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CHARACTERIZATION OF IN VITRO FITNESS AND ANTIGENIC DRIFT DIFFERENCES BETWEEN CIRCULATING H1N1 INFLUENZA CLADES
Get PDFInfluenza viruses are a significant contributor to morbidity and mortality, with multiple subtypes circulating seasonally and causing annual epidemics. New viral clades emerge regularly through the acquisition of mutations, which have the potential to cause antigenic drift leading to reduced recognition by host immunity. New mutations may also alter virological fitness, and due to the overlap between antigenic and functional regions a mutation may alter both phenotypes simultaneously. Studying how these separate components are balanced in circulating viruses is crucial to understanding the processes driving viral evolution.
The 2019-20 Northern Hemisphere Influenza Season was characterized by a predominance of the H1N1 influenza subtype, and was one of the most severe seasons of the past decade. During this season, the predominant 5a clade branched into two cocirculating clades, 5a.1 and 5a.2, which were differentiated by several clade-defining mutations on their hemagglutinin protein. While the 5a.1 clade quickly predominated, 5a.2 performed poorly and was almost nonexistent by the end of 2020. The differing success of these two clades indicate phenotypic differences, and this dissertation identifies a reduction in in vitro fitness of the 5a.2 clade that likely contributed to its failure to predominate.
At the start of 2021 the 5a.2 clade rapidly acquired a series of hemagglutinin mutations, and by 2022 the 5a.2a subclade quickly overtook 5a.1 to become the predominant H1N1 clade. 5a.2a then further branched into 5a.2a.1 which has continued to cocirculate with 5a.2a. The rapid success of this clade indicates phenotypic advantages over its 5a.2 predecessor, and this dissertation identifies improvements in in vitro fitness and antigenic drift of 5a.2a and 5a.2a.1 compared with 5a.2. An infectious clone system of H1N1 was employed to study the phenotypic effects of individual clade-defining mutations, and it was found that the mutations that contributed to antigenic drift reduced in vitro fitness, while the mutation that improved viral fitness actually increased virus neutralization by human serum antibodies. These findings highlight the dual evolutionary pressures on influenza to evade host immunity while maintaining viral fitness and point to epistatic interactions that optimize both components while mitigating negative pleiotropic effects of any single mutation
CTP SYNTHASE 1 IS A SYNTHETIC VULNERABILITY IN PROSTATE CANCER TREATED WITH SUPRAPHYSIOLOGICAL ANDROGEN
No full textBipolar androgen therapy (BAT) is the cyclical administration of supraphysiological androgen (SPA), which can be an effective treatment for 30-40% of patients with castration-resistant prostate cancer. We sought to improve the efficacy of BAT by better understanding its molecular consequences in prostate cancer. Given that the androgen receptor (AR) regulates cellular metabolism, we hypothesized that SPA induces dependencies on specific metabolic pathways that might be exploited therapeutically. A negative selection metabolism-focused CRISPR-KO screen in LNCaP cells treated with SPA suggested that the deletion of several enzymes involved in de novo nucleotide synthesis enhances growth suppression by SPA. A top hit was cytidine triphosphate synthase 1 (CTPS1). CTPS1 converts UTP to CTP in the final step of de novo pyrimidine synthesis. Exposure of SPA-treated prostate cancer cell lines to STP-B, a potent and highly selective inhibitor of CTPS1 (PMID 37008165), increased cell death in vitro and in vivo, indicating that CTPS1 constitutes a metabolic vulnerability in this context. Inhibition of CTPS1 with STP-B induced S phase cell cycle arrest and replication stress, as indicated by phosphorylation of RPA and CHEK proteins, which was augmented by treatment with SPA. CTPS1 likely becomes a vulnerability in SPA-treated prostate cancer due to the downregulation of MYC by SPA, which we found leads to a reduced abundance of enzymes required for nucleotide synthesis and nucleotides, particularly CTP. This rewires nucleotide synthesis and salvage pathway such that de novo synthesis of CTP is required to avoid replication stress and cell death. Altogether, this work suggests that inhibition of CTPS1 may enhance the efficacy of BAT through the induction of replication stress. Selective inhibitors of CTPS1 have entered clinical development (NCT05463263), increasing the feasibility of a combination therapy clinical trial design for patients with prostate cancer
MANAGEMENT OF FINANCIAL CONFLICT OF INTEREST DISCLOSURES AT EMERGING RESEARCH INSTITUTIONS
Get PDFTo ensure research integrity and maintain public trust in scientific research, the Public Health Service (PHS) and other federal agencies require researchers conducting federally funded projects to disclose significant financial interests. Financial conflict of interest (FCOI) management is particularly challenging for small colleges and universities because of limited financial resources. Research at small colleges is increasing, partly due to federal investment programs supporting undergraduate research and promoting equity in scientific research. The CHIPS and Science Act of 2022 codified the term "emerging research Institutions,” defined as colleges or universities with less than $50 million in federal research expenditures, designating more funding for smaller colleges and universities. As research activity increases at these institutions, so does the potential for FCOI, particularly those arising from private-sector partnerships. The research project collected data on FCOI management practices at ERIs of various sizes and levels of research intensity. The aim was to identify best practices carried out by more research-intensive ERIs that research administrators at smaller colleges might adapt for their own institutions. The sample size was too limited to correlate institution size and research intensity with successful practices, but patterns emerged in the research that warrant further investigation
