soluble monomers released by the parasite during infection and these AChE are distinct from those enzymes which the nematodes use for synaptic transmission in their neuromuscular system. Thus far, Dictyocaulus viviparus is the only animal-parasitic nematode for which distinct genes that encode both neuromuscular and secreted AChEs have been defined. Here, we describe the isolation and characterization of a cDNA encoding a putative neuromuscular AChE from D. viviparus which contains a tryptophan amphiphilic tetramerization (WAT) domain at its C-terminus analogous to the common ‘tailed’ AChE form found in the neuromuscular systems of vertebrates and in the ACE-1 AChE from Caenorhabditis elegans. This enzyme differs from the previously isolated, D. viviparus neuromuscular AChE (Dv-ACE-2), which is a glycosylphosphatidylinositol-anchored variant analogous to vertebrate ‘hydrophobic’ AChE.
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Lewis-Beck, Michael S., and Andrew Skalaban. "The R-Squared: Some Straight Talk." Political Analysis 2 (1990): 153–71. http://dx.doi.org/10.1093/pan/2.1.153.
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In political science research these days, the R2 is out of fashion. A chorus of our best methodologists sounds notes of caution, at varying degrees of pitch. Berry and Feldman (1985, 15) remark in their popular regression monograph: “A researcher should be careful to recognize the limitations of R2 as a measure of goodness of fit.” In their more general statistics text, Hanushek and Jackson (1977, 59) claim that “one must be extremely cautious in interpreting the R2 value for an estimation and particularly in comparing R2 values for models that have been estimated with different data sets.” Perhaps the most pointed attack comes from Achen (1982, 61), who argues that the R2 “measures nothing of serious importance.” His contention is that it should be abandoned, and the standard error of the regression (SEE) substituted as a goodness-of-fit measure. Developing these lines of inquiry further, King (1986) provides the latest set of criticisms. Accordingly, “In most practical political science situations, it makes little sense to use [the R2]” (King 1986, 669). And, concerning the “proportion of variance explained” definition more particularly, “it is not clear how this interpretation adds meaning to political analyses.” (King 1986, 678).
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Wood, Eric, Stephen Dittmore, Sarah Stokowski, and Bo Li. "Division I Athletic Director Trends and Perceptions of Requisite Professional Skills." Journal of Higher Education Athletics & Innovation, no. 5 (July 3, 2019): 102–21. http://dx.doi.org/10.15763/issn.2376-5267.2018.1.5.102-121.
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Abstract
The focus of this study was to understand perceptions of National Collegiate Athletic Association (NCAA) Division I athletic director (ADs) skills and experiences and their relative importance to their current position. Division I ADs hold the highest position of authority in intercollegiate athletic departments at the highest level of competition in the NCAA (Swift, 2011). What once was seen as a job for retired coaches, has now transformed into a role that attracts some of the top executives both in and outside the sports industry (Belzer, 2015). Indeed, universities have begun to resemble a corporate culture, with ADs frequently considered to be CEOs of their department and the universities they serve (Hardin, Cooper & Huffman, 2013). Since much of the research on AD career paths has employed a content analysis methodology, examining biographies of ADs to establish patterns, (e.g., Fitzgerald, Sagaria, & Nelson, 1994; Hardin et al., 2013; Lumpkin, Achen & Hyland, 2015), the current study sought to understand ADs perceptions of requisite skills and experiences by directly surveying the group. Results indicate current ADs place a high emphasis on developing skills relative to revenue generation, fundraising and development, while considering internal experiences such as working with academic services and life skills not nearly as important.
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Rittenhofer, Iris. "Elisabeth Plum 2007. Kulturel Intelligens. In cooperation with Benedicte Achen, Inger Dræby and Iben Jensen. Copenhagen: Børsens Forlag. ISBN 978-87-7664-213-6." HERMES - Journal of Language and Communication in Business 22, no. 42 (August 30, 2017): 251. http://dx.doi.org/10.7146/hjlcb.v22i42.96855.
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Malhotra, Neil. "Democracy for Realists: Why Elections Do Not Produce Responsive Government. By Christopher H. Achen and Larry M. Bartels. Princeton, NJ: Princeton University Press, 2016." Journal of Politics 78, no. 4 (October 2016): E1—E2. http://dx.doi.org/10.1086/688172.
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Camacho, M., S. Alsford, and A. Agnew. "Molecular forms of tegumental and muscle acetylcholinesterases of Schistosoma." Parasitology 112, no. 2 (February 1996): 199–204. http://dx.doi.org/10.1017/s0031182000084766.
