Dissertations from the School of Arts and Sciences

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The York Cycle and the Law
Degree awarded: Ph.D. English Language and Literature. The Catholic University of America, The York Cycle Passion sequence yields numerous references to fifteenth-century laws and the practice of law. The trial of Jesus is conducted using the language of contemporary English trials, and during the trial, Jesus is accused of such fifteenth-century crimes as witchcraft, defamation, preaching without a license, and high treason. Many scholars have studied the trial and Passion sequence, noting the references to contemporary law practice and debating how Jesus' trial follows or flouts the justice system. What has not yet been discussed thoroughly is the pervasive reference to law and law-breaking throughout the cycle as a whole. Throughout the Old Testament plays and the New Testament plays that precede the Passion sequence, characters are accused of English crimes from scolding to adultery to high treason. Furthermore, these crimes cut across jurisdictional boundaries, including deeds that would be tried before ecclesiastical courts, local law courts, and royal justices.This dissertation examines not only the trial and Passion sequence but also focuses on the more neglected legal aspects of the earlier plays. As stated above, the crimes described encompass many jurisdictions; what they also include is a genuine cross-section of contemporary English society. Peasant farmers (Adam and Eve) break their promise to their lord, middle-class wives scold their husbands (Noah and his wife), and Jesus, who is often depicted as royal, especially in "The Entry into Jerusalem," is put to death for crimes against the state. What seems true in all cases is that when God is involved directly in judgment, innocent parties are exonerated; however, when earthly justice comes into play, judgment is no longer impartial, fair, or correct. Attention to the many nuances of laws, judges, jurisdictions, and legal practices can profoundly alter our understanding of the York Cycle and its legal contexts., Made available in DSpace on 2013-06-25T14:59:16Z (GMT). No. of bitstreams: 1 Wilson_cua_0043A_10409display.pdf: 1321883 bytes, checksum: 876cfe7af30e3325c8163c265e845793 (MD5)
Words, Thoughts, and Phrases: Defining and Measuring Literalness in English Bible Translations
The bulk of the project is spent examining five English translations of eight texts from the Hebrew Bible in order to determine how literal each translation is. According to this project, a literal translation is a word-for-word translation in which lexical items and formal features are retained. The English translations are the King James Version, the New International Version, the New Revised Standard Version, the English Standard Version, and Robert Alter’s The Hebrew Bible: A Translation with Commentary. The Hebrew texts are Genesis 1, 2 Sam 18:1-15, Ruth 3, Ps 120, Ps 121, Ps 130, Eccl 4, and Obad 1-18. The texts are first subjected to a constituent analysis to ascertain whether each translation accurately represents each constituent of the Hebrew text in English. Next, a word order analysis is performed on each text to show divergences between the Hebrew and English texts. Finally, each text is examined for lexical variation, showing how each English version translates repeated uses of the same Hebrew word. In each of these analyses, the English translations are given scores to rate how closely they reflect the underlying Hebrew text. In the end, Alter’s translation is the closest to the definition of literal proposed in this paper, while the NIV is the furthest. This is not to say that the NIV is inherently inferior to the other translations surveyed. Conclusions are meant to be objective and not evaluative., Near Eastern studies, Bible translation, Linguistics, Old Testament, Translation theory, Semitic and Egyptian Languages and Literatures, Degree Awarded: Ph.D. Semitic and Egyptian Languages and Literatures. The Catholic University of America
Wings That They Might Flit: The Naturalist Poet Discovers a World in Motion
William Wordsworth and John Clare were well-versed in contemporary scientific debates and depicted natural phenomena with unerring precision. Their purely naturalistic passages have been largely neglected or maligned in the mistaken belief that artistic and scientific endeavors are either contradictory or mutually exclusive. Furthermore, these passages prove difficult to interpret, as there are so few historical treatments of natural history to provide necessary context and, of them, fewer still that include discredited theorists and theories. This study compares poetic passages to those scientific explanations encountered by the poets themselves, drawing from John Ray’s Observations (1673), Thomas Pennant’s Tours (1771-74), Gilbert White’s Natural History of Selborne (1789), and Erasmus Darwin’s Temple of Nature (1803). Wordsworth and Clare adopt progressive scientific attitudes on various issues and promote their views by uniquely effective, artistic means, particularly through their invocation of flitting, or nature in continual motion. This study’s first chapter defines flitting in the context of migration and probes the way in which Clare’s spiriting away of the nightingale in “The Flitting” and the “Nightingale’s Nest” prompts a reevaluation of the expectations of home. The second chapter develops the two types of flitting, around and between places, and the possibility of its extension from bird to human life, evidenced by Dorothy Wordsworth’s flitting about the garden in the Grasmere Journals and William’s explorations as a newcomer in Home at Grasmere. The multiplicity of Wordsworth’s streams, elements, and energies in the Excursion, analyzed in the third