The thesis argues that never-married gentlewomen dissociated themselves from negative and ubiquitous stereotypes of the old maid by focussing on their gentility rather than their marital status. By demonstrably fulfilling the familial and social roles which belonged to their sex and rank, and by representing themselves in terms of approved genteel feminine virtues and conduct, they located themselves in networks of social reciprocity which extended from household and family into the wider social sphere. In doing so they confounded popular caricatures of mature unmarried women as selfish parasites whose failure to marry and procreate drained the resources of their natal families and undermined the nation’s strength. The thesis focuses on a number of case studies drawn from the extensive collections of family papers in the National Records of Scotland and the National Library of Scotland. Several of these never-married women were kin by birth or marriage, and their correspondence illustrates the reach of their relationship networks, their status, and influence. Their personal and, in some cases, published writing shows how they used ideals of gentility and associated language to support the familial and social positions they claimed. The thesis chapters examine the relationships they forged, and the resulting influence they were able to exercise, by considering them variously as members of households headed by male kin, as heads of their own households, and as familial patrons. While never-married women are increasingly the subjects of research, the lives of never-married gentlewomen remain under-examined. Yet gentlewomen, habituated to writing as an essential social skill, have left a wide range of sources by which their management of social status and singlehood can be assessed. This thesis shows some of the perspectives opened up by study of these sources.

Indiana University-Purdue University Indianapolis (IUPUI) / Single women living in nineteenth- and twentieth-century America faced ever-changing, but constant, analyses of their lives. It seemed privacy was revoked when a woman chose to remain single in the nineteenth and twentieth centuries, leaving them to be hyperaware and conscious of all other choices that they made in their lives. Not only was their business not theirs alone, but single women were often also defined by their lack of spouse, regardless of their accomplishments or fulfilled lives. Despite the full life that she led and ways in which her singleness allowed her to contribute to her family, friendships, and community, Julia Graydon Sharpe, a white, elite woman from Indianapolis, Indiana, was one of the many women whose legacy has been defined by her marital status. Sharpe was many things in her life: an artist and clubwoman being two of the most visible. However, it was her role as a sister, aunt, daughter, and friend that were the most fulfilling and important to her in her life as a single woman. An examination of what Sharpe saw as her defining roles within her immediate family and close friendships, as well as what coming from elite family afforded her, helps reveal the life she was able to lead and how she chose to present herself. The exploration of her many intimate roles also put into context how indispensable Sharpe’s commitment and contributions, albeit not monetary, were to her family and friends. Understanding these roles challenges the way we view the “spinsters” of the late-nineteenth to early-twentieth century.

Doctor of Philosophy / Autoimmune diseases are caused when a person's immune system attacks its own healthy cells. In a person with multiple sclerosis, their immune system becomes sensitized to the myelin sheath that covers their neurons in the central nervous system. This results in the degradation of the myelin sheath and irreversible degradation of the nerve cell axons. This damage leads to the development of several neurological impairments, such as pain, fatigue, mobility problems, and numbness. While there is no cure for multiple sclerosis, disease-modifying therapies are typically taken by patients to suppress their immune system and slow disease progression. Sphingsoine-1-phosphate (S1P) is a lipid that is important for the trafficking of lymphocytes into a person's central nervous system. This trafficking is largely due to the natural gradient of S1P which is high levels in blood but low in tissues. Lymphocytes will follow this gradient from areas of low S1P concentration (lymphatic tissue) to areas with higher S1P concentrations. Modulation of S1P levels is the mechanism of action for several FDA approved drugs as they target primarily S1P1 receptors to achieve lower levels of circulating lymphocytes. However, targeting this receptor also results in cardiovascular side effects such as first-dose bradycardia. The transporter for S1P, spinster homolog 2 (Spns2), which is upstream of the S1P receptors, is another viable target that our lab has recently been targeting. Spns2 inhibition decreases extracellular S1P levels and result in reduced lymphocytes in mice models. In this dissertation, several inhibitors were developed and assessed for their in vitro and in vivo ability to inhibit Spns2.

