Effects of BRCA1-Mediated Ubiquitination of HuR on RNA Metabolism in Breast Cancer

BRCA1, a gene encoding for the tumor suppressor protein BRCA1, is involved in DNA repair as well as many other important cellular processes. BRCA1, together with BARD1 (BRCA1 Associated RING Domain 1) also functions as an E3 ubiquitin (Ub) ligase. BRCA1 mutation in the RING domain, which is responsible for E3 ligase activity, is associated with increased risk of developing breast cancer. Despite extensive research on the activities of BRCA1, the E3 ligase activity and implications of this activity in cancer are not well understood. This dissertation examines the ubiquitination of the RNA binding protein Human antigen R (HuR) by BRCA1/BARD1 and the implications of this ubiquitination event on gene expression in breast cancer. HuR binds to mRNA targets in the nucleus and escorts them to the cytoplasm, typically stabilizing them and, hence, regulating gene expression. Oligomerization of HuR is necessary for proper interaction with and stabilization of these mRNA targets. HuR targets are involved in important processes such as cell proliferation, apoptosis, carcinogenesis, and DNA damage response (DDR). Cytoplasmic HuR is correlated with more severe forms of breast cancer, and HuR is a potential target for breast cancer therapies. Previous studies have shown that non- degradative ubiquitination of HuR causes detachment from target transcripts. Additionally, data from our lab showed that BRCA1/BARD1 can ubiquitinate HuR. However, the effects of this ubiquitination on HuR sub-cellular localization, HuR oligomerization, and transcript binding and stabilization have not been established yet. In this dissertation, I show that HuR is ubiquitinated by BRCA1/BARD1 at Lysine 313 (K313) in the RNA recognition motif 3 (RRM3), and that HuR localization in chromatin increases when ubiquitination at K313 is compromised. Furthermore, my studies indicate that the UV- induced increase in cytoplasmic HuR observed in breast cancer cells with functional BRCA1 is lost in cells with compromised BRCA1-mediated ubiquitination. Furthermore, BRCA1/BARD1- mediated ubiquitination of HuR at K313 alters HuR oligomerization and its binding to target transcript CDKN1A, and preliminary data indicates CDKN1A stability is also affected. Together, these findings elucidate a new pathway through which BRCA1 mutations may lead to transcriptome dysregulation and alter gene expression in breast cancer patients, influencing disease outcomes and therapy success

Factors Affecting Pretonic Deletion in English Syllables: A Corpus Study

One type of variation in pronunciation that is associated with fast and/or conversational speech is massive reduction, in which entire syllables are deleted. We focus on a subtype of massive reduction, pretonic vowel deletion, where the vowel in an unstressed syllable is deleted and the flanking consonants form an onset cluster, V --\u3e φ / C__C, such as the word Columbus reduced to the two-syllable pronunciation [klʌmbəs], resulting in the onset cluster [kl]. The main question asks what predictors are associated with pretonic vowel deletion. Furthermore, we evaluate the Lexicalist Hypothesis and Sonority Projection as explanations of the phenomenon. The results indicate that sonority distance, cluster type frequency, and word frequency have significant and independent contributions to massive reduction. This supports a combination of the Lexicalist Hypothesis and Sonority Projection accounts

Complicity

What does it mean to be complicit in diffuse collective wrongs like structural racism, gender-based oppression, or environmental damage, and what responsibilities are entailed by complicity? Moral philosophers have often understood complicity to consist in some degree of inherited culpability, arising from knowing or intentional contributions to the bad acts of a primary wrongdoer. But these theories fail to explain complicity in the foregoing contexts, and cannot justify needed efforts to hold individuals accountable for unwitting contributions to systemic wrongs and injustices. In response to this gap, my dissertation defends a novel reconceptualization of complicity as participation in collectively perpetrated wrongs, including structural injustice. A broad notion of participation – which requires neither intentions nor knowledge (nor culpable ignorance) – can explain the source of complicity across a range of collective wrongs, and capture a variety of actions and omissions including those that merely reproduce or ratify harmful systems. I further demonstrate that complicity does not entail blameworthiness, but that even non-culpable complicity will generate moral obligations and reasons for action, and will make various moral responses and expectations appropriate (e.g. shame, regret, mistrust, criticism, mutual education, reparative and resistant action). While existing theories of complicity cannot explain why and how we hold individuals accountable for unknowing, blameless participation in diffuse wrongs and structural injustice, my view clarifies our actual practices and supports a wider repertoire of ethical responses