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SummaryAcetylcholinesterase (ACHE) is present in the muscle and on the tegument of schistosomes. Molecular forms of schistosome AChE were examined because particular AChEs are found in tissues of distinct function elsewhere. The dimeric globular form (G2) is the only form evident in adult Schistosoma haematobium: 32 % of the muscle AChE is hydrophilic and 61 % is membrane associated. A substantial amount of this enzyme is phosphatidylinositol (PI) anchored since it could be released by PI-specific phospholipase C from both muscle and tegumental membranes.
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Toublet, François-Xavier, Cédric Lecoutey, Julien Lalut, Bérénice Hatat, Audrey Davis, Marc Since, Sophie Corvaisier, et al. "Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease." Molecules 24, no. 15 (July 31, 2019): 2786. http://dx.doi.org/10.3390/molecules24152786.
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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
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Dos Santos, Adriana M., Ariele C. Moreira, Bianca Rebelo Lopes, Mariana F. Fracola, Fernando G. de Almeida, Odair C. Bueno, Quezia B. Cass, and Dulce Helena F. Souza. "Acetylcholinesterases from Leaf-Cutting antAtta sexdens: Purification, Characterization, and Capillary Reactors for On-Flow Assays." Enzyme Research 2019 (July 1, 2019): 1–9. http://dx.doi.org/10.1155/2019/6139863.
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Acetylcholinesterase (AChE) is responsible for catalyzing the hydrolysis of the neurotransmitter acetylcholine (ACh) leading to acetate and choline (Ch) release. The inhibition of AChE produces a generalized synaptic collapse that can lead to insect death. Herein we report for the first time the isolation of two AChEs fromAtta sexdenswhich were purified by sulphate ammonium precipitation followed by ion exchange chromatography. AsAChE-A and AsAChE-B enzymes have optimum pH of 9.5 and 9.0 and higher activities in 30/50°C and 20°C, respectively, using acetylthiocholine (ATCh) as substrate. Immobilized capillary enzyme reactors (ICERs) were obtained for both enzymes (AsAChE-A-ICER and AsAChE-B-ICER) and their activities were measured by LC-MS/MS through hydrolysis product quantification of the natural substrate ACh. The comparison of activities by LC-MS/MS of both AChEs using ACh as substrate showed that AsAChE-B (free or immobilized) had the highest affinity. The inverse result was observed when the colorimetric assay (Elman method) was used for ATCh as substrate. Moreover, by mass spectrometry and phylogenetic studies, AsAChE-A and AsAChE-B were classified as belonging to AChE-2 and AChE-1 classes, respectively.
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Incardona, J. P., and T. L. Rosenberry. "Construction and characterization of secreted and chimeric transmembrane forms of Drosophila acetylcholinesterase: a large truncation of the C-terminal signal peptide does not eliminate glycoinositol phospholipid anchoring." Molecular Biology of the Cell 7, no. 4 (April 1996): 595–611. http://dx.doi.org/10.1091/mbc.7.4.595.
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Despite advances in understanding the cell biology of glycoinositol phospholipid (GPI)-anchored proteins in cultured cells, the in vivo functions of GPI anchors have remained elusive. We have focused on Drosophila acetylcholinesterase (AChE) as a model GPI-anchored protein that can be manipulated in vivo with sophisticated genetic techniques. In Drosophila, AChE is found only as a GPI-anchored G2 form encoded by the Ace locus on the third chromosome. To pursue our goal of replacing wild-type GPI-anchored AChE with forms that have alternative anchor structures in transgenic files, we report the construction of two secreted forms of Drosophila AChE (SEC1 and SEC2) and a chimeric form (TM-AChE) anchored by the transmembrane and cytoplasmic domains of herpes simplex virus type 1 glycoprotein C. To confirm that the biochemical properties of these AChEs were unchanged from GPI-AChE except as predicted, we made stably transfected Drosophila Schneider Line 2(S2) cells expressing each of the four forms. TM-AChE, SEC1, and SEC2 had the same catalytic activity and quaternary structure as wild type. TM-AChE was expressed as an amphiphilic membrane-bound protein resistant to an enzyme that cleaves GPI-AChE (phosphatidylinositol-specific phospholipase C), and the same percentage of TM-AChE and GPI-AChE was on the cell surface according to immunofluorescence and pharmacological data. SEC1 and SEC2 were constructed by truncating the C-terminal signal peptide initially present in GPI-AChE: in SEC1 the last 25 residues of this 34-residue peptide were deleted while in SEC2 the last 29 were deleted. Both SEC1 and SEC2 were efficiently secreted and are very stable in culture medium; with one cloned SEC1-expressing line, AChE accumulated to as high as 100 mg/liter. Surprisingly, 5-10% of SEC1 was attached to a GPI anchor, but SEC2 showed no GPI anchoring. Since no differences in catalytic activity were observed among the four AChEs, and since the same percentage of GPI-AChE and TM-AChE were on the cell surface, we contend that in vivo experiments in which GPI-AChE is replaced can be interpreted solely on the basis of the altered anchoring domain.