chapter, advances the currently-accepted theory of river origins, a theory, which, when broadly applied, suggests that spontaneity and action nourish not only rivers but all natural beings. In the fourth chapter, which investigates animal longevity, Wordsworth’s White Doe leads readers to the acknowledgement of life’s brevity but also toward a ranging lifestyle, an exchange of the darkness of immobility for the lightness of adaptation. The final chapter treats the fledglings of Clare’s “Pewit’s” and “Woodpigeon’s Nest,” as phenomena not yet understood, but whose embodiment of nature’s rhythms, its resting and running, nonetheless inspires humankind in its continued quest for home in nature., English literature, early Romanticism, John Clare, Natural History, William Wordsworth, English Language and Literature, Degree Awarded: Ph.D. English Language and Literature. The Catholic University of America
"What Rough Beast": The Evolution of Cormac McCarthy's "Prophet of Destruction"
Degree Awarded: Ph.D. English Language and Literature. The Catholic University of America, The character finally named as the "prophet of destruction" in No Country for Old Men, is present from the very beginning of Cormac McCarthy's writing, and his malevolent presence, in a variety of forms and strengths, recruits men to destructive acts and leads them to self-destruction over and over again as the novels progress. McCarthy's myth-making is on a cosmic scale, conjuring an entire world presided over by a god of destruction for whom good is not a concept. His ten novels each present some aspect of the prophet and the determinist universe he represents, and tests that universe against a variety of potential heroes. In the end, for there to be any hope at all, the prophet must be victorious and burn the world down. Only from its ashes can a new prophet, one of creation, rise.McCarthy is not only a member of long and richly varied literary history, but also a singular phenomenon with his own history of ideas, a claim that both his biography and his work thus far corroborate. Echoes of Yeats' beast "slouching toward Bethlehem" inform the McCarthy canon from its inception, birthing the prophet of destruction in the process and envisioning an arc of destruction that begins with the Orchard Keeper and ends with The Road. For McCarthy, temporality is not just a helix, but a widening gyre, a spiral rapidly losing coherence. For McCarthy, we begin with destruction, witnessing its prophet's slow rise, recognizing its culmination in the superhuman giant of Judge Holden, and watching it subside again into humanity, to eventually end in apocalypse. If there is hope in McCarthy, it is most often felt by its marked absence, but as Steven Frye insists, it is there nonetheless, and in the final pages of McCarthy's tenth novel do we finally feel the ascendancy of the prophet of creation, the second half of the cycle beginning. Hope paired with despair, a sense of human worth and dignity in the face of nearly unimaginable depravity, all roped into a system slowly losing its integrity, is pure McCarthy.
Weaving the Structure of the Cosmos: Cloth, Agency, and Worldview at Cerrillos, An Early Paracas Site in the Ica Valley, Peru
Degree awarded: Ph.D. Anthropology. The Catholic University of America, This study of approximately 2,200 yarns and textile fragments excavated under controlled conditions from Cerrillos, an Early Paracas civic-ceremonial site located in the upper Ica Valley of south coastal Peru, uses chaîne opératoire research and practice theory to explore patterns in quantitative and qualitative data that infer weaving praxis. This technique reveals that the weavers who made the Cerrillos fabrics negotiated normative weaving practices (e.g., Z spinning) and procedural centers (e.g., a preference for red camelid hair), while at the same time they enjoyed significant leeway, perhaps even encouragement, to experiment, which in turn changed routine weaving practices over time that most likely reflect simultaneous changes in social processes.The present study employs parenthetical notation (a notational system for recording yarn structure) and a relational database with data forms to collect, store, and process large amounts of data and look for patterns of co-variance that disclose the choices Paracas people made while making, using, and discarding fabrics. The results of this study suggest four things: (1) there were aesthetics that influenced (and were influenced by) spinners (regarding the yarns they made) and weavers (pertaining to the way colors, materials, patterning, and fabric structures were combined); (2) Early Paracas weavers apparently negotiated normative practices and procedural centers while at the same time creating remarkably diverse plain-weave fabric structures; however, by Late Paracas times plain-weave structures became highly standardized; (3) dualistic concepts appear to be invoked in the choice of weft-selvage structures as well as the color, material, and width of warp stripes and weft bands; and (4) patterns in heading cords, weft-selvage structures, and the apparently deliberate destruction of fabric edges--combined with ethnographic, ethnohistorical, and archaeological evidence suggesting that borders (e.g., selvages, walls, stripes, etc.) have protective properties--imply animistic principles or beliefs., Made available in DSpace on 2011-02-24T20:49:29Z (GMT). No. of bitstreams: 1 Splitstoser_cua_0043D_10028display.pdf: 82670405 bytes, checksum: a6a7234bf567de5ac663e87723bcacdd (MD5)
Walt Whitman’s Personalist Political Theory
