Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
8,682
result(s) for
"George, Andrew A."
Sort by:
Superelectrophiles and their chemistry
Superelectrophiles and Their Chemistry contains, for the first-time, a discussion of the basics of this emerging field of organic chemistry, alongside tools to help the reader apply the chemistry. Specific tools include an evaluation of the ways to increase the strength of electrophiles, the classification of superelectrophiles, the solvation issues, a review of methods for studying superelectrophilicity, with details of the superelectrophiles that have been identified and studied. Additional information includes substituent effects in activation of superelectrophiles, and solvation in chemical reactions, as well as an insightful look into future applications.
eBook
Beyond oil and gas : the methanol economy
Examining the major challenges of future energy and environmental problems, this work discusses in a clear and accessible manner, the use of methanol as a viable alternative to dangerous and dwindling energy resources.
Book
Sleep-related hypermotor epilepsy associated mutations uncover important kinetic roles of α4β2- nicotinic acetylcholine receptor intracellular structures
Sleep-related hypermotor epilepsy (SHE) is a group of seizure disorders prominently associated with mutations in nicotinic acetylcholine receptors (nAChR). The most prevalent central nervous system nAChR subtype contains α4 and β2 subunits, in two ratios. (α4β2) 2 β2-nAChR have high agonist sensitivity (HS-isoform), whereas (α4β2) 2 α4-nAChR agonist responses exhibit a small high-sensitivity, and a predominant low-sensitivity, phase of function (LS-isoform). Multiple non-synonymous mutations in the second and third transmembrane domains of α4 and β2 subunits are associated with SHE. We recently demonstrated that two additional, SHE-associated, missense mutations in the major cytoplasmic loops of these subunits [α4(R336H) and β2(V337G)] cause increased macroscopic function-per receptor. Here, we use single-channel patch-clamp electrophysiology to show that these mutations influence single-channel amplitudes and open- and closed-state kinetics. Pure populations of HS- or LS-isoform α4β2-nAChR were expressed by injecting either 1:10 or 30:1 α4:β2 cRNA ratios, respectively, into Xenopus laevis oocytes. Functional properties of the resulting mutant α4β2-nAChR isoforms were compared to their wildtype counterparts. α4(R336H) subunit incorporation minimally affected single-channel amplitudes, whereas β2(V337G) subunit incorporation reduced them significantly in both isoforms. However, for both mutant subunits, increased function-per-receptor was predominantly caused by altered single channel kinetics. The α4(R336H) mutation primarily destabilizes desensitized states between openings. By contrast, the β2(V337G) mutation principally stabilizes receptor open states. The use of naturally-occurring and physiologically-impactful mutations has allowed us to define valuable new insights regarding the functional roles of nAChR intracellular domains. Further mechanistic context is provided by intracellular-domain structures recently published for other members of the Cys-loop receptor superfamily (α3β4-nAChR and 5-HT 3A R).
Journal Article
The George Bell-Gerhard Leibholz correspondence : in the long shadow of the Third Reich, 1938-1958
George Bell was one of the most significant British church leaders of the mid-20th century and in many ways he came to define the involvement of British church people with the issues which arose from the Third Reich. 'The George Bell-Gerhard Leibholz Correspondence' presents the extensive correspondence between George Bell and Gerhard Leibholz, the brother-in-law of Dietrich Bonhoeffer and one of the most senior German lawyers of the period. The two figures encountered each other in the context of dictatorship, exile and political intervention and together they fashioned a vigorous moral response to the crises of Nazism, Soviet communism, total war and cold war.
Book
A potential cost of evolving epibatidine resistance in poison frogs
Background
Some dendrobatid poison frogs sequester the toxin epibatidine as a defense against predators. We previously identified an amino acid substitution (S108C) at a highly conserved site in a nicotinic acetylcholine receptor β2 subunit of dendrobatid frogs that decreases sensitivity to epibatidine in the brain-expressing α4β2 receptor. Introduction of S108C to the orthologous high-sensitivity human receptor similarly decreased sensitivity to epibatidine but also decreased sensitivity to acetylcholine, a potential cost if this were to occur in dendrobatids. This decrease in the acetylcholine sensitivity manifested as a biphasic acetylcholine concentration–response curve consistent with the addition of low-sensitivity receptors. Surprisingly, the addition of the β2 S108C into the α4β2 receptor of the dendrobatid
Epipedobates anthonyi
did not change acetylcholine sensitivity, appearing cost-free. We proposed that toxin-bearing dendrobatids may have additional amino acid substitutions protecting their receptors from alterations in acetylcholine sensitivity. To test this, in the current study, we compared the dendrobatid receptor to its homologs from two non-dendrobatid frogs.
Results
The introduction of S108C into the α4β2 receptors of two non-dendrobatid frogs also does not affect acetylcholine sensitivity suggesting no additional dendrobatid-specific substitutions. However, S108C decreased the magnitude of neurotransmitter-induced currents in
Epipedobates
and the non-dendrobatid frogs. We confirmed that decreased current resulted from fewer receptors in the plasma membrane in
Epipedobates
using radiolabeled antibodies against the receptors. To test whether S108C alteration of acetylcholine sensitivity in the human receptor was due to (1) adding low-sensitivity binding sites by changing stoichiometry or (2) converting existing high- to low-sensitivity binding sites with no stoichiometric alteration, we made concatenated α4β2 receptors in stoichiometry with only high-sensitivity sites. S108C substitutions decreased maximal current and number of immunolabeled receptors but no longer altered acetylcholine sensitivity.