Sphingosine-1-phosphate (S1P) is an amino-alcohol signaling molecule produced from the intracellular phosphorylation of the lipid sphingosine. Despite possessing several identified intracellular targets, the predominant signaling functionality of S1P is derived from its activation of membrane-bound G-protein coupled receptors (GPCRs). The binding of S1P to these receptors (S1P1-5) is closely associated with immune cell development and recruitment. As such, the modulation of S1P-related pathways is of particular interest for the development of immunomodulating agents. To reach its native GPCRs, S1P must be released from the cell. This process is facilitated by the transmembrane transport protein Spinster homolog 2 (Spns2) in most vertebrates. Studies in murine species have demonstrated that the protein plays a key role in directing immune cell chemotaxis and the progression of autoimmune diseases. Consequently, Spns2 represents an attractive target for the pharmaceutical induction of immunosuppression. While several drugs that act through the modulation of S1P receptor signaling have received FDA approval for the treatment of autoimmune disorders (fingolimod, siponimod, ozanimod, and ponesimod), they typically manifest on-target cardiovascular side-effects. Therefore, the development of novel Spns2 inhibitors is a prudent alternative approach to achieve S1P-mediated lymphopenia. In this dissertation, the design, synthesis, and activities of highly potent Spns2 inhibitors are disclosed. These structures spanned several scaffolds and culminated in the discovery of a phenylurea derivative 4.11i. In vitro assessment of 4.11i demonstrated that the compound possessed an IC50 value of 92 nM, making it the most potent inhibitor of Spns2 disclosed to date. Intraperitoneal administration of 4.11i (10 mg/kg dose) into mice reduced circulating lymphocyte counts and impaired the progression of experimental autoimmune encephalomyelitis (a murine model of multiple sclerosis). Taken together, these data validated the target of 4.11i in vivo and represented the first reported instance of Spns2 inhibition as a viable multiple sclerosis treatment. Additional work is currently being undertaken to further improve in vivo activity and pharmacokinetic properties of 4.11i. / Doctor of Philosophy / White blood cells comprise a significant portion of the body's natural defense mechanisms. In healthy individuals, these white blood cells identify and destroy foreign materials and organisms. However, in patients with multiple sclerosis, immune cells can become sensitized to protein fragments lining the myelin sheath of neurons. These autoreactive immune cells recognize the body's natural neuronal proteins as antigens. Damage exerted by autoreactive cells leads to the development of neurological impairments (i.e., fatigue, muscle weakness, and slurred speech) as nerve impulses are disrupted before reaching their target. First-line treatment of multiple sclerosis often centers on the administration of immunosuppressive drugs to curtail the progression of the disease and mitigate immune cell-directed demyelination. A driving factor in white blood cell localization is the lipid sphingosine-1-phosphate (S1P). Concentrations of S1P are often not static in the body, with different tissue types and fluids possessing variable levels. Immune cells, and lymphocytes in particular, use this natural S1P gradient to dictate their movement within the body. Lymphocytes will track with the S1P gradient, going from areas of lower S1P concentration (lymph tissue) to areas of higher S1P concentration where synthetic enzyme expression is upregulated (multiple sclerosis lesions). Consequently, the development of drugs that can alter this S1P gradient represents an ideal avenue to achieve immunosuppression. One key mediator of S1P release is the transmembrane transport protein Spinster homolog 2 (Spns2). This protein directs the secretion of intracellular S1P into the extracellular space and is necessary for lymphocytes to enter circulation. However, little effort has been devoted to the development of Spns2 inhibitors. As such, the inhibition of this protein represents a novel and underexplored target for the treatment of autoimmune disorders. In this disclosure, the structures of several highly potent Spns2 inhibitors are revealed. The work around these structures led to the discovery of 4.11i. This compound proved highly potent in biological assays and animal models. Mice treated with 4.11i experienced a reduction in circulating lymphocyte counts and demonstrated less symptom manifestation in multiple sclerosis disease models.