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Villafaña, Jaime A., Giuseppe Marramà, Stefanie Klug, Jürgen Pollerspöck, Markus Balsberger, Marcelo Rivadeneira, and Jürgen Kriwet. "Sharks, rays and skates (Chondrichthyes, Elasmobranchii) from the Upper Marine Molasse (middle Burdigalian, early Miocene) of the Simssee area (Bavaria, Germany), with comments on palaeogeographic and ecological patterns." PalZ 94, no. 4 (June 2, 2020): 725–57. http://dx.doi.org/10.1007/s12542-020-00518-7.
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Abstract Elasmobranch remains are quite common in Miocene deposits and were the subject of numerous studies since the middle of the nineteenth century. Nevertheless, the taxonomic diversity of the Marine Molasse sharks, rays and skates is still largely unknown. Here, we describe 37 taxa from the lower Miocene of the Molasse Basin: 21 taxa could be identified at species level, whereas 15 taxa could only be assigned to genus and one taxon is left as order incertae sedis. The material was collected from deposits of the Auwiesholz Member of the Achen Formation (middle Burdigalian, middle Ottnangian age, ca. 17.8 Ma) exposed near Simssee, Upper Bavaria. This faunal assemblage is a mixture of shallow marine, near-coastal, pelagic and deep-water taxa. The fauna from Simssee displays different biogeographic dynamics at local and regional scales, possibly related to the intense climatic, oceanographic and tectonic events that occurred during the Eggenburgian–Ottnangian stages. The faunal relationships of the early Miocene chondrichthyan faunas from the Mediterranean Sea and Paratethys with others regions are established on the basis of qualitative (presence/absence) data. The beta diversity (Sørensen–Dice coefficient) of the Miocene Molasse elasmobranchs was used to characterize the taxonomic differentiation between localities and regions. According to our results, the fauna from Simssee shows close similarities with those from Switzerland, Austria, France and northern Germany. Faunal similarities and differences are mainly related to tectonic events and oceanographic variables (i.e. migration through seaway passages) or might represent collecting biases.
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Chen, Mao-hua, Zhao-jun Han, Xian-feng Qiao, and Ming-jing Qu. "Mutations in acetylcholinesterase genes of Rhopalosiphum padi resistant to organophosphate and carbamate insecticides." Genome 50, no. 2 (February 2007): 172–79. http://dx.doi.org/10.1139/g07-021.
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Apple grain aphid, Rhopalosiphum padi (Linnaeus), is an important wheat pest. In China, it has been reported that R. padi has developed high resistance to carbamate and organophosphate insecticides. Previous work cloned from this aphid 2 different genes encoding acetylcholinesterase (AChE), which is the target enzyme for carbamate and organophosphate insecticides, and its insensitive alteration has been proven to be an important mechanism for insecticide resistance in other insects. In this study, both resistant and susceptible strains of R, padi were developed, and their AChEs were compared to determine whether resistance resulted from this mechanism and whether these 2 genes both play a role in resistance. Bioassays showed that the resistant strain used was highly or moderately resistant to pirimicarb, omethoate, and monocrotophos (resistance ratio, 263.8, 53.8, and 17.5, respectively), and showed little resistance to deltamethrin or thiodicarb (resistance ratio, 5.2 and 3.4, respectively). Correspondingly, biochemistry analysis found that AChE from resistant aphids was very insensitive to the first 3 insecticides (I50 increased 43.0-, 15.2-, and 8.8-fold, respectively), but not to thiodicarb (I50 increased 1.1-fold). Enzyme kinetics tests showed that resistant and susceptible strains had different AChEs. Sequence analysis of the 2 AChE genes cloned from resistant and susceptible aphids revealed that 2 mutations in Ace2 and 1 in Ace1 were consistently associated with resistance. Mutation F368(290)L in Ace2 localized at the same position as a previously proven resistance mutation site in other insects. The other 2 mutations, S329(228)P in Ace1 and V435(356)A in Ace2, were also found to affect the enzyme structure. These findings indicate that resistance in this aphid is mainly the result of insensistive AChE alteration, that the 3 mutations found might contribute to resistance, and that the AChEs encoded by both genes could serve as targets of insecticides.
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Boschetti, N., U. Brodbeck, S. P. Jensen, C. Koch, and B. Nørgaard-Pedersen. "Monoclonal antibodies against a C-terminal peptide of human brain acetylcholinesterase distinguish between erythrocyte and brain acetylcholinesterases." Clinical Chemistry 42, no. 1 (January 1, 1996): 19–23. http://dx.doi.org/10.1093/clinchem/42.1.19.