Conclusions
The most parsimonious explanation of our current and previous work is that the S108C substitution renders the β2 subunit less efficient in assembling/trafficking, thereby decreasing the number of receptors in the plasma membrane. Thus, while β2 S108C protects dendrobatids against sequestered epibatidine, it incurs a potential physiological cost of disrupted α4β2 receptor function.
Journal Article
Low Chicago : a Wild cards mosaic novel
\"In George R.R. Martin's latest Wild Cards adventure, a gang of criminals are scattered across time and threaten the stability of the world. Perfect for current fans and new readers alike, Low Chicago is an all-new time travel adventure that leads to the criminal underworld of 1920s Chicago, featuring a fresh cast of characters from the Wild Cards universe.\"-- Provided by publisher.
Book
Distinctive single-channel properties of α4β2-nicotinic acetylcholine receptor isoforms
Central nervous system nicotinic acetylcholine receptors (nAChR) are predominantly of the α4β2 subtype. Two isoforms exist, with high or low agonist sensitivity (HS-(α4β2)2β2- and LS-(α4β2)2α4-nAChR). Both isoforms exhibit similar macroscopic potency and efficacy values at low acetylcholine (ACh) concentrations, mediated by a common pair of high-affinity α4(+)/(-)β2 subunit binding interfaces. However LS-(α4β2)2α4-nAChR also respond to higher concentrations of ACh, acting at a third α4(+)/(-)α4 subunit interface. To probe isoform functional differences further, HS- and LS-α4β2-nAChR were expressed in Xenopus laevis oocytes and single-channel responses were assessed using cell-attached patch-clamp. In the presence of a low ACh concentration, both isoforms produce low-bursting function. HS-(α4β2)2β2-nAChR exhibit a single conductance state, whereas LS-(α4β2)2α4-nAChR display two distinctive conductance states. A higher ACh concentration did not preferentially recruit either conductance state, but did result in increased LS-(α4β2)2α4-nAChR bursting and reduced closed times. Introduction of an α4(+)/(-)α4-interface loss-of-function α4W182A mutation abolished these changes, confirming this site's role in mediating LS-(α4β2)2α4-nAChR responses. Small or large amplitude openings are highly-correlated within individual LS-(α4β2)2α4-nAChR bursts, suggesting that they arise from distinct intermediate states, each of which is stabilized by α4(+)/(-)α4 site ACh binding. These findings are consistent with α4(+)/(-)α4 subunit interface occupation resulting in allosteric potentiation of agonist actions at α4(+)/(-)β2 subunit interfaces, rather than independent induction of high conductance channel openings.
Journal Article
Knaves over queens
As the alien Xenovirus reaches Britain, Prime Minister Sir Winston Churchill, now gifted with extraordinary longevity, joins with Alan Turing to set up a special organization, the Order of the Silver Helix, to outmaneuver the terrifying mutations of the virus in Britain.
BOOK
Sleep-related hypermotor epilepsy associated mutations uncover important kinetic roles of alpha4beta2- nicotinic acetylcholine receptor intracellular structures
Sleep-related hypermotor epilepsy (SHE) is a group of seizure disorders prominently associated with mutations in nicotinic acetylcholine receptors (nAChR). The most prevalent central nervous system nAChR subtype contains [alpha]4 and [beta]2 subunits, in two ratios. ([alpha]4[beta]2).sub.2 [beta]2-nAChR have high agonist sensitivity (HS-isoform), whereas ([alpha]4[beta]2).sub.2 [alpha]4-nAChR agonist responses exhibit a small high-sensitivity, and a predominant low-sensitivity, phase of function (LS-isoform). Multiple non-synonymous mutations in the second and third transmembrane domains of [alpha]4 and [beta]2 subunits are associated with SHE. We recently demonstrated that two additional, SHE-associated, missense mutations in the major cytoplasmic loops of these subunits [[alpha]4(R336H) and [beta]2(V337G)] cause increased macroscopic function-per receptor. Here, we use single-channel patch-clamp electrophysiology to show that these mutations influence single-channel amplitudes and open- and closed-state kinetics. Pure populations of HS- or LS-isoform [alpha]4[beta]2-nAChR were expressed by injecting either 1:10 or 30:1 [alpha]4:[beta]2 cRNA ratios, respectively, into Xenopus laevis oocytes. Functional properties of the resulting mutant [alpha]4[beta]2-nAChR isoforms were compared to their wildtype counterparts. [alpha]4(R336H) subunit incorporation minimally affected single-channel amplitudes, whereas [beta]2(V337G) subunit incorporation reduced them significantly in both isoforms. However, for both mutant subunits, increased function-per-receptor was predominantly caused by altered single channel kinetics. The [alpha]4(R336H) mutation primarily destabilizes desensitized states between openings. By contrast, the [beta]2(V337G) mutation principally stabilizes receptor open states. The use of naturally-occurring and physiologically-impactful mutations has allowed us to define valuable new insights regarding the functional roles of nAChR intracellular domains. Further mechanistic context is provided by intracellular-domain structures recently published for other members of the Cys-loop receptor superfamily ([alpha]3[beta]4-nAChR and 5-HT.sub.3A R).
Journal Article