Walt Whitman has long been considered one of the great poets of modern democracy. The focus on Whitman’s democratic poetry and prose, however, has obscured his deeper purpose, to explicate the “fathomless” person who stands as the reason for and justification of democracy. This dissertation seeks to remedy this misperception in the understanding of Whitman’s political thought by exploring his “personalism.” The poet coined the term for American English not as a synonym for individualism or egoism, but as an attempt to evoke the person as a whole, in all of their spiritual, material, relational, historical, and national complexity. Yet this means that such persons can never be captured in words; they remain elusive. Absent, even as they are present, universal categories fail to contain them. Modern democratic regimes are the first to acknowledge this feature of all persons, to take their uniqueness, their “limitlessness” and “inevitability” seriously. Other forms of political life held that only a few could develop, explore, and act out of their inner depth, but democracies aspire to this realization in all persons. Whitman’s idea of democracy was one drawn from several strands, especially the Radical Enlightenment and the Anglo-American republican tradition. The poet, however, was not satisfied with their impersonal focus on laws, institutions, and progress. Because of this, he also incorporated two currents that opposed these impersonal tendencies by engendering a new appreciation for the person: Romanticism and German Idealism. This theoretical background is combined with an attention to the details of life as lived by democratic citizens, evoking persons in all of their inner complexity and outer activity.Whitman’s poetry thus makes an important contribution to liberal democratic political thought in the way that it explores the theoretical meaning of personhood in the reality of daily democratic life. Understanding this personalist perspective shows that his democratic poetry is more than an artistic exercise to aesthetically connect citizens to each other and to democracy. Rather, poetry is the only linguistic tool capable of explicating democracy’s deepest intuition of what it means to be a person., Political science, American literature, American studies, German Idealism, Liberalism, Personalism, Political Theory, Romanticism, Walt Whitman, Politics, Degree Awarded: Ph.D. Politics. The Catholic University of America
The Voice of Mary: Later Medieval Representations of Marian Communication
It is nearly impossible to overstate the importance of the Virgin Mary’s role in the landscape of medieval Christian spirituality. Innumerable prayers, hymns, sermons, liturgical traditions, and other devotional practices praised her as the Mother of God and imagined her speaking profusely to her supplicants. Yet Mary only spoke in the Bible on four occasions (Luke 1:26-38, 1:46-56, 2:41-52, and John 2:1-11). Why then, given this limited speaking presence, were late medieval authors so intent on giving her an enhanced speaking role in textual sources that augmented her power?The striking transformation from the muted early Christian portrayals of Mary to the later medieval depictions of her as an outspoken matriarch cannot be ignored. My dissertation explores the emergence of Mary’s powerful persona through an examination of her speech as reported in narrative sources from the twelfth to the fifteenth century, including miracle collections, passion narratives, and mystery plays. Within both Latin and vernacular sources, authors expanded upon stories rooted in biblical and apocryphal literature to give Mary a new voice. I argue that the creation and development of “Marian speech” enabled Mary to emerge in the late Middle Ages as a more dominant, influential figure in Christian thought and worship who functioned as an active speaker and effective intercessor. Marian speech as a constructed category has yet to be considered as a means of studying devotion to the Virgin Mary. An analysis of Marian speech reveals the development in articulating her power and place in Christian piety. By analyzing Mary’s voice, this dissertation raises questions about the religious and cultural conditions that prompted this change in how authors depicted Mary. Each section of the dissertation maps out different representations of Mary’s voice, as expressed in a series of speaking roles: as student and teacher, as wife and mother, and in the sovereign roles of Queen of Heaven, mediatrix, and Empress of Hell. This thematic approach draws attention to the widespread concerns for regulating women’s speech in the Middle Ages and serves as an effective barometer for measuring both religious and social change., Medieval history, Gender studies, Religious history, Devotional materials, Hagiography, Later Middle Ages, Medieval England, Religious Culture, Virgin Mary, History, Degree Awarded: Ph.D. History. The Catholic University of America
Verbal Hendiadys Revisited: Grammaticalization and Auxiliation in Biblical Hebrew Verbs
Degree awarded: Ph.D. Semitic and Egyptian Languages and Literatures. The Catholic University of America, Verbal hendiadys is described in Biblical Hebrew textbooks and grammars as a verbal construction consisting of two verbs whereby one qualifies the other. Such constructions occur as a sequence of two finite verbs or in a construction in which a finite verb is complemented by an infinitive. It is usually assumed that the first verb expresses an adverbial idea whereas the second verb contributes a lexical meaning. A historical survey reveals that the rhetorical term hendiadys was used without restrictions for various, sometimes linguistically unrelated, categories. This dissertation argues that the traditional term hendiadys is inadequate for such verbal constructions and proposes to call them auxiliary verb constructions and the verbs that are assumed to express an adverbial idea as auxiliary verbs. It provides a linguistic framework of grammaticalization and auxiliation and offers a comprehensive analysis of Hebrew auxiliary verbs on the basis of this framework. Grammaticalization is explained as a complex diachronic change whereby a lexical item gradually becomes a grammatical marker. The analysis explains how the verb HLK `go' became an auxiliary of gradual progression, the verb SHWB `return'--an auxiliary of repetition, the verb YSP `add'--an auxiliary of addition and continuation, the verb QWM `get up'--an auxiliary of ingressiveness, the verb MHR `hurry'--an auxiliary of speed and urgency., Made available in DSpace on 2011-06-24T17:11:33Z (GMT). No. of bitstreams: 1 Chrzanowski_cua_0043A_10241display.pdf: 1531387 bytes, checksum: f186cb0a1197dcac5b101a40bef07ba2 (MD5)