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Abstract Monoclonal antibodies (mAbs) were raised against a peptide of the 10 C-terminal amino acids of human brain acetylcholinesterase (AChE): H-Tyr-Ser-Lys-Gln-Asp-Arg-Cys-Ser-Asp-Leu-OH. Two positive clones (mAbs 190-1 and 190-2) were selected and tested for their ability to distinguish between mammalian brain and erythrocyte AChEs. In a solid-phase enzyme antigen immunoassay as well as by Western- and dot-blot analysis, both antibodies showed clear binding to AChE from human and bovine brain but not to AChE from erythrocytes. MAbs 190-1 and 190-2 reacted with neither AChE from electric eel nor butyrylcholinesterase from human serum. Both antibodies were used in a quantitative assay for AChE in amniotic fluids, where AChE activity could be found only in samples from open neural tube-defect pregnancies, but not in fluids from normal pregnancies or in artificially blood-contaminated samples.
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Paris. "Reconciling Democratic Theories and Realities: A Review of Christopher H. Achen and Larry M. Bartels, Democracy for Realists: Why Elections Do Not Produce Responsive Government." Good Society 25, no. 1 (2017): 119. http://dx.doi.org/10.5325/goodsociety.25.1.0119.
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Camacho, M., R. Tarrab-Hazdai, B. Espinoza, R. Arnon, and A. Agnew. "The amount of acetylcholinesterase on the parasite surface reflects the differential sensitivity of schistosome species to metrifonate." Parasitology 108, no. 2 (February 1994): 153–60. http://dx.doi.org/10.1017/s0031182000068244.
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SUMMARYAcetylcholinesterase (AChE) is present in all stages of the life-cycle of schistosomes and is located in muscle and on the surface of the parasite. Metrifonate is a drug that inhibits AChE. We compared the AChEs from three schistosome species (Schistosoma mansoni, Schistosoma haematobium and Schistosoma bovis) that have different susceptibilities to metrifonate in vivo. Sensitivities to AChE inhibitors were similar. The subunits of AChE were 110 kDa and 76 kDa and the dominant molecular form of AChE was a G2 form in all three species. This was the major form on the tegument while additional molecular forms were associated with the internal tissues. Differences in relative amounts of AChE activity between these species were found in the adults but not in the schistosomula. At the adult stage the major difference between species lay in the relative amounts of AChE activity in their teguments. S. haematobium teguments carried 20 times and S. bovis 6·9 times the activity present on S. mansoni teguments. These quantitative differences associate with the relative sensitivities of these species to metrifonate.
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Hill, Jennifer L., and Hanspeter Kriesi. "Classification by Opinion-Changing Behavior: A Mixture Model Approach." Political Analysis 9, no. 4 (2001): 301–24. http://dx.doi.org/10.1093/oxfordjournals.pan.a004872.
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We illustrate the use of a class of statistical models, finite mixture models, that can be used to allow for differences in model parameterizations across groups, even in the absence of group labels. We also introduce a methodology for fitting these models, data augmentation. Neither finite mixture models nor data augmentation is routine in the world of political science methodology, but both are quite standard in the statistical literature. The techniques are applied to an investigation of the empirical support for a theory (developed fully by Hill and Kriesi 2001) that extends Converse's (1964) “black-and-white” model of response stability. Our model formulation enables us (1) to provide reliable estimates of the size of the two groups of individuals originally distinguished in this model, opinion holders and unstable opinion changers; (2) to examine the evidence for Converse's basic claim that these unstable changers truly exhibit nonattitudes; and (3) to estimate the size of a newly defined group, durable changers, whose members exhibit more stable opinion change. Our application uses survey data collected at four time points over nearly 2 years which track Swiss citizens' readiness to support pollution-reduction policies. The results, combined with flexible model checks, provide support for portions of Converse and Zaller's (1992) theories on response instability and appear to weaken the measurement-error arguments of Achen (1975) and others. This paper concentrates on modeling issues and serves as a companion paper to Hill and Kriesi (2001), which uses the same data set and model but focuses more on the details of the opinion-changing behavior debate.
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Virta, Jere R., Sari Laatu, Riitta Parkkola, Vesa Oikonen, Juha O. Rinne, and Juhani Ruutiainen. "Cerebral acetylcholinesterase activity is not decreased in MS patients with cognitive impairment." Multiple Sclerosis Journal 17, no. 8 (March 3, 2011): 931–38. http://dx.doi.org/10.1177/1352458511399613.
