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Tyrosine Kinases as Multifaceted Drug Targets for Therapeutic Intervention in the Treatment of Alzheimer's Disease
No full textPh.D.Alzheimer’s Disease (AD) is a neurodegenerative disease of aging for which there currently exists no cure. Clinical symptoms include cognitive impairment, loss of memory, impaired visuospatial and executive skills, and psychological symptoms such as anxiety and depression. The primary pathological hallmarks of AD include neurotoxic aggregations of amyloid-beta and hyperphosphorylated tau as well as rampant neuroinflammation involving activation of microglia, which are believed to synergistically contribute to synaptic dysfunction, neuron death, and accelerated cognitive decline. Disease-modifying therapies targeting these features are being developed aimed at alleviating progression of dementia, but approved drug therapies have demonstrated only modest, temporary, and palliative benefits. One class of enzyme being explored in both preclinical and clinical settings for efficacy in treating neurodegenerative diseases is tyrosine kinases (TKs). Many of these enzymes are upregulated in postmortem brains from AD patients, while recent data has implicated TK activity in AD pathology, suggesting them as therapeutic targets for alleviating pathology. Thus, I hypothesized that pharmacological inhibition of TKs would alleviate pathological features of AD. I first showed that TK inhibition with nilotinib in a human cohort of AD patients is associated with changes to biomarkers known as miRNAs indicative of reduced pathology, including vascular fibrosis, autophagy, and inflammation. Then, using novel small molecule compounds, I was able to demonstrate that tyrosine kinase inhibition is associated with reduced pathological markers in animal models of AD, including peripheral mast cell activation, aggregation of neurotoxic protein, and microglial-mediated neuroinflammation, resulting in improved behavioral outcomes in transgenic AD mice. Together, these data identify tyrosine kinase inhibition as a potential therapeutic medium for treating patients with AD
Regulation of Steroid Hormone Biosynthesis by Thymic Epithelial Cells
No full textPh.D.Selective processes early in T cell development ensure that most thymocytes expressing αβ T cell antigen receptors (TCRs) are eliminated, and only self-restricted and self-tolerant cells join the peripheral T cell repertoire. Glucocorticoids produced by thymic epithelial cells (TECs) promote the survival of such thymocytes to increase the breadth and efficacy of the repertoire. There are two TEC subsets, cortical (cTECs) and medullary (mTECs), each contributing to selection at different developmental stages. The exact source and regulation of thymic-derived glucocorticoid production are not fully understood, and their precise identification will help determine whether they enhance positive selection or antagonize negative selection. It was hypothesized that glucocorticoids are synthesized by cTECs, with the potential to influence both stages of selection. To test this, a transgenic reporter mouse was utilized in which endogenous Cyp11b1, the final and essential enzyme in de novo glucocorticoid biosynthesis, was fused with fluorescent mScarlet. Cyp11b1mScarlet was detected in a lineage of mTECs that express the transcription factor Aire, which is known to drive promiscuous expression of tissue-restricted antigens (TRAs) involved in negative selection and the establishment of peripheral immune tolerance. In Aire-knockout mice, detection of Cyp11b1mScarlet, transcripts encoding enzymes required for the de novo pathway, and ex-vivo glucocorticoid synthesis were significantly reduced, supporting Aire’s role in regulating glucocorticoid biosynthesis. This presents a novel yet paradoxical role for Aire in promoting both positive and negative thymocyte selection, the combined effect serving to enlarge the pool of self-restricted yet self-tolerant T cells. This also supports a new function for Aire in coordinating the expression of genes involved in an entire biosynthetic pathway whose secondary products have known paracrine functions. To this end, Aire was found to drive de novo sex steroid biosynthesis, supporting a broader role for Aire in shaping the thymic microenvironment and paving the way for future investigations
Generalizability and Genre Effects in Discourse Understanding and Parsing in Rhetorical Structure Theory
No full textPh.D.Recent advances in discourse parsing create the impression that, like other types of Natural Language Processing analyses, state-of-the-art performance for high-resource languages such as English is finally becoming reliable and applicable to arbitrary data. However, there is by now substantial evidence showing that even for English, hierarchical discourse parsing within formal frameworks such as Rhetorical Structure Theory (RST) remains challenging, and that our understanding of the reasons for this are as yet limited.This dissertation aims to thoroughly investigate the impact of data diversity on RST parsing stability in English. We show that state-of-the-art neural models trained on the standard English newswire benchmark do not generalize well, even within the news domain. We also pinpoint and systematically evaluate the role of linguistic features and other factors that hinder state-of-the-art tools from achieving robust and stable performance across diverse text types and domains, through statistical methods and predictive models.Our results demonstrate that a heterogeneous training regime is critical for stable and generalizable models, across parser architectures. In addition, we show that as in shallow discourse parsing, the explicit/implicit distinction plays a role, but that long-distance dependencies are the main challenge, while lack of lexical overlap is less of a problem, at least for in-domain parsing.Moreover, this dissertation presents a corpus-based analysis of genre variation in RST discourse relations across 20 genres from two English RST corpora. The goal is to better understand genre effects at the discourse level both quantitatively and qualitatively.Lastly, this dissertation evaluates how effective RST extracts such as central discourse unit are as summaries by comparing them with both model-generated and human-written summaries across genres