Meconium: A Potential Means to Predicting Later-Life Cognition

Maternal perinatal stress is a commonly experienced, yet chronically undiagnosed condition (CDC, 2010). Literature has suggested that perinatal stress exposure has long lasting implications of the developing child both physically and mentally (Behrman et al., 2007; Hobel et al., 2008; Bowman et al., 2004; Polanska et al., 2017; Van de Bergh et. al, 2020). The use of meconium in the clinical setting has become one that serves a purpose of detection in medical conditions like in utero drug exposure. Using meconium as a predictor for brain behavior, however, is still an emerging concept in the literature. It is quickly gaining attention as interest in the gut microbiome and its large-scale impact on the body grows. Hu et al. (2019), for example, investigated the relationship between maternal anxiety and the infant gut microbiome. They found that pregnancy related anxiety was associated with lower levels of enterococcaceae from newborn meconium. This study seeks to evaluate meconium’s predictive value in identifying child risk for cognitive impairment. One-way ANOVA, two-way ANOVA, and linear regression analysis were used to test the relationship of 43 participants enterococcaceae levels at birth and cognitive scores measured using the Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition (WPPSI-IV) between the ages of four and seven years old. No significant associations of enterococcaceae level and cognition were found. Despite the negative findings, the limited sample size of this study warrants an expanded investigation into the relationship of enterococcaceae level and cognition in perinatally stress children in order to achieve a greater understanding of the “brain- gut connection”. That, in turn, will add further description on the gut microbiota influence on brain behavior

The Film, the Stadium and the Jail: The Post-Industrial Transformation of Downtown Durham

By the late 1980s, Durham, North Carolina’s downtown-based industrial economy had been replaced by a powerful knowledge economy in the city’s peripheries. Downtown Durham’s vast array of tobacco and textiles manufacturing buildings stood empty, along with most of its commercial spaces, offices and sidewalks. This thesis argues that the local development of two major public works, a baseball stadium (the Durham Bulls Athletic Park) and a jail (the Durham County Detention Center), conceived and constructed on similar timelines in close physical proximity, was indicative of how—and for whom—city and county officials envisioned a revitalized downtown. The first chapter examines the complex mythic and material interplay between the film Bull Durham (1988) and post-industrial Durham, how the film helped produce the Durham Bulls Athletic Park, and how the stadium represented (and ultimately, helped instantiate) city officials’ efforts to attract a wealthier knowledge economy class to the city center, in lieu of ameliorating the city’s residual social needs. The second chapter argues that the development and architectural form of the Durham County Detention Center—belying its reformist aspirations—served foremost to expand the county’s capacity to confine its post-industrial, overwhelmingly Black, ‘surplus’ population. By the time both were fully open, the stadium and the jail, dominating the skyline from the vantage point of the city’s busiest thoroughfare, broadcast officials’ split vision for downtown’s future—white knowledge-class leisure and Black working-class confinement

An Introduction to Film (3rd ed.)

This textbook provides an introduction to films and the filmmaking process. Each chapter covers a different facet of filmmaking starting with a brief history of film, primarily focused on that in the USA. Then it moves into exploring how to watch films from a critical perspective. After that, there are chapters exploring the various aspects of filmmaking: mise-en-scène, narrative, cinematography, editing, sound, and acting. Finally, the textbook ends wiith a look at documentary and experimental films with an additional look at animation