The Varied Meanings of Death Among Individuals Who Have Considered Suicide
Although over 12 million adults in the U.S. experienced suicidal thoughts in 2020 (SAMHSA, 2023), the experience of suicidal ideation has been under-prioritized in research and clinical practice (Jobes & Joiner, 2019). Given the burden and suffering represented by suicidal thinking, it is thus imperative that more efforts be undertaken to elucidate the scope, content, and dimensions of such thinking (House et al., 2020). One unexplored facet of ideation about suicide has been ideation about death. Although thinking about suicide entails thinking about the end of life (i.e., death), little attention has been devoted to what people who are suicidal actually think about death. Within suicidology, ideation about death has largely been considered a precursor to, or “passive” component of, ideation about suicide and has consequently been severely understudied (Liu et al., 2020). The minimal research on death ideation that does exist has comprised separate, unintegrated streams of research, and these bodies of work have been limited by a reliance on researcher-defined, assumption-laden constructs. Accordingly, through semi-structured interviews with 12 adult individuals who have experienced suicidality within the past year, the current study sought to explore, from the “bottom up,” how attitudes toward death relate to the experience of suicidality. Interviews involved questions regarding how individuals conceptualize, imagine, and approach death; the sources from which they have developed their understandings of death; how their ideas about death influence their suicidal ideation; and their reflections on the value of discussing these ideas in therapy. This study represented the first to provide adults who are currently or formerly suicidal the opportunity to elaborate in depth upon these dimensions of suicidality. The results of these interviews indicate that participants hold rich and nuanced beliefs and feelings about death that complicate extant conceptualizations of and theories about suicidal ideation. Altogether, the study suggests the value of continuing to explore the meaning of death with people who are suicidal as well as considering the sociocultural dimensions of how suicide comes to be a meaningful response to suffering. , Clinical psychology, death, death concepts, meaning-making, qualitative, suicidal ideation, suicide, Psychology, Degree Awarded: Ph.D. Psychology. The Catholic University of America
The Use of Military Astrology in Late Medieval Italy: The Textual Evidence
Degree awarded: Ph.D. History. The Catholic University of America, This study examines the thirteenth-century astrologer Guido Bonatti's Liber Astronomicus as a case study to investigate one aspect of the many practical applications of astrology in the later Middle Ages. Specifically, it looks at the application of military astrology to analyze Bonatti's use of his source material in relation to his own practice. The dissertation develops a methodology to discern the astrologer's practice from his textual inheritance. Bonatti was possibly the most important astrologer of the high middle ages. His work was an encyclopedic, yet detailed survey of the entire field of astrological study in the Europe of his day. He acknowledged his Arab sources but was not merely a compiler of their material. Like many of his European contemporaries in other fields such as Thomas Aquinas, Albertus Magnus and Roger Bacon, Bonatti put his own stamp on the field of astrology. Staying within the basic traditions as he inherited them, he systematized and expanded often terse material, and frequently innovated in certain applications of astrology. By close and detailed examinations of Bonatti's text and comparison with his sources, we can see the changes that reflect his personal experience which in turn caused him to alter and emend the tradition. From this we can distinguish the practitioner from the compiler of astrological materials. This study argues that such close internal textual analysis of the astrological treatises themselves reveals the medieval uses of astrology far better than external narrative sources. Ultimately over the course of this study it also becomes clear that in the area of astrology Bonatti carried out the same kinds of intellectual synthesis and systematization that we see in the works of notable contemporaries in other fields., Made available in DSpace on 2014-02-11T18:35:57Z (GMT). No. of bitstreams: 1 Hand_cua_0043A_10465display.pdf: 4159241 bytes, checksum: 5c12ebf1111ffe8b56dbd54d50412a28 (MD5)
The Use of Clinical Risk Assessment Coding Systems with Suicidal Soldiers