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Background: Neuropsychological studies have extensively described the presence of cognitive dysfunction in MS patients. One possible pharmacological treatment of the impairment could be based on acetylcholinesterase inhibitors (AChEIs), which have shown efficacy in alleviating cognitive impairment in many other disorders. The findings on the efficacy of AChEI medication in MS associated cognitive symptoms are preliminary and no studies concerning cerebral acetylcholinesterase (AChE) activity in these patients have been published. Objective: The objective of the study was to examine cerebral AChE activity in cognitively deteriorated MS patients. Cerebral AChE activity of 10 MS patients with secondary progressive disease and marked cognitive impairment, and 10 healthy controls, was studied with positron emission tomography using tracer 11C-MP4A. Methods: The cognitive profile of the patients was assessed with CERAD (Consortium to Establish a Registry for Alzheimer’s Disease). Results: No differences in cortical AChE activity between MS patients and controls were seen. Conclusions: In the patient group regional AChE activities had inverse correlations with Word learning and MMSE (Mini-Mental State Examination) scores. In the group of cognitively deteriorated MS patients no change in cerebral AChE activity, compared with controls, was observed, but within the patient group more pronounced cognitive symptoms were associated with higher cerebral AChE activity.
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Incardona, J. P., and T. L. Rosenberry. "Replacement of the glycoinositol phospholipid anchor of Drosophila acetylcholinesterase with a transmembrane domain does not alter sorting in neurons and epithelia but results in behavioral defects." Molecular Biology of the Cell 7, no. 4 (April 1996): 613–30. http://dx.doi.org/10.1091/mbc.7.4.613.
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Drosophila has a single glycoinositol phospholipid (GPI)-anchored form of acetylcholinesterase (AChE) encoded by the Ace locus. To assess the role that GPI plays in the physiology, of AChE, we have replaced the wild-type GPI-AChE with a chimeric transmembrane form (TM-AChE) in the nervous system of the fly. Ace null alleles provided a genetic background completely lacking in endogenous GPI-AChE, and Ace minigene P transposon constructs were used to express both GPI- and TM-AChE forms in the tissues where AChE is normally expressed. Control experiments with the GPI-AChE minigene demonstrated a threshold between 9 and 12% of normal AChE activity for adult viability. Ace mutant flies were rescued by GPI-AChE minigene lines that expressed 12-40% of normal activity and were essentially unchanged from wild-type flies in behavior. TM-AChE minigene lines were able to rescue Ace null alleles, although with a slightly higher threshold than that for GPI-AChE. Although rescued flies expressing GPI-AChE at a level of 12% of normal activity were viable, flies expressing 13-16% of normal activity from the TM-AChE transgene died shortly after eclosion. Flies expressing TM-AChE at about 30% of normal levels were essentially unchanged from wild-type flies in gross behavior but had a reduced lifespan secondary to subtle coordination defects. These flies also showed reduced locomotor activity and performed poorly in a grooming assay. However, light level and electron microscopic immunocytochemistry showed no differences in the localization of GPI- and TM-AChE. Furthermore, endogenous and ectopic-induced expression of both AChEs in epithelial tissues of the adult and embryo, respectively, showed that they were sorted identically. Most epithelial cells sorted GPI- and TM-AChE to the apical surface, but cuticle-secreting epithelia sorted both proteins basolaterally. Our data suggest that rather than having a primary role in protein sorting, the GPI anchor or AChE plays some other more subtle cellular role in neuronal physiology.
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Bowers, Jake, and Katherine W. Drake. "EDA for HLM: Visualization when Probabilistic Inference Fails." Political Analysis 13, no. 4 (2005): 301–26. http://dx.doi.org/10.1093/pan/mpi031.
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Nearly all hierarchical linear models presented to political science audiences are estimated using maximum likelihood under a repeated sampling interpretation of the results of hypothesis tests. Maximum likelihood estimators have excellent asymptotic properties but less than ideal small sample properties. Multilevel models common in political science have relatively large samples of units like individuals nested within relatively small samples of units like countries. Often these level-2 samples will be so small as to make inference about level-2 effects uninterpretable in the likelihood framework from which they were estimated. When analysts do not have enough data to make a compelling argument for repeated sampling based probabilistic inference, we show how visualization can be a useful way of allowing scientific progress to continue despite lack of fit between research design and asymptotic properties of maximum likelihood estimators.Somewhere along the line in the teaching of statistics in the social sciences, the importance of good judgment got lost amid the minutiae of null hypothesis testing. It is all right, indeed essential, to argue flexibly and in detail for a particular case when you use statistics. Data analysis should not be pointlessly formal. It should make an interesting claim; it should tell a story that an informed audience will care about, and it should do so by intelligent interpretation of appropriate evidence from empirical measurements or observations.—Abelson, 1995, p. 2With neither prior mathematical theory nor intensive prior investigation of the data, throwing half a dozen or more exogenous variables into a regression, probit, or novel maximum-likelihood estimator is pointless. No one knows how they are interrelated, and the high-dimensional parameter space will generate a shimmering pseudo-fit like a bright coat of paint on a boat's rotting hull.—Achen, 1999, p. 26
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Cohen, Ofer, Chanoch Kronman, Arie Lazar, Baruch Velan, and Avigdor Shafferman. "Controlled Concealment of Exposed Clearance and Immunogenic Domains by Site-specific Polyethylene Glycol Attachment to Acetylcholinesterase Hypolysine Mutants." Journal of Biological Chemistry 282, no. 49 (October 11, 2007): 35491–501. http://dx.doi.org/10.1074/jbc.m704785200.