Movimento de Arte Pornô (1980–84): Poetry, Performance, and Pansexuality

This dissertation focuses on the Movimento de Arte Pornô (Porn Art movement), a networked group of Brazilian visual artists and poets who embraced pornography in their aesthetic practices from 1980 to 1984, during the Abertura, a transitional process from dictatorship to democracy. Seeking to uproot the conservative values that had shaped Brazilian society under the dictatorship, the group proposed a provocative—pansexual—cultural project with performances and interventions in the public sphere, visual works, and DIY porn art publications. Centering the body as a major source of artistic enunciation and the ultimate site for its fruition, the movement embraced porn as a tool of subject production and identity formation through pleasure. In this dissertation I argue that the artists from the Porn Art movement embraced porn to assert it as an important mode for sexual minorities to mobilize as an agent of their own representation and pleasure, creating diverse pornographies with hybrid media and inviting viewers to cultivate multiple subjectivities. Chapter 1 places the movement in dialogue with the historical Brazilian avant-garde, most notably the “cannibalist” movement of Antropofagia. This chapter highlights how both groups embraced societal taboos rooted in the body—cannibalism and pornography—to stimulate new formal experimentation. In this chapter I compare these two movements to argue that if Antropofagia embraced the image of the cannibal to construct national identity through the metaphorical digestion of cultures, the Porn Art movement turned to the production of subjects who are shaped by images and embodied experiences. Chapter 2 examines the Porn Art interventions of Gang, a subgroup of artists who articulated the movement as a whole and organized publications and performances in Rio de Janeiro. I argue that Gang’s artworks subverted the traditional experience of pornography, from the private and individual to the public and collective realm, converting pornographic affect (e.g., sexual arousal) into shared experiences, such as collective laughter and the vocalization of bawdy words, that might transform the public sphere. Chapter 3 focuses on the production of women artists participating in the movement: Leila Míccolis, Teresa Jardim, Sandra Terra, Denise Trindade, and Cynthia Dorneles. These artists embraced sexuality and the body as fundamental themes in their artistic and poetic practices, asserting themselves as desiring subjects and criticizing social structures that repress women. In this chapter I argue that these women artists subverted the masculinist and heteronormative conventions of the genre by asserting their voices as sexual subjects and agents of production and claiming their right to pleasure. Chapter 4 focuses on the Xerox artworks by Hudinilson Jr. and Eduardo Kac, as well as the Porn Art network facilitated by this technology. In this chapter I argue that, for these artists, the Xerox machine functioned as an allegory of pornography. By considering porn as an apparatus that followed specific codes of representation, these artists tampered with the Xerox machine to evidence the artificiality of pornography and the role of reproductive technology in the creation of subjects

Racial and Neighborhood Disparities in New York City Criminal Summons Practices

The purpose of this study is to assess trends in criminal summons practices by the New York City Police Department (NYPD), including if and how they disproportionately impact low income and/or Black and Brown communities. The New York City Council commissioned the study as part of the Police Reform and Reinvention Collaborative Plan. Approved March 2021, the goals of this plan were both to document and ameliorate policies and practices that have led to historic injustices and over-policing of low-income New Yorkers and communities of color

Herding Cats: The Benefits and Challenges of a Large Research and Development Team

We explore the journey of a nine-member-and-growing research team that is collaborating to develop, implement, and study a Computer Integrated Teacher Education (CITE) program at an urban commuter college. Team members have a range of subject area expertise and research training, as well as full-time jobs in the education field. The multi-member team has learned from each other and enriched the final products while facing challenges resulting from the composition of the team