Degree Awarded: Ph.D. Psychology. The Catholic University of America, military, suicide, suicide index score, suicide motivation, suicide orientation, suicide typologies, Suicide is a leading cause of death among United States active duty military wherein there are more deaths due to suicide than combat (Luxton et al., 2011). The majority of suicide deaths occur among Caucasian junior enlisted Soldiers under the age of 35, at rates far greater than those of their civilian counterparts (Bruce, 2010; DOD Task Force on the Prevention of Suicide by Members of the Armed Forces, 2010; Lagana-Riordan, 2015). The present study is the first simultaneous application of three suicide coding systems, "Scale for Suicide Ideation Suicide Index Score" (SSI-SIS; a quantitative ratings index of the wish to live or die), SSF "Suicide Orientation" (classifying qualitative responses for the preoccupation with self or others), and SSF "Suicide Motivation" (a count and comparison of identified reasons for living and dying) to a relatively large sample of suicidal Soldiers. Hypotheses predicted the presence of between-group differences, within each typology, on measures of current suicidal ideation, history of suicide attempts, psychological distress, and resiliency. Results demonstrated that those identified as Wish to Die from the SSI-SIS had greater suicidal ideation than those identified as Wish to Live or Ambivalent. There were no significant between-group differences within the Suicide Orientation typology. Application of the Suicide Motivation typology yielded significant between-group differences on measures of lifetime suicide attempts, psychological distress, and resiliency wherein those coded as Death-Motivated were more symptomatic and less resilient than their Life-Motivated and Ambivalent counterparts.
The Urbanization of Poverty in Latin America and Maternal Depression: Prevalence, Correlates, and Relationship to Child Development
Degree awarded: Ph.D. Psychology. The Catholic University of America, Latin America is undergoing the most rapid urbanization of poverty worldwide, straining an already limited psychosocial care system. Urban migrants, especially women, are at high risk for depression because of urban poverty, migratory trauma, and social isolation. Existing research from developing countries suggests that depression is detrimental to women and jeopardizes the healthy development of their children. However, this relationship has not been examined within urban migrant communities in Latin America, despite these communities having disproportionate risk and a paucity of mental health services. In an attempt to further this field of inquiry, the current study examines 1) prevalence and correlates of depression among a community of urban migrant women in Latin America, 2) if/how maternal depression among these women affects the developmental potential of their children, and 3) possible relationship-based and community-based variables that mediate or moderate the relationship between maternal depression and child outcomes, with the goal of informing psychosocial interventions for urban migrant communities.In collaboration with a non-governmental organization (NGO), data were collected from 97 low-income mothers and their school-aged children (ages 5-10 years) living in the El Porvenir region of Trujillo, Peru. This community reflects many of the demographic, physical, political, and social factors characteristic of urban migrant communities throughout Latin America. Analysis revealed that two-thirds of the mothers met criteria for clinical depression: a rate significantly higher than low-income Latin American mothers not affected by urban migration. Urbanization stress was a significant predictor of maternal depression, with single parent status and ongoing domestic violence being the only significant isolated risk factors. Maternal depression was significantly correlated with internalizing and externalizing behavior in children. Maternal depression was related to more negative attitudes about parenting, and indirect effects were found between maternal depression and externalizing behavior via parenting attitudes. Parenting factors were tied to both socioemotional and cognitive outcomes for children. Finally, ongoing domestic violence was tied to parenting behaviors and child outcomes. Implications of these findings are discussed in detail, with emphasis on interventions that target depression, domestic violence, and parenting skills while also utilizing fewer specialized mental health resources., Made available in DSpace on 2013-11-05T15:05:17Z (GMT). No. of bitstreams: 1 Kohrt_cua_0043A_10434display.pdf: 945641 bytes, checksum: d5592e7e7c3b4f066ce66a1210e1f96a (MD5)
Unintended microbial targets of antidepressants
Antidepressants (ADs) are prescribed to more than 40 million people annually in the United States to treat major depressive disorder (MDD). Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are the most commonly prescribed classes of antidepressants. In addition to the known effects of SSRIs and TCAs on serotonin and/or noradrenaline neurotransmitter levels, both classes of drugs have antimicrobial activities toward a variety of bacteria, fungi, and even viruses found in the human gut, the so-called gut microbiota. Patients taking ADs frequently experience weight gain and gastrointestinal (GI) issues such as diarrhea, nausea, and constipation. Given that the gut microbiota plays important roles in drug metabolism and brain function, it is essential to understand the mechanisms underlying changes in microbial composition, which are largely unknown. Using Escherichia coli, we show that the SSRI fluoxetine and the TCA amitriptyline exert strong selection pressure for enhanced efflux activity of the AcrAB-TolC pump, a member of the resistance-nodulation-cell division (RND) super family of transporters. In accordance with the broad specificity of the AcrAB-TolC pump, these mutants conferred resistance to several classes of antibiotics. We demonstrate that the converse also occurs, as spontaneous chloramphenicol-resistant mutants displayed cross-resistance to SSRIs and TCAs. In chemical-genomic screens, 35 genes with an unknown role in drug resistance were identified that conferred cross-resistance to