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Cholinesterases are efficient scavengers of organophosphates and are currently being developed as drugs for treatment against poisoning by such compounds. Recombinant ChE bioscavengers have very short circular longevity, a limitation that can be overcome by complex post-translation manipulations or by chemical modification such as polyethylene glycol conjugation. Series of multiple Lys-Ala mutants of human acetylcholinesterase were prepared allowing the generation of homogenous and well defined polyethylene-glycol conjugated AChEs with either one, two, three, four, or five appended polyethylene glycol (PEG) moieties/molecule. The rank order of circulatory longevity of these molecules was dependent on the number of PEG appendages up to a certain threshold: 5 = 4 > 3 > 2 > 1 > 0. Hypolysine acetylcholinesterases (AChEs) carrying the same number of PEGs, and therefore with identical masses, allowed us to demonstrate that circulatory longevity correlates with the predicted extent of concealment of the AChE surface. Furthermore, circulatory profiles of high number and low number PEG-AChEs differing in their sialic acid contents demonstrate a direct relationship between PEG loading and the effective seclusion of AChE from the hepatic asialoglycoprotein receptor clearance system. Finally, an inverse relationship is found between the extent of PEG loading and the ability of the human acetylcholinesterase to elicit specific anti-HuAChE antibodies. In conclusion, these findings suggest that for the extension of circulatory longevity, protein surface domain concealment exerted by polyethylene glycol attachment is at least as important as its effect on size enlargement and highlights the role of PEG attachment in masking interactions between biomolecules and their cognate receptors.
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Wu, Wenhao, Xintong Liang, Guoquan Xie, Langdi Chen, Weixiong Liu, Guolin Luo, Peiquan Zhang, et al. "Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease." Molecules 23, no. 10 (October 5, 2018): 2540. http://dx.doi.org/10.3390/molecules23102540.
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A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 × 106; for 8r, IC50 BuChE/IC50 AChE = 1.32 × 107). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC50 values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.
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de Castro, Alexandre A., Letícia C. Assis, Flávia V. Soares, Kamil Kuca, Daniel A. Polisel, Elaine F. F. da Cunha, and Teodorico C. Ramalho. "Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)." Biomolecules 10, no. 3 (March 12, 2020): 436. http://dx.doi.org/10.3390/biom10030436.
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Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.
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Rosenberry, Terrone L. "Solvent Deuterium Oxide Isotope Effects on the Reactions of Organophosphorylated Acetylcholinesterase." Molecules 25, no. 19 (September 25, 2020): 4412. http://dx.doi.org/10.3390/molecules25194412.
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Organophosphates (OPs) are esters of substituted phosphates, phosphonates or phosphoramidates that react with acetylcholinesterase (AChE) by initially transferring the organophosphityl group to a serine residue in the enzyme active site, concomitant with loss of an alcohol or halide leaving group. With substituted phosphates, this transfer is followed by relatively slow hydrolysis of the organophosphoryl AChE, or dephosphorylation, that is often accompanied by an aging reaction that renders the enzyme irreversibly inactivated. Aging is a dealkylation that converts the phosphate triester to a diester. OPs are very effective AChE inhibitors and have been developed as insecticides and chemical warfare agents. We examined three reactions of two organophosphoryl AChEs, dimethyl- and diethylphosphorylated AChE, by comparing rate constants and solvent deuterium oxide isotope effects for hydrolysis, aging and oxime reactivation with pralidoxime (2-PAM). Our study was motivated (1) by a published x-ray crystal structure of diethylphosphorylated AChE, which showed severe distortion of the active site that was restored by the binding of pralidoxime, and (2) by published isotope effects for decarbamoylation that decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE. We previously reconciled these results by proposing a shift in the rate-limiting step from proton transfer for the small carbamoyl group to a likely conformational change in the distorted active site of the large carbamoyl enzyme. This proposal was tested but was not supported in this report. The smaller dimethylphosphoryl AChE and the larger diethylphosphoryl AChE gave similar isotope effects for both oxime reactivation and hydrolysis, and the isotope effect values of about two indicated that proton transfer was rate limiting for both reactions.
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HAJIMEHDIPOOR, HOMA, MAHMOUD MOSADDEGH, FARZANEH NAGHIBI, ALI HAERI, and MARYAM HAMZELOO-MOGHADAM. "Natural sesquiterpen lactones as acetylcholinesterase inhibitors." Anais da Academia Brasileira de Ciências 86, no. 2 (June 2014): 801–6. http://dx.doi.org/10.1590/0001-3765201420130005.
