An Ethics of Refusal: Sympathy, Intimacy and Fidelity in British Romanticism

Despite a current emphasis in Romantic scholarship on intersubjectivity, this study suggests that we still have much to learn about how theories of intersubjectivity operate in Romantic-era writings that focus on the family—the most common vehicle for exploring relationships during the period. By investigating how sympathy, intimacy, and fidelity are treated in the works of Mary Hays, Felicia Hemans, and Mary Shelley, this dissertation discovers the presence of an “ethics of refusal” within women’s Romantic-era texts. Texts that promote an ethics of refusal, I argue, almost advocate for a particular mode of relating within a given model of the family as the key to more equitable social relations, but, then, they ultimately refuse to support any particular model. Although drawn towards models of relating that, at first, seem to offer explicit pathways towards a more ethical society, texts that promote an ethics of refusal ultimately reject any program of reform. Such rejection is not unaccountable, but stems from anxieties about appearing to dictate what is best for others when others are, in reality, other than the self. In this dissertation, I draw from feminist literary critiques that focus on ethics; genre-focused literary critiques; and studies of sympathy, intimacy, and fidelity that investigate modes of relating within the context of literary works and reader-textual relations. Psychoanalytic theory also plays an important role within my third chapter on Mary Shelley’s novel Falkner. Scholarship that investigates the dialectical nature of Romantic-era literature informs my entire project. Through theorizing and studying an ethics of refusal, we can more fully understand how intersubjective modes functioned in Romantic literature and discover a Romanticism uniquely committed to attempting to turn dialectical reasoning into a social practice.

HIV Reverse Transcriptase Fidelity And Inhibition Are Modulated By Divalent Cations In A Concentration-Dependent Manner In Vitro

Human immunodeficiency virus (HIV) rapidly evolves through generation and selection of mutants that can escape drug therapy. This process is fueled, in part, by the presumably highly error prone polymerase reverse transcriptase (RT). Fidelity of polymerases can be influenced by cation co-factors. Physiologically, magnesium (Mg2+) is used as a co-factor by RT to perform catalysis, however, alternative cations including manganese (Mn2+), cobalt (Co2+), and zinc (Zn2+) can also be used. I demonstrate here that fidelity and inhibition of HIV RT can be influenced differently, in vitro, by divalent cations depending on their concentration. The reported mutation frequency for purified HIV RT in vitro is typically in the 10-4 range (per nucleotide addition), making the enzyme several-fold less accurate than most polymerases. Paradoxically, results examining HIV replication in cells indicate an error frequency that is ~10 times lower than the error rate obtained in the test tube. Here, I reconcile, at least in part, these discrepancies by showing that HIV RT fidelity in vitro is in the same range as cellular results, in physiological concentrations of free Mg2+ (~0.25 mM). At low Mg2+, mutation rates were 5-10 times lower compared to high Mg2+ conditions (5-10 mM). Alternative divalent cations also have a concentration-dependent effect on RT fidelity. Presumed promutagenic cations Mn2+ and Co2+ decreases the fidelity of RT only at elevated concentrations, and Zn2+, when present in low concentration, increases the fidelity of HIV-1 RT by ~2.5 fold compared to Mg2+. HIV-1 and HIV-2 RT inhibition by nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) in vitro is also affected by the Mg2+ concentration. NRTIs lacking 3'-OH group inhibited both enzymes less efficiently in low Mg2+ than in high Mg2+; whereas inhibition by the “translocation defective RT inhibitor”, which retains the 3ʹ-OH, was unaffected by Mg2+ concentration, suggesting that NRTIs with a 3ʹ-OH group may be more potent than other NRTIs. In contrast, NNRTIs were more effective in low vs. high Mg2+ conditions. Overall, the studies presented reveal strategies for designing novel RT inhibitors and strongly emphasize the need for studying HIV RT and RT inhibitors in physiologically relevant low Mg2+ conditions.