Maternal Sepsis Clinical Pathway Education and Equity Focused Gap Analysis
No full textD.N.P.Early diagnosis and prompt treatment can prevent the majority of maternal sepsis deaths. Implementing maternal sepsis screening and management tools improves perinatal outcomes. With a mixed methods design, this project piloted an educational session on the OB Sepsis Pathway for labor and delivery nurses and conducted a retrospective equity-focused gap analysis on maternal sepsis screening and management. The Lewin Change Model guided implementation.The project site is a medical center in northern California. Sixty-three nurses attended an educational session on the maternal sepsis pathway, 52 were assessed for knowledge and intention to change practice, and eight super users completed a survey on implementation facilitators and barriers three months post education. The care of 82 patients that met criteria for suspected maternal sepsis from 2014-2023 was reviewed.Nurse OB Sepsis Pathway knowledge scores increased from 58.73% to 70.94%. Mean scores for intention to change practice were highest for the constructs “beliefs about consequences” (6.87) and “moral norms” (6.84). Benchmarks for provider notification of suspected infection, timing of antibiotic administration, and diagnostic evaluation were met for 69.2%, 18.5%, and 18.3% of patients respectively, and 20.7% of patients were transferred to an ICU. Patients with suspected sepsis were most likely to identify ethnically as Hispanic, X2(1) = 9.03, p = .003, and racially as “other,” Black/African American, Native Hawaiian or Pacific Islander, or mixed race, X2(2) = 10.1, p = .007.Overall, the super users reported the pathway was clear and improved communication and awareness on maternal sepsis. Barriers to implementation were distinguishing chorioamnionitis from maternal sepsis and resistance to change. Super users recommended the following implementation improvements: EMR integration, easier access to the pathway, and working with multidisciplinary teams for efficient hospital workflow.While nurses were motivated to follow the OB Sepsis pathway, there were gaps in pathway knowledge post-education. Retrospectively evaluating management of OB sepsis was challenging due to a lack of standardized care. The findings support comprehensive multidisciplinary education on maternal sepsis and EMR integration to facilitate maternal sepsis screening and management that achieves benchmark goals. These findings will inform the next steps for implementation of the OB Sepsis Pathway
Letter from Gabriel R. Sanz-Rexach, Chief, Operations Sec., Office of Intelligence, DOJ, to Anthony J. Trenga, Presiding Judge, Foreign Intelligence Surveillance Court, In Re Accuracy Concerns Regarding FBI Matters Submitted to the FISC
No full textFirst page of documen
“Undisputed MVP” of the 92nd Oscars: Constructing a Korean-English Interpreter’s Hero Identity Through Praise on X
No full textM.S.This study examines the language of praise as it appears in posts on the social media platform, X (formerly known as Twitter) in posts directed at Sharon Choi, who served as the official interpreter for the South Korean film Parasite (2019), directed by Bong Joon-ho, during the 2019-2020 film awards season. Praise is an everyday speech act that conveys positive appraisal (of someone or some object). Applying Du Bois’ (2007) stance framework in accordance with Martin and White’s (2005) appraisal theory, which primarily operates on the assertion that language should be viewed in terms of its social functions, I build on the theory of praise as it is related to stance-taking, and the subsequent development and expression of ideologies online. To this end, I analyze 23 quote-tweets of a post containing an exclusive article written by Choi and digitally published by Variety. Four main categories of praise content, i.e. what the subject (Choi) is being praised for, emerge in my analysis. First, users on X are seen to use various stance-taking techniques to praise Choi as an expert in her field. Second, users use affective language to praise Choi as someone who (I) relate to and/or understands (me). Third, users reference the social and political context of the 2020 Oscars in which Choi and Parasite (2019) were situated to praise Choi as a hero who represents something greater than herself. Finally, the fourth category reflects specialized use of slang terms such as “stan” and “queen” to accomplish acts of praise, reflecting the utility of slang as tools for community alignment and “diva worship” (Koestenbaum, 1993). This study adds a qualitative perspective to the study of praise as it is expressed in microblogging and broader computer-mediated discourse
Report of the Attorney General on the Use of Pen Registers and/or Trap and Trace Devices Under the Foreign Intelligence Surveillance Act, July 1, 2023 to December 31, 2023
No full textFirst page of documen
Assessing the Relationship Between Cardiometabolic Diseases and the Risk of Developing Metastatic Prostate Cancer, a Systematic Review and Meta-Analysis