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Background and the purpose of the study: The amount of elder people who suffer from Alzheimer disease is continuously increasing every year. Cholinesterase inhibitors have shown to be effective in alleviating the symptoms of the disease, thus opening a field of research for these treatments. Herbal products, owning a reputation as effective agents in many biological studies are now drawing attention for inhibiting acetylcholinesterase, in other words, Alzheimer disease. In the present study, the ability of three sesquiterpene lactones from Inula oculus-christi and I. aucheriana to inhibit AChE has been evaluated through Ellman assay.Materials and Methods: Gaillardin and pulchellin C were obtained from I. oculus-christi and britannin from I. aucheriana by chromatographic methods. They were dissolved in methanol in concentration of 3 mg/mL and the AChEI activity of the compounds was determined by Ellman method using Acethylthiocholine iodide as the substrate and 5, 5′-dithiobis-2-nitrobenzoic acid as the reagent, in 96-well plates at 405 nm.Results: AChEI activity of the examined compounds was obtained as 67.0, 25.2 and 10.9% in concentration of 300 µg/L for gaillardin, britannin and pulchellin C, respectively.Conclusion: Among the three sesquiterpene lactones, gaillardin with 67% inhibition of AChE could be considered a good candidate for future Alzheimer studies.
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COHEN, Ofer, Chanoch KRONMAN, Baruch VELAN, and Avigdor SHAFFERMAN. "Amino acid domains control the circulatory residence time of primate acetylcholinesterases in rhesus macaques (Macaca mulatta)." Biochemical Journal 378, no. 1 (February 15, 2004): 117–28. http://dx.doi.org/10.1042/bj20031305.
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An array of 13 biochemically well defined molecular forms of bovine, human and newly cloned rhesus macaque (Macaca mulatta) AChEs (acetylcholinesterases) differing in glycosylation and subunit assembly status were subjected to comparative pharmacokinetic studies in mice and rhesus macaques. The circulatory lifetimes of recombinant bovine, macaque and human AChEs in mice were governed by previously determined hierarchical rules; the longest circulatory residence time was obtained when AChE was fully sialylated and tetramerized [Kronman, Chitlaru, Elhanany, Velan and Shafferman (2000) J. Biol. Chem. 275, 29488–29502; Chitlaru, Kronman, Velan and Shafferman (2001) Biochem. J. 354, 613–625]. In rhesus macaques, bovine molecular forms still obeyed the same hierarchical rules, whereas primate AChEs showed significant deviation from this behaviour. Residence times of human and rhesus AChEs were effectively extended by extensive sialylation, but subunit tetramerization and N-glycan addition had a marginal effect on their circulatory longevity in macaques. It appears that the major factor responsible for the differential pharmacokinetics of bovine and primate AChEs in macaques is related to differences in primary structure, suggesting the existence of a specific mechanism for the circulatory clearance of primate AChEs in rhesus macaques. The 35 amino acids that differ between bovine and primate AChEs are clustered within three defined domains, all located at the enzyme surface, and may therefore mediate the facilitated removal of primate cholinesterases specifically from the circulation of monkeys. These surface domains can be effectively masked by poly(ethylene glycol) appendage, resulting in the generation of chemically modified human and macaque AChEs that reside in the circulation for extraordinarily long periods of time (mean residence time of 10000 min). This extended residence time is similar to that displayed by native macaque butyrylcholinesterase (9950 min), which is the prevalent cholinesterase form in the circulation of adult macaques.
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Ali-Shtayeh, Mohammed Saleem, Rana Majed Jamous, Salam Yousef Abu Zaitoun, and Iman Basem Qasem. "In-vitro screening of acetylcholinesterase inhibitory activity of extracts from Palestinian indigenous flora in relation to the treatment of Alzheimer’s disease." Functional Foods in Health and Disease 4, no. 9 (September 1, 2014): 381. http://dx.doi.org/10.31989/ffhd.v4i9.149.