antibiotics were identified, and a number of these deletions exhibited enhanced efflux activities. Further, AD-resistant mutants exhibit quicker development of resistance to ciprofloxacin. These findings indicate that combinations of specific antidepressants and antibiotics may have significant effects when both are used simultaneously or successively, as they can impose selection for common mechanisms of resistance. Our research indicates that selection for enhanced efflux activities is an important factor to consider when attempting to comprehend the changes in microbial diversity caused by antidepressant treatments. Toward a mechanistic understanding of the antimicrobial action of ADs, I speculated that eliminating the possibility of mutations that enhance the efflux of the ADs might increase our chances of identifying mutations in the target(s) of the ADs. Toward this end, we isolated spontaneously-resistant mutants to ADs in parental strains in which components of the AcrAB-TolC pump were deleted. Mutations in pgsA and mscM were found in AcrA and AcrB-deficient strains that displayed resistance to ADs. pgsA encodes for a phosphatidylglycerophosphate synthetase that catalyzes a step in the biosynthesis of acidic phospholipids. MscM is a low-conductance mechanosensitive ion channel that is part of an operon with phosphatidylserine decarboxylase, which produces the main phospholipid phosphatidylethanolamine, which is a major lipid component of the cellular membrane in E. coli. This result suggests that either these proteins are direct targets of ADs or the ADs target the activities these proteins perform. Based on these results and biophysical studies of ADs that show they have membrane activity, I hypothesized that ADs might compromise membrane integrity, leading to cell death. Chemical-genomic screening identified several mutants, including those with deletions in LPS and efflux pump channels, indicating that the cell membrane may be the target. A modest decrease in fluorescein isothiocyanate-labeled poly(l-lysine) (FITC-PLL) labeling in the fluoxetine-resistant mutant compared to the parental strain, indicating a potential reduction in the amount of phosphatidylglycerol (PG) and cardiolipin (CL) in the pgsA mutants that were isolated. Two assays were used to measure membrane permeabilization, revealing that fluoxetine led to the permeabilization of both inner and outer membranes. FITC labeling showed that the LPS layer was disrupted in the presence of fluoxetine, and E. coli LPS mutants displayed sensitivity to fluoxetine compared to the parental strain, highlighting the role of LPS in protecting the cell from the toxic effects of fluoxetine. These studies provide novel mechanistic insights into how antidepressants (ADs) can affect the gut microbiota (GM), and highlight the potential for drug modifications that may mitigate unintended microbial effects and prevent negative GI side effects. Moreover, the studies emphasize the need for further research into the complex relationship between ADs and the GM, and suggest that targeting the GM may hold promise as a strategy for developing new treatments for MDD. Overall, these findings underscore the importance of understanding the gut-brain axis in the context of psychiatric disorders, and may inform the development of more effective and personalized therapies for MDD and related conditions., Biology, Biology, Degree Awarded: Ph.D. Biology. The Catholic University of America
A Unified Model of How Jurors Update and Re-Evaluate Evidence to Reach a Verdict
Degree Awarded: Ph.D. Psychology. The Catholic University of America, Prominent researchers have suggested that criminal prosecutions should require more than the testimony of a single eyewitness. The present study investigated the effects of how additional evidence, beyond a single eyewitness, affected mock jury decision making. The results are compared to predictions from Bayes Theorem, which provides a normative/rational/statistical model of how mock jurors should update judgments given new information. Participants (N = 440, data collected via MTurk) read a summary of testimony from the victim of a home invasion, and then at Time 1 (T1), they judged the Likelihood of the defendant's Guilt, rated their Trust in the Victim's testimony, and rendered a Verdict. At Time 2 (T2), participants read one of six additional types of evidence: strong or weak forensic, strong or weak eyewitness, or strong or weak confession evidence, and answered the same questions as at Time 1. All participants were then instructed to disregard the additional T2 evidence, and at Time 3 (T3), they answered the questions for a third time. Three independent evaluations of each piece of additional evidence supported a "true" value of that information for Bayesian predictions. However using these values, Bayesian predictions for Likelihood of Guilt at T2 and T3 always over-adjusted the change in Likelihood of Guilt. At T2, Bayes over-predicted guilt, whereas at T3, Bayes underpredicted guilt. Contrary to Bayes Theorem, the value of prior information, such as the eyewitness's testimony, changed as new evidence was added or removed. All participants other than the weak forensic group increased in Likelihood, Trust, and Verdict at Time 2, and declined at Time 3 to levels similar to Time 1. The weak forensic evidence group declined on all measures at Time 2, which replicated Martire et al. (2013), but surprisingly they rebounded on Trust and Verdict at Time 3 to levels significantly higher than at Time 1. In conclusion, Bayes theorem does not describe how mock jurors use more than one piece of evidence in making decisions. The value of any piece of evidence depends in part on the value of other evidence. Multiple regression predicted mock juror decision-making better than Bayes theorem.