No full textM.S.Background:Prostate cancer is one of the most prevalent cancers among men within the U.S. and across the world. Since 2014, the incidence rate for prostate cancer has increased by 3% annually and 5% annually for those with advanced-stage prostate cancer (ACS, 2024b). This systematic review and meta-analysis provides an overview between the relationship between cardiometabolic disease (diabetes, dyslipidemia, obesity, hypertension) and prostate cancer metastasis, synthesizing existing literature.Methods:A rigorous PubMed search revealed 24 cohort studies of > 500,000 men, adhered to PRISMA guidelines and met the inclusion and exclusion criteria. Following the systematic review of these prospective studies of men with prostate cancer, I used R to run a random effects model, yielding hazard ratios with 95% confidence intervals (CI) and generating forest plots with measures of heterogeneity.Results:Meticulous examination of relevant studies reveals that a positive association exists. When comparing the overall association between cardiometabolic diseases (as a group) and prostate cancer metastasis, the random effects model generated a HR of 1.07 (95% CI:1.04, 1.10; pDiscussion:Three of the four individual cardiometabolic diseases (diabetes, obesity and hypertension) were shown to have statistical significance and offered intriguing evidence on their potential associations with metastasis of prostate cancer. Dyslipidemia’s association was not statistically significant, which could be attributed to variations in methods of assessment and differing mechanistic effects. Limitations for all of these cardiometabolic associations exist due to scarcity of literature available and high levels of heterogeneity.Conclusion:If these associations are true and can be corroborated in future studies, as controllable and treatable cardiometabolic diseases are, the awareness of oncologists can allow for working alongside primary care physicians to assess whether more control can be achieved to improve patient outcomes and reduce the incidence of metastatic disease. Through the promotion of lifestyle modifications, tighter cardiometabolic control, and targeted interventions, public health efforts might improve prostate cancer outcomes
The Relationship Between Family Dynamics and the Incidence of Experiencing Major Depressive Episodes Among Adolescents
No full textM.P.P.Amid the COVID-19 pandemic, U.S. adolescents have encountered an unprecedented mental health crisis, including a notable increase in reported Major Depressive Episodes (MDE), signaling a worrying trend in adolescent mental health issues. This thesis explores the relationship between family dynamics and the incidence of adolescents experiencing MDE. Leveraging data from the 2021 National Survey on Drug Use and Health (NSDUH), I use regression analysis to examine an array of factors, including family support/supervision, demographic characteristics, socioeconomic status, behavioral and lifestyle factors, environmental influences, and mental health service utilization. My results suggest a significantly negative relationship between strong family dynamics and the incidence of MDE among adolescents. This study contributes to the understanding of the protective role of family dynamics in bolstering adolescent mental health, especially in the context of escalating post-pandemic challenges
The Atomic Continent: A Comparative Study of African Countries’ Relationships with the Nuclear Nonproliferation Regime
No full textPh.D.Why do some African countries commit to the nuclear nonproliferation (NNP) regime while others do not? The wider academic outlets rarely explore the motivations for supporting international regimes from the Global South perspective. This is especially true for the NNP regime, where research typically focuses on interactions between states with nuclear weapons. Conventional international relations theorists use a realist framework for explaining these interactions as purely about military security and survival. A growing body of research suggests that nonsecurity issues drive states’ NNP regime decisions. This is especially true for Africa. Africa contributes the most signatories to nuclear nonproliferation treaties, yet few researchers have focused on how and why these states make their decisions. This study assesses how eleven African states with nuclear energy ambitions committed to five agreements from 1964 to 2017. These agreements include the Organization of African Unity Declaration on the Denuclearization of Africa, the Treaty on the Nonproliferation of Nuclear Weapons, the Pelindaba Treaty, the Comprehensive Nuclear Test Ban Treaty, and the Treaty for the Prohibition of Nuclear Weapons. Archival research and semistructured interviews of elite stakeholders provide accounts of how each country interacts with the NNP regime. Process tracing provides insight into the causal mechanisms from the time countries are presented with each treaty to when they decide to sign, ratify, or disregard it. The study finds that nonsecurity issues drive commitment or noncommitment to the NNP regime in contrast to the widely upheld belief that security issues drive these decisions. These nonsecurity issues do not relate to nuclear nonproliferation and disarmament as the traditional discourse within the NNP regime. Instead, the issues pertain to the NNP regime’s agreement to establish nuclear technology transfer programs. This agreement is a priority for African states experiencing an electricity crisis due to acute energy shortages. For African countries specifically, access to nuclear energy represents a priority when making NNP regime decisions