Strengthening Assessment Practices for Students with Low-Incidence Disabilities
Get PDFEducators of students with low-incidence disabilities face unique challenges in assessing their students related to complicated diagnoses, the lack of resources for special education teachers, and the lack of knowledge of best practices to meet the student populations’ diverse needs (Hom et al., 2021). Accurate assessment data has implications for classroom instructional decisions, class placement decisions, and related service programming design in special education settings. Using artifact analysis of secondary data sources and a participatory action research approach, called the SEED Method, this paper explores the challenges related to assessing students with low-incidence disabilities, identifies key areas for improvement, and establishes an action plan for a school in an urban city that serves students in self-contained special education classrooms
THE CLINICAL VALUE OF UNSTRUCTURED ELECTRONIC HEALTH RECORD DATA IN CASE IDENTIFICATION AND POPULATION HEALTH MANAGEMENT OF ALZHEIMER’S DEMENTIA
No full textProblem: Alzheimer’s disease and related dementia (ADRD), a disease of aging, is a significant and growing public health burden with substantial economic and healthcare utilization impacts. This dissertation comprises three analytical studies designed to characterize the potential added value of using unstructured electronic health record (EHR) data to identify and manage the care of patients with ADRD at the population health and individual levels.
Methods: In Study 1, we describe the application of a novel keyword search method to unstructured EHR data to identify previously undiagnosed cases of ADRD and quantify the effectiveness of this method across specific demographic subpopulations. In Study 2, we describe modeling healthcare utilization outcomes using the novel data identified in Study 1 as additional inputs to existing risk stratification analytic methods. In Study 3, we describe an analysis of data obtained from clinicians’ manual classification of ADRD patients and explore the possibility of using clinical expertise to classify ADRD patients.
Results: The application of our keyword search methodology resulted in identifying a demographically distinct subpopulation of patients with signs and symptoms of ADRD in their unstructured EHR data that were not matched in their structured data by a corresponding diagnosis code associated with ADRD. Including this evidence of signs and symptoms of ADRD found in unstructured EHR data as a predictor in population health prediction models improved their predictive power even after including other measures of patient health. Prediction models performed more poorly in the subpopulation of patients identifiable as having ADRD based solely on evidence from the unstructured EHR data but lacking corresponding evidence for ADRD based on structured data.
In Study 3, we describe the results of a study in which clinicians reviewed the EHR data of patients with ADRD and performed a classification exercise intended to resemble clinical triage. We observed high variation in clinical priorities and decision- making but also observed that asking clinicians to generate a new, small volume of unstructured data produced a relatively performant model.
Conclusions: Unstructured EHR data has value in case identification and population health management (prediction and triage) of patients with ADRD
Simulations of incomplete lineage sorting provide insights into turtle evolution
Get PDFTestudines (i.e. turtles) have historically been an erratic clade within the amniote phylogenetic tree. Though current genomic data assert a turtle-archosaur relationship (i.e. turtles as sister lineage to Archosauria), discordance from single gene and morphological data suggest a potential biological explanation for these inconsistences. As such, turtles have also been postulated to be sister to all reptiles, reflecting the anapsid skull condition, and sister to Lepidosauria, reflecting ‘lizard’-like skeletal traits. Incomplete lineage sorting (ILS) offers a possible explanation to this dilemma, causing incongruencies between gene trees and the species tree via the preservation of ancestral genetic polymorphisms during rapid speciation events. The conservation of this ancestral allelic polymorphism may contribute to turtles’ unique phenotypic character and highly derived body-plan. Previous Bever Lab research has recovered 221 genes with potential ILS signal and representing 3 gene tree topologies: 1) turtles sister to Archosauria, 2) turtles sister to all other reptiles (94 genes), and 3) turtles sister to Lepidosauria (127 genes). To link turtle morphological trait hemiplasy to the above identified ILS genes, we calculated frequencies of expression at the organ level in mice homologs. Though this work did not locate body regions particularly affected by ILS, the pervasive phenotypic patterning of turtle ILS genes demonstrates potential ubiquity throughout the Testudines genome. The theoretical basis of this study is underpinned by an evolutionary simulation modelling the effects of deep coalescence on the genomes of 9 amniote taxa representing each most inclusive clade. Simulated amino acid sequences were generated along 4 topologies varying tree hypothesis and deep coalescence, and under 8 experimental proportions evaluating predicted ILS ratios vs predicted introgression ratios. Maximum likelihood phylogenetic reconstruction facilitated the generation of gene trees from sequence data, and a resultant species tree was estimated for each replicate. Relative frequency analyses and Bayesian estimates of species divergence times were calculated. Comparisons between the divergence time estimates of the Lepidosauria-Testudines-Archosauria node reveal that ILS ‘signal’ is masked with sufficiently high proportions of deep coalescence in species tree topology, despite deep coalescence in alternate phylogenies, among other conclusions
