Handling George Eliot’s Fiction

An argument that George Eliot was a novelist intellectually, philosophically, and aesthetically ahead of the majority of her peers thankfully needs no defense two hundred years after her birth. This lofty status, however, does not mean that Eliot was impervious to the cultural preoccupations of her time. Quite the contrary. A central contention of this essay is that Eliot, despite her imposing intellectual reputation, engaged with her culture’s popular interest in human hands in ways that profoundly affected her fiction. As I have argued elsewhere,1 the Victorians became highly cognizant of the physicality of their hands in large part because unprecedented developments in mechanized industry and new advancements in evolutionary theory made them the first culture to experience a radical disruption of this supposedly age-old, God-given, “distinguishing” mark of their humanity. Eliot did not write any “industrial” novels per se, and so it may be fair to assume that she was relatively unmoved by the human hand’s supersession by mechanized industry. And though she was not religious in any traditional sense, she definitely maintained a keen interest in the rapidly changing scientific paradigms of her day. This scientific interest, as we shall see, plays an unusually interesting—and as of yet unconsidered—role in the development of her characters’ bodies

The Victorian Body

The nineteenth century is extremely important for the study of embodiment because it is the period in which the modern body, as we currently understand it, was most thoroughly explored. This was the era when modern medical models of the body were developed and disseminated, when modern political relations to the body were instantiated, and when modern identities in relation to class, race, and gender were inscribed. While questions about the distinctions between personhood and the body were studied by the ancients, nineteenth-century developments in technology, economics, medicine, and science rendered such categories newly important for Britons who were the first to experience a fully industrialized society. This entry is designed to outline the changing experiences of embodiment in the Victorian period, and is therefore divided into the following sections: anatomy, gender, femininity, masculinity, health and sickness, industrialized and technologized bodies, physiology and reading, evolution and race, disability, adolescence, and old age

Idiomatic Surrogacy and (Dis)Ability in \u3ci\u3eDombey and Son\u3c/i\u3e

To assert that Charles Dickens possessed a mastery of language unique among nineteenth-century novelists for its vernacular inventiveness is hardly controversial. The Oxford Dictionary of English Idioms lists Dickens among its most cited sources (others include the Bible and Shakespeare). Dickens’s use of ordinary, unembellished, and what Anthony Trollope termed vulgarly “ungrammatical” lower-class language sets his novels apart in style and tone from those of his famous peers (249). William Thackeray, the Brontës, George Eliot, Elizabeth Gaskell, Margaret Oliphant, Thomas Hardy and others – despite their many differences – generally composed their fiction in higher, more formal linguistic registers than Dickens. The difference with Dickens is most likely the result of a complex amalgamation of circumstance and sensibility, but his unusual upbringing is undoubtably a major factor. His early life experiences gave him access to a range of rhetorical speech that his peers simply did not possess. Working as a young boy at Warren’s Blacking Factory, regularly visiting his father at the Marshalsea Prison, and later, spending time as a law clerk, a Parliamentary stenographer, and a newspaper editor gave Dickens a broad spectrum of linguistic resources from which to build his fictional idiolect. Garrett Stewart captures this exceptional sense of rhetorical ingenuity in his assessment that “it often seems as if the untapped reserves of the English vernacular were simply lying in wait for Dickens to inherit them – by marrying their riches to his storyteller’s instinct” (“Language” 136). Given Dickens’s unparalleled command of the English vernacular, I would like to focus on how one idiomatic figuration that has so far escaped critical attention works to produce meaning in one particular novel: the idiomatic expression “right-hand man” in Dombey and Son (1846–48). I concede that this phrase may have escaped critical attention for good reason; it appears only six times in Dombey and Son – Dickens’s longest novel at 356,610 words. But unlike virtually every other idiom that turns up in Dickens’s work, “right-hand man” appears only these six times in Dombey and never again his fictional oeuvre (comprised of twenty-one texts).

Preventive Intervention as Means of Clarifying Direction of Effects in Socialization: Anxious-Withdrawn Preschoolers Case

An indicated preventive intervention research program integrating attachment, attributional, and behaviorist perspectives was conducted to test the hypothesis that parent-child relationship disturbances directly effect the child\u27s adjustment to the preschool. Anxious-withdrawn preschool children and their mothers were divided equally into treatment and control groups, and assessed on maternal self-report of parenting stress, behavioral ratings of mother-child interaction, and teacher ratings of the children in the preschool classroom. Results showed significant changes in the treatment group: mothers in the treatment group moderated their level of control to a more appropriate, less intrusive level, while children in the treatment group showed an increase in cooperation and enthusiasm during a problem solving task with mother. Teacher-rated social competence and anxious-withdrawn behavior indicated improvement, although only the former was significant. The demonstration of effects of this home intervention for the mother on the child\u27s behavior in the preschool confirm the transactional model underlying this study and demonstrate the utility of a parent-child interaction training component for the prevention of behavioral-emotional problems in young children

Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D2R including NAMs (19fc) with sub-?M affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i)

Novel fused arylpyrimidinone based allosteric modulators of the M1 muscarinic acetylcholine receptor

Benzoquinazolinone 1 is a positive allosteric modulator (PAM) of the M1 muscarinic acetylcholine receptor (mAChR), which is significantly more potent than the prototypical PAM, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (BQCA). In this study, we explored the structural determinants that underlie the activity of 1 as a PAM of the M1 mAChR. We paid particular attention to the importance of the tricyclic scaffold of compound 1, for the activity of the molecule. Complete deletion of the peripheral fused benzene ring caused a significant decrease in affinity and binding cooperativity with acetylcholine (ACh). This loss of affinity was rescued with the addition of either one or two methyl groups in the 7- and/or 8-position of the quinazolin-4(3H)-one core. These results demonstrate that the tricyclic benzo[h]quinazolin-4(3H)-one core could be replaced with a quinazolin-4(3H)-one core and maintain functional affinity. As such, the quinazolin-4(3H)-one core represents a novel scaffold to further explore M1 mAChR PAMs with improved physicochemical properties

Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor

Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side-effects (EPS) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side-effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and reveal that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimisation of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles

4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor

Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer’s and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization

Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R