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Background: Cholinesterase inhibitory therapy serves as a strategy for the treatment of Alzheimer’s disease (AD). Several acetylcholinesterase inhibitors (AChEIs) are used for the symptomatic treatment of AD. These compounds have been reported to have adverse effects, including gastrointestinal disturbances. This study was therefore partly aimed at investigating in vitro possible AChEIs in herbal medicines traditionally used in Palestine to treat cognitive disorders, and to point out the role of these plants as potential sources for development of newly potent and safe natural therapeutic agents of AD. Assay of AChE activity plays an important role in vitro characterization of drugs including potential treatments for AD. The most widely used method, is based on Ellman’s method. The reactant used in this method shows chemical reactivity with oxime antidots and thiol leading to false positive reactions. A new alternative assay could be of high interest.Methods: The effect on AChE activity of 92 extracts of 47 medicinal plants were evaluated using a new micro-well plate AChE activity (NA-FB) and Ellman’s assays. In addition, antioxidant activity using DPPH was determined.Results: The main advantages of the new method (NA-FB) is that the colorimetric change is better observable visually allowing spectrophotometric as well as colorimetric assay, and does not show any chemical reactivity with thiol. 67.4% and 37% of extracts inhibited AChE by >50% using the NA-FB and Ellman’s assays, respectively. Using NA-FB assay, 84 extracts interacted reversibly with the enzyme, of which Mentha spicata (94.8%), Foeniculum vulgare (89.81), and Oxalis pes-caprae (89.21) were most potent, and 8 showed irreversible inhibition of which leaves of Lupinus pilosus (92.02%) were most active. Antioxidant activity was demonstrated by 73 extracts Majorana syriaca (IC50 0.21mg/ml), and Rosmarinus officinalis (0.38) were the most active.Conclusions: NA-FB assay has shown to be simple, accurate, sensitive, spectrophotometric and colorimetric, and superior to Ellman’s, and therefore can be used efficiently for qualitative and quantitative studies of AChEI activities of extracts. Palestinian flora have shown to be a rich source for, new and promising agents (AChEIs) for the treatment of AD Further studies are needed to isolate and identify the active compounds responsible for AChEI activities.Keywords: Alzheimer's disease, ACh, medicinal plants, β-naphthyl acetate, micro-well plate AChE activity Assay (NA-FB)
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Amat-ur-Rasool, Hafsa, Mehboob Ahmed, Shahida Hasnain, and Wayne G. Carter. "Anti-Cholinesterase Combination Drug Therapy as a Potential Treatment for Alzheimer’s Disease." Brain Sciences 11, no. 2 (February 2, 2021): 184. http://dx.doi.org/10.3390/brainsci11020184.
Full textAbstract:
Alzheimer’s disease (AD) is a burgeoning social and healthcare problem. Cholinesterase inhibitors (ChEIs) are employed for symptomatic treatment of AD, but often elicit adverse drug reactions (ADRs). Herein, the potency of the ChEIs, donepezil, tacrine, berberine, and galantamine to inhibit human or Torpedo californica acetylcholinesterase (tcAChE) proteins were evaluated. The efficacy of dual-drug combinations to inhibit human AChE directly and within differentiated neurons was also quantified. ChEI potency was in the order: donepezil > tacrine > berberine > galantamine for both AChEs. Dual-drug combinations of berberine and tacrine (BerTac), berberine and galantamine (BerGal), and tacrine and donepezil (TacDon) all produced synergistic outcomes for AChE inhibition. Donepezil and berberine (DonBer) and tacrine and galantamine (TacGal) elicited antagonistic responses. Donepezil and galantamine (DonGal) was synergistic for human AChE but antagonistic for tcAChE. After application of dual-drug combinations to neuronal cells, BerTac, BerGal, DonGal, and DonBer all showed synergistic inhibition of AChE, TacDon additive, and TacGal antagonistic effects. BerGal produced the most potent synergism and reduced total drug dose by 72%. Individual ChEIs or dual-drug combinations were relatively non-toxic to neuronal cells, and only reduced cell viability at concentrations two–three orders of magnitude greater than that required to inhibit AChE. In summary, dual-drug combinations of ChEIs potentially represent a novel means of AD patient treatment, with reduced and more cost-effective drug dosing, and lowered likelihood of ADRs.
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Purushothaman, Yasodha, Silambarasan Gunaseelan, and Sudarshana Deepa Vijayakumar. "SPILANTHES ACMELLA AND ITS MEDICINAL USES – A REVIEW." Asian Journal of Pharmaceutical and Clinical Research 11, no. 6 (June 7, 2018): 45. http://dx.doi.org/10.22159/ajpcr.2018.v11i6.24697.
Full textAbstract:
ABSTRACT In common plant life has been recognized to alleviate various diseases. Spilanthes acmella- a vital native medicinal plant, is also found in sub continent of America. A range of abstracts and active metabolites from different parts of this plant is found to contain valuable pharmacological activities. Traditionally recognized as tooth ache plant, it is known to suppress the ailment allied with tooth aches and is found to stimulate saliva secretion. On Survey of literatures it has been projected that, it has numerous drug related actions, which comprises of antimicrobial, antipyretic, local anaesthetic, bioinsecticide against insects of agricultural importance, antioxidant, analgesic, antimicrobial, vasorelaxant, anti-human immune deficit virus, tooth ache relief and anti-inflammatory effects. Based on the traditional claims against a range of diseases, researchers have classified and estimated plants for their bioactive compounds. However researchers found it to be a difficult task for the extraction of bioactive constituents from these plants. Therefore the scientific information about Spilanthes acmella could be obtained from this current review.