UNTITLED: NASREEN MOHAMEDI, GEETA KAPUR, AND ART HISTORY’S TIME
No full textNasreen Mohamedi (1937–1990) was an abstract artist born in Karachi (now in Pakistan), who lived and worked in South Asia, the United Kingdom, Bahrain, and France, and who travelled extensively in Europe, Asia, and the Middle East, synthesizing the historical avant-garde with Indo–Islamic aesthetic theory to sustain a decades–long vocabulary of lines, planes, vectors, and arcs. Geeta Kapur (b. 1943), a self–designated “historian–critic,” was born in New Delhi, and has lived and worked in South Asia, North America, and the United Kingdom, developing through the second half of the twentieth century strategies through with which to reconcile the Indian nation–state (b. 1947) with world modernism, arguing for the significance of representational painting in this effort. From 1990 to 2016, mourning both her friend and the death of the secular nation, Kapur drafted two extended essays on Mohamedi’s practice, “Elegy for an Unclaimed Beloved” and “Again a Difficult Task Begins” that offer us a reassessment of her critical project. Periodizing modernism toward a new history of avant-garde practices, with Mohamedi as an anchor, these texts skim aesthetics, craft, theories of aesthetic labor, and a “re–enchantment of the secular,” to disclose a radically transhistorical poetics. I use this pivot to offer, first, a reading of Kapur’s criticism, including interpretations of two major, somewhat misunderstood, texts, “Partisan Views about the Human Figure” (1981) and “When Was Modernism in Indian/Third World Art?” (1993). Second, against their poetic weight, I historicize Mohamedi’s untitled works—self–portraits in the 1950s; prints, landscapes, and “automatic” watercolors in the 1960s; allover ink drawings in the 1970s; and optical diagrams in the 1980s—as serial material investigations. I demonstrate the remarkable range of her aesthetic resources for such attentive duration, which include weaving, music, poetry, metaphysics, the ocean, the desert, architecture, and urban planning, and situate her abstraction as an “artisanal” practice translated to the seriality, anonymity, and procedural innovations (print, drawing, collage, and montage) that characterize art after capitalism. Five chapters meet Kapur and Mohamedi at conceptual and historical intersections. In the first, “Double Self-Portrait,” I develop Mohamedi’s early self–portraits and their relationship to Kapur’s theory of the citizen–subject in When was Modernism. The second, “Nature,” situates Mohamedi’s prints, landscapes, and automatic drawings from the 1960s as a material quest for immersion in deep time, as against Kapur’s theory of recognition, embedded in readings of Négritude, in her 1968 essay “In Quest of Identity.” The third, “Artisan,” explores Mohamedi’s abstraction in the 1970s as the revival of parallel artisanal practices such as weaving and Hindustani music, and the centrality of their ritual time to Kapur’s reevaluation of abstraction as an embodied labor, theorized through Bhakti poetry, in her 2016 “Again a Difficult Task Begins.” The fourth, “The Binding” draws out the phenomenological experience of viewing Mohamedi’s abstraction, as well as its effects in Kapur’s writing, establishing the ethically reciprocal labors both critic and artist solicit. In the fifth, “History,” I outline Kapur’s theory of narrative figuration in her “Partisan Views on the Human Figure” and contrast it to the corporeal departures of Mohamedi’s late drawings. Throughout, I use Kapur/Mohamedi as a model to understand the consolidation of “Indian” art history, as well as to write a history of untitled abstract art by a range of 20th-and 21st-century practitioners. Emphasizing material, procedural, and phenomenological accounts of works of art and criticism, and drawing on extensive archival research, I bring Mohamedi and Kapur together to position abstract art as inseparable from art history’s time. By this I mean three things: the time of artistic labor (looking, making, creating, beholding, etc.); abstraction’s contingence on a long history of art and aesthetics (in its regional sense as “South Asian,” “Islamic,” “third-world,” or “Asian,” in its philosophical sense as “Indo–Islamic”; and in its temporal sense as “modern,” “contemporary,” “postcolonial,” or “avant-garde”); and the coincidence of abstract art and art history’s disciplinary consolidation
ILLUMINATING ABIOLOGICAL BIOCATALYSIS: LEVERAGING AZIDATION AND FLUOROGENIC CLICK-CHEMISTRY TO UNLOCK NEW REACTION PARADIGMS IN NON-HEME IRON ENZYMES