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Binding of the Rev protein with Rev Response Element (RRE) RNA present in singly- and unspliced mRNA transcripts is necessary for the replication of HIV-1. This interaction transports the mRNA transcripts from the nucleus to the cytoplasm for translation of the necessary structural and enzymatic proteins for the newly budding virus as well as for providing its genetic material. Given the high rate of mutation in HIV-1, the highly conserved and pertinent RRE RNA is of high interest for pharmaceutical intervention. Consequently, a branched peptide library containing unnatural amino acids was developed to target RRE RNA with the goal of increasing stability, potency, selectivity, and in vivo activity for RRE RNA. An unnatural amino acid branched peptide library (46,656 sequences) was synthesized and screened against RRE IIB and several hits in the sub-micromolar regime were found. A number of hits demonstrated selectivity in the presence of other RNAs in addition to two hits, 4A5 and 4B3, significantly inhibiting HIV-1 growth in vitro. These peptides inhibited HIV-1 replication in a concentration dependent manner and were demonstrated to be non-toxic. Further analysis of 4A5 and 4B3 via footprinting and SHAPE-MaP experiments determined that these peptides blocked binding of Rev through binding at the primary and secondary binding sites of RRE RNA. Sphingosine 1-phosphate (S1P) is a signaling molecule that plays a role in various biological processes including immunity, neurogenesis, and angiogenesis. The role S1P plays is largely determined by its location, in which Spinster homolog 2 (spns2) and mfsd2b are the two known transporters. The two transporters exist in different cell types and cellular localizations, with spns2-produced S1P being responsible for trafficking of lymphocytes. As such, spns2 has become of interest for therapeutic targeting in autoimmune and inflammatory diseases. To validate spns2 as a target in pharmaceutical intervention, a series of spns2 inhibitors were developed. A screening of a library of inhibitors found that compound SLP7120922 demonstrated inhibition of spns2 transport activity. The design, synthesis, and biological evaluation of inhibitors based on SLP7120922 is described. Modifications to the lipophilic tail region were performed with one compound 4.40f discovered to be potent, minimally toxic, and active in vivo. A series of modifications to the head region were then conducted that evaluated linear head derivatives with alkyl-, amide-, and amino acid-based groups. A number of compounds are reported that demonstrate good in vitro activity and minimal toxicity with two compounds, 4.48b and 4.52c, showing favorable in vivo activity in mice. / Doctor of Philosophy / Human immunodeficiency virus (HIV-1) has a high rate of mutation, which commonly leads to the need for many types of medications throughout the lifetime of a patient. In order to design a therapeutic that the virus has a low chance of growing resistance to, a target needs to be chosen with a low mutation rate. One such target is the Rev Response Element (RRE) RNA and it is necessary for the virus to replicate. A protein named Rev binds to RRE RNA in order for RRE to carry out its pertinent function. To block this function we have chosen branched peptides to target the RNA. Peptides are made of the same building blocks of proteins, but are much shorter than proteins. The peptides described here are made up of modified building blocks, called unnatural amino acids. This work describes the generation of an unnatural amino acid branched peptide library and how it was screened in order to find branched peptides that bind RRE RNA. Many peptides were found to bind RRE RNA but two in particular, 4A5 and 4B3, were the best binders that inhibited HIV-1 growth. The remainder of the work describes how these peptides bind to RRE RNA, while demonstrating that they are non-toxic and bind HIV-1 in a concentration dependent manner. A transporter protein termed Spinster homolog 2 (spns2) transports a signaling molecule known as sphingosine 1-phosphate (S1P). For our immune system to function properly, spns2 has to transport S1P to the appropriate places to signal to immune cells. Unfortunately, this is a problem in autoimmune and inflammatory diseases, such as multiple sclerosis, due to these diseases having an overactive immune system. A potential way to treat these diseases would be by inhibiting spns2. This work describes the design, synthesis, and biological evaluation of spns2 inhibitors. Many compounds were found to inhibit spns2 to a degree, but three compounds, in particular, show potent and effective inhibition in mice.

Perçu pendant fort longtemps comme un saint anaphrodite et « castré » avant d’être reconnu comme l’écrivain le plus sensuel des Lettres grecques modernes, Alexandre Papadiamantis (1851-1911), auteur prolifique de près de cent quatre-vingt nouvelles et de trois romans et trésor national hellène, est un artiste antinomique qui ne cesse d’intriguer la critique et de susciter des débats contradictoires. Le présent travail propose une lecture de son œuvre complète axée sur un sujet controversé dont aucune étude systématique n’a été entreprise, malgré un siècle de surabondante critique littéraire : le désir érotique, que nous entendons essentiellement comme le rapport à un objet de convoitise explicitement ou implicitement désigné comme tel, humain ou inhumain, vivant ou inanimé, suscitant un certain nombre de réactions physiques et/ou psychiques et sollicitant un réseau complexe de sens, de sensations, de méditations, d’excitations et de significations représentées par le biais des mots. Une telle définition emphatise l’imbrication de la pulsion et du langage et distingue le désir de l’amour, ce dernier constituant plutôt une stase du désir, un arrêt et une fixation sur l’« autre ». Notre objectif est de comprendre comment l’érotisme ainsi défini s’exprime dans les textes, quels en sont les enjeux psychologiques, les interconnexions avec les techniques narratives, les choix stylistiques et les particularités linguistiques et quelles transformations littéraires il subit dans l’œuvre, en somme, quels sont sa destinée mythique, son aboutissement idéologique et son apothéose thématique, en somme son issue dans l’écriture. / Viewed for ages as an anaphrodite and « castrated » saint before being recognized as the most sensual writer in modern Greek literature, Alexandros Papadiamantis (1851-1911), prolific author of approximately one hundred and eighty short stories, and three historical novels, and deemed to be a Hellenic national treasure, is an antinomic artist who keeps intriguing critics and arousing open debates. The present thesis offers a reading of his complete work based on a controversial subject of which no systematic study has been undertaken before, despite a century of numerous literary comments : erotic desire, defined as the connexion with an objet of lust explicitely or implicitely defined as such, human or inhuman, alive or inanimated, and which rises a number of physical and/or psychological reactions, a complex network of meanings, sensations, meditations, actions and fantasies represented through words. This definition emphasizes the interweaving of drive and language and discerns between desire and love, the latter being rather a stasis of desire, and a fixation on the « other ». Our goal is to understand how eroticism thus defined is expressed throughout the texts, to point out the psychological issues associated with it, its interconnections with the narrative techniques, stylistic choices and linguistic particularities and the literary transformations it undergoes throughout the Papadiamantian opus, that is to say its mythic destiny, its ideological culmination and its thematic apotheosis, in short its outcome in writing.

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