Understanding the Role of RUNX1-TLE1 Interaction in the Pathogenesis of Familial Platelet Disorder with associated Myeloid Malignancy
Megakaryopoiesis is the developmental process of megakaryocytes, which are the cells responsible for platelets production. This process is defective in patients with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM). FPDMM patients are presented with decreased platelet count and/ or function. Importantly, 20-60% of FPDMM patients develop hematological malignancies later in their lives. FPDMM’s defective megakaryopoiesis is caused by a heterozygous germline mutation in the Runt-related Transcription Factor-1 (RUNX1). RUNX1 is essential during definitive hematopoiesis and megakaryopoiesis.FPDMM family was identified carrying a novel GC insertion in the RUNX1 gene, leading to a frameshift mutation (L472fsX). This caused a disruption of the VWRPY domain, a conserved binding site for the repressor protein, Transducin-like Enhancer of split-1 (TLE1). The significance of RUNX1 and TLE1 interaction in megakaryopoiesis and FPDMM pathogenesis has not been studied yet. To address those questions, we evaluated the functional defects of the RUNX1 L472fsX mutation in three different experimental models. In cell lines, FRET assay and Co-immunoprecipitation revealed loss of binding between RUNX1 L472fsX mutant and TLE1. In addition, transactivation assays against RUNX1’s target promoters, Csf1r and Hmga2, showed loss of TLE1’s repression effect on RUNX1 L472fsX mutant activity compared to wild type RUNX1. These preliminary data are consistent with the proposed regulatory role for RUNX1 and TLE1 interaction during hematopoiesis. Moreover, the findings support a gain of function mutation, which presents a new mechanism of RUNX1 action in FPDMM pathogenesis. To evaluate these defects in our FPDMM patients, we reprogrammed the patients’ cells to induced Pluripotent Stem Cells (iPSCs). Differentiating the patients’ iPSCs revealed a defect in their megakaryopoiesis similar to previous FPDMM studies. In addition, the patients’ iPSCs showed defects in Hematopoietic Stem Cells (HSCs) maturation and differentiation. This finding is first reported with this RUNX1 L472fsX mutation since no other FPDMM studies reported a similar phenotype. Significantly, these hematopoietic defects were rescued after correcting the RUNX1 L472fsX mutation in the patients’ iPSCs. Moreover, a mouse model missing the VWRPY domain expression was generated using CRISPR-Cas9 system. The homozygous mouse model showed minor defects in the peripheral blood, but not in the bone marrow. In conclusion, the data indicates the significance of RUNX1 and TLE1 interaction through the VWRPY domain to ensure efficient hematopoiesis and megakaryopoiesis, essentially in HSCs maturation and differentiation. More importantly, this RUNX1 L472fsX mutation presents a novel mechanism of FPDMM pathogenesis. It would give more insights into RUNX1’s function in hematopoiesis and how would FPDMM patients develop hematological malignancies., Cellular biology, FPDMM, iPSCs, Megakaryopoiesis, RUNX1, TLE1, VWRPY, Biology, Degree Awarded: Ph.D. Biology. The Catholic University of America
Understanding the Role of p53 in Metabolic Regulation in Acute Myeloid Leukemia (AML)
This study focused on investigating the role of mutations in the TP53 tumor suppressor gene in the metabolic regulation of human acute myeloid leukemia (AML) using the Tohoku Hospital Pediatrics-1 (THP-1) cell line as a model. The THP-1 cell line represents the AML-M5 subtype, which is a subtype that mainly affects young children (< 2 years). We generated stable isogenic cell lines by overexpressing TP53 in the THP-1 cell line via different constructs of plenti6-based plasmids. The generated cell lines were TP53 WT THP-1, TP53R175H THP-1, and TP53R273H THP-1. The TP53R175H and TP53R273H missense mutations are among the most common mutations of TP53 in human cancer. In AML, their overexpression on a background of TP53 loss has been linked to gain of function phenotypes in cell-based research, suggesting tumor cell growth, invasion, migration, treatment resistance, and metastasis. Specifically, the mutation R175H leads to structural changes in the binding domain of the TP53 gene, while the mutation R273H changes the protein’s ability to bind DNA in the TP53 gene. Subsequently, we identified