No full textEnzymes, the molecular machines that support life, are remarkable catalysts. Enabled by their unique three-dimensional structures, enzymes enact precise control over reaction pathways. Although over the past several decades, research has demonstrated that the myriad of enzyme functions are encoded and programmable, enabling detailed rationalizations and predictions of function from structure, efforts towards the opposite – designing efficient enzymes for user-defined transformations – have largely remained elusive. Nevertheless, researchers have reconstructed the biological optimization algorithm to bypass our present lack of understanding the biocatalytic ‘language’. Directed evolution, or iterative cycles of mutation, selection, and amplification, can be used to enhance enzyme performance even in the absence of design principles. While a potent tool, directed evolution necessitates an observable amount of activity, and was therefore initially employed for ‘small’ changes to known activity such as enzyme substrate and condition compatibility. Recently, the same precepts of so-called enzyme promiscuity have been applied to the mechanisms of chemical reactivity. Indeed, through chemical intuition scientists have predicted instances of and developed unquestionably novel enzymes. However, several synthetic reactions remain unrecognized in the biocatalytic repertoire. In this dissertation, we contribute multiple novel transition-metal catalyzed abiological reactivities to this space through building and employing a standardized approach to engineering non-heme iron enzymes. In the same way that others have targeted or mimicked key aspects of biochemical mechanisms, we viewed the known Fe(III)-N¬3 intermediate in non-heme iron enzymes as a source of radical reactivity. Moreover, by leveraging the reportability of the azide-functionalized product by fluorogenic click chemistry, directed evolution efforts were empowered through development of a high-throughput screening platform. Within this framework, we demonstrate the power of this integrated approach through discovery of three unique biocatalytic systems with distinct putative radical generation systems, N-Fluoroamides, hypervalent iodine reagents, and nitrene precursors, and unique chemistry, C-H functionalization, and alkene difunctionalization. We anticipate these results to be a starting point for further biocatalytic innovation by providing a breakthrough into sequence spaces for these novel chemistries and inspiring other applications of non-heme iron enzymes. Furthermore, the fluorogenic assay reported here has potential to bolster these efforts through enabling ultra-high throughput instrumentation
The Spectral Defect: Death, Diagnosis, and Determinism Across the Atlantic World
No full textThis dissertation is an intellectual and cultural history of medical diagnoses that have been used to 'explain away' concerns about racialized fatalities that occur in state custody, dating from roughly the 1960s to the present. Many of the diagnoses that I examine throughout the project (i.e. excited delirium, ganja psychosis, vegan syndrome) are not recognized by the American Medical Association, the World Health Organization, and the like. Yet, these conditions still appear in autopsies, toxicology reports, death certificates, and state inquests into ‘suspicious deaths’ across the United States, Canada, Britain, and the West Indies, prompting the question: How does the medicalization of racial violence travel across the boundaries of the nation-state and what might we say about a kind of transatlantic pathologization of Black life and death? Proponents as well as skeptical members of these diagnoses oftentimes frame their concerns around the same question: Are these ‘real’ biomedical conditions? However, I argue that limiting our engagement to this question misses an opportunity to assess the constitutive relations through which medical concepts come into view and the logics that makes certain medical determinations possible. In each chapter, I revisit the archives of forensic pathology — autopsy observations, clinical trials, medical case files, toxicology test values — and trace the politics of knowledge that give rise to present-day cultural and political claims. From these documentary techniques, I hope to craft new ways for social scientists and historians to think about medical ethics, the construction of biomedical accounts, and the use of epidemiological information
A two-stage mixture model for bivariate competing events
Get PDFCOVID-19 has presented hospitalized patients with two critical, competing outcomes: death and discharge. Healthcare providers are interested in determining whether patients will experience in-hospital death or discharge, as well as the duration of their hospital stay. To address these concerns, we need to design an approach that can yield a binary outcome and can also utilize time-to-event information that includes censoring for survival time prediction. Therefore, we propose a novel two-stag mixture model for bivariate competing events. The first stage of our model uses a logistic regression to deliver an immediate judgement. Subsequently, the second stage, focusing on prediction, constructs separate Cox regression models conditional on each event type, which can provide insights of survival times given the outcome. The two stages are connected by a conditional structure and all the parameters are estimated simultaneously with the EM algorithm. For new patients, this two-stage model can predict both the eventual occurrence probability and individual risk development for each possible outcome. We conduct simulation studies to assess the parameter estimation, and the two-stage model demonstrates strong performance. Applying our model to COVID-19 inpatients data sourced from the Johns Hopkins showcases it value in clinical decisions and healthcare resource management