Maternal Subjectivities in the 18th and 19th Century British Novel

How is the maternal subjectivity narrated in the pages of the 18th and 19th century British novel? This dissertation examines this question. The novel’s close connection to the child’s subjectivity and perspective is something woven into its very fabric, and so the mother is often a side character, an object in the story. She is an obstacle to be overcome, a distant idea, an absent figure, or even someone too perfect to be represented on the page. The novel often reflects or mirrors this culturally and psychologically accepted way of viewing the mother. The tracing of the narratives in which this is challenged- where the rare maternal subjectivity is highlighted and developed in its own right- is the work of this project. There are no current books historicizing the trajectory of representations of maternal protagonists from the rise of the novel to successive 18th and 19th century British novels, although there are an increasing number of works that examine and recover maternal figures in the literature in a less systematic way through the lens of feminist, psychoanalytic, and maternal theory. By looking at these protagonists both through informed close readings and through contextual, biographical and historical lenses, this work traces an evolution of the representation of the maternal subjectivity within this specific literary genre. The novel begins in its incipience by only featuring mothers behaving badly- “monstrous mothers”- mothers who deny their maternity and therefore narratively live out a more traditional protagonist’s story of adventure, scandal, and romance. Daniel Defoe’s heroines, Moll Flanders and Roxana, are perfect examples. The fact that this distorted and unpleasant portrayal of the mother is embedded into the novel’s birth and rise makes it understandable that the mother providing good care for her children is largely omitted and will not be featured textually until more than a century later. Novels by Mary Wollstonecraft and Mary Shelley in the Romantic period enact a dramatization of the tug between the mother’s subjectivity and the child’s. Despite the real tragedy that separated this mother and daughter, their works exist in fascinating overlap and conversation. Both authors employ extreme plots and create much narrative drama around the relation of parent to child, producing unusual circumstances of devastating and unhealthy separation. The commitment of the authors to giving significant narrative space to voices of both the parent and the child indicates their sense of the importance of each perspective for a peaceful and productive co-existence. In Lady Susan by Jane Austen and Belinda by Maria Edgeworth we see the portrayal of more monstrous mothers, who are thoroughly dominant, wiley, and fascinating figures. As aristocrats, their adventures are circumscribed within the social realm. Both maternal subjects neglect their daughters for their own interests and amusements. Lady Susan is presented as powerfully wielding words to her advantage, and Lady Delacour emerges as a stage director, seizing the role of determining the conclusion of the text. Despite their flaws, Austen and Edgeworth recognize not only a personal but also a type of artistic and narrative vigor located within the maternal subject. The novel eventually features “good mothers” like Helen Huntingdon and Ruth Hilton, but only because the narrative interest is kept up by their transgressions against patriarchal law, Helen’s in leaving an abusive husband, and Ruth’s in having a child out of wedlock. These mothers successfully raise their boys in healthy environments secluded from the corrupting influence of wayward fathers. Brontё and Gaskell imply that these arrangements are not simply in the benefit of the child, but that the talents and skills of the mothers themselves are actually activated by the necessity of this care. Helen’s maternal subjectivity is wrapped up also in her identity as an artist. Ruth’s maternal subjectivity is entwined in her role as a teacher and eventually as a nurse. Despite the somber nature of Tenant of Wildfell Hall and the tragic conclusion of Ruth, both novels present optimistic portraits of the deep meaning of motherhood in the lives of these protagonists. Surrogate and adoptive mothers take on the subjectivity of the mother just as biological mothers do, as we see in the examples of Albinia Kendal of The Young Step-Mother and Nettie Underwood of The Doctor’s Family. In fact, these examples of mothers who step in to care for children who are not their own are also defined in the novels as desirous of and deeply committed to lives of incredible energy and activity dedicated to the children in their care. They are characterized as something like superheroes, while the blame for wayward children is placed, at least partly, with biological mothers (and fathers). As the novel approaches modernity, however, it also evokes the randomness that affects even the best intentioned mother/child relationships. There are actual limits to the care that mothers can take of children, both with respect to the ultimate outcome of their lives, which is outside their control, as well as with respect to their own maternal subjectivity, which can be damaged when it does not recognize a need to care for and preserve itself. Andrea O’Reilly, in her contributions to maternal theory and in her call for a matricentric feminism, paves a path to an innovative and expansive way of reading our mother characters. The 18th and 19th century novels often built around the bildungsroman or marriage plot limit the subjective relationality of the maternal. In fact, the novel asks of mothers what families often do: that they defer their needs to those of others, that they sacrifice self. This dissertation’s work in digging deeply into the varied, interesting, multi-dimensional maternal subjectivities that made it to prominence joins in the movement to revise our literary critical practices when it comes to understanding the mother’s role in narrative