signature genes associated with TP53 WT found in TP53 WT THP-1 cell line (n=4), TP53R175H found in TP53R175H THP-1 cell line 1 (n=34), and TP53R273H found in TP53R273H THP-1 cell line (n=111) with the most significant changes in metabolic processes, GO:0008152. Moreover, we found that TP53R175H and TP53R273H decreased oxidative phosphorylation and TP53R175H increased the Warburg effect in the mitochondria in the AML cells. Furthermore, we found by using the TARGET AML cohort that AML patients with AML-TP53R175H had a significantly poor prognosis associated with a relatively long (> 5-years) survival compared to the patients with other signature genes (n=440, p=0.006432). In contrast, we found by using the TCGA LAML cohort that AML patients with AML-TP53R273H had a significantly poor prognosis associated with a relatively short (< 5-years) survival compared to the patients with other signature genes (n=179, p=0.01629). This study supports further evaluation of understanding the role of p53 mutants in metabolic regulation in AML, which might provide a framework for predicting AML patient survival and suggest potential p53-based therapy and novel strategies to treat human AML., Molecular biology, Oncology, Genetics, Acute Myeloid Leukemia, Metabolic regulation, Metabolism, p53, Role, TP53, Biology, Degree Awarded: Ph.D. Biology. The Catholic University of America
Understanding the molecular basis of human craniofacial disorders using Caenorhabditis elegans as a model organism
Twist family members are highly conserved basic helix-loop-helix (bHLH) transcription factors that are important for mesoderm development in all animals. Twist either forms homodimers or heterodimers with other bHLH proteins through their HLH domains. Twist-containing dimers regulate the expression of downstream target genes by binding an enhancer element called the E-box (CANNTG). Humans have two paralogous genes, TWIST1 and TWIST2, and mutations in each gene have been identified in specific craniofacial disorders. Sweeney-Cox (SwCoS) and Barber-Say syndrome (BSS) are craniofacial disorders that are caused by heterozygous mutations in TWIST1 and TWIST2, respectively. C. elegans has a single Twist homolog, known as HLH-8. C. elegans strains with the analogous disease alleles in HLH-8 that are found in SwCoS and BSS are referred to as Glu29 mutants. When expression of an HLH-8 target gene, arg-1, was examined in these mutants, it was found in the head mesodermal cell (HMC) and enteric muscles (EMs) but not in vulval muscles (VMs). These observations indicate that these Glu29 alleles retain some tissue-specific transcriptional activity. The studies in this dissertation have been aimed to better understanding the mechanism of how Glu29 mutants are activating transcription of arg-1. First, we wanted to determine if Glu29 mutants maintain their dimerization properties. Thus, to test protein-protein interactions, we used biomolecular fluorescence complementation (BiFC) method. We established this method and tested proteins dimerization pattern for wild-type and Glu29 HLH-8 in vivo. During these studies, we discovered that as human TWIST1/2, HLH-8 partner choice can be determined by its phosphorylation state. Although wild-type and Glu29 HLH-8 proteins are not able to form homodimers in vivo, Phospho-null HLH-8 proteins do form homodimers. The 385 bp arg-1 promoter region contains three different E box DNA sequences (E1-E2-E3) bound by either HLH-8/HLH-8 homodimers or HLH-8/HLH-2 heterodimers. Upon examining the region near the E-boxes, a GT box was identified previously that promotes arg-1 expression in the VMs. The GT box isn’t bound by any of HLH-8-containing dimers, suggesting that there is an additional factor (X) that contributes to arg-1 expression in the VMs. To further understand the molecular basis of how Glu29 mutants activate arg-1 expression, we used the yeast one-hybrid assay (Y1H) to identify (X). Results from this experiment revealed HMG-11 as an accessory protein that binds to the GT box sequence, cooperate with HLH-8, and regulates arg-1 expression in VMs. Therefore, in Glu29 mutants, this cooperation may be defective which disrupts arg-1 expression in VMs., Developmental biology, C. elegans, HLH-8, TWIST, Biology, Degree Awarded: Ph.D. Biology. The Catholic University of America

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