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Advancing Small Molecule Drug Discovery by Targeting Biomolecular Condensates and Evaluating Novel Chemical Scaffolds
No full textSmall molecule drugs comprise nearly 90% of global drug sales. However, existing small molecules have struggled to treat complex disease landscapes such as those found in neurodegenerative diseases, emerging viral outbreaks, and evolving drug resistance. A promising approach to develop treatments for these unmet medical needs is to discover new small molecules by combining improved target selection with novel drug modalities. In Chapter 1 of this thesis, I describe the identification of small molecule modulators of SARS-CoV-2 nucleocapsid (N) protein condensation. These compounds exhibit pan-human coronaviral N condensation modulatory activity – an early but crucial demonstration that targeting viral condensation can be a viable means to achieve antiviral efficacy. In Chapter 2, I describe the development of two alternative high throughput screening assays that robustly report on changes in protein condensation states in response to small molecule condensate modulators, expanding the toolkit available for future condensate modulator screening campaigns. Finally, in Chapter 3, I detail the discovery of potent cellular uptake inhibitory activity exhibited by several groups of plant polyphenols, highlighting how their bioactivity is related to certain chemical moieties typically under-represented in small molecule drug discovery. Altogether, this thesis demonstrates the feasibility of targeting “undruggable” condensates and exploiting unique chemical moieties for potential therapeutic outcomes, challenging the boundaries of modern drug discovery.Chemical Biolog
An exploration of nurturing care environments: Micro, meso and macro systems
No full textOver recent decades, child health approaches have expanded from focusing solely on reducing mortality to a broader framework emphasizing both survival and thriving. Early efforts by organizations like UNICEF addressed immediate child health needs, prioritizing basic healthcare and immunizations. This approach evolved in the 1980s and 1990s to include holistic child development, influenced by the 1989 Convention on the Rights of the Child, which recognized cognitive, emotional, and social well-being alongside physical health. The inclusion of child development in the MDGs and SDGs reinforced this integrated approach. By 2017, the Multigenerational Life Course Framework encapsulated this perspective, highlighting the role of caregivers, families, and communities in supporting child development through nurturing care inputs, such as health, nutrition, safety, responsive caregiving, and early stimulation and learning.
This dissertation is grounded in the Multigenerational Life Course Framework, which emphasizes the importance of both nurturing care inputs and enabling environments in promoting child development. It examines caregiver, household and community resources within this framework, analyzing their interactions across multiple levels of influence—macro, meso, and micro—as described in Bronfenbrenner’s ecological systems theory (1979). Specifically, the dissertation investigates how caregiver, household, and community resources affect caregivers' ability to deliver nurturing care in low- and middle-income countries (LMICs), focusing on the broader cultural, social, and economic contexts that shape these environments.
The research is structured into three papers. Paper 1 examines the role of women’s empowerment in caregiving practices in rural Pakistan. The study found positive associations between women’s bodily autonomy and household decision-making power and their responsiveness as caregivers. Qualitative insights revealed that cultural norms around gender roles often limited women’s autonomy, and that caregiving responsibilities are often shared among family members, suggesting that parenting programs in similar settings should include other family members to support caregiving roles effectively. Paper 2 focuses on a nationally implemented parenting program in Brazil, evaluating how program outcomes on caregiver knowledge of child stimulation are influenced by caregiver characteristics, such as education and household resources. The findings suggest that customizing program dosage to align with caregiver characteristics may enhance program performance. Paper 3 assesses the availability of community resources, such as healthcare and nutrition services, across Brazilian municipalities and their association with early childhood development (ECD) outcomes. Results showed that access to quality exams and early home visits positively impacted child development at 3 years old, underlining the role of multisectoral public services in resource-limited settings. Overall, the dissertation highlights the interconnectedness of nurturing care, caregiving practices, and broader societal contexts. It calls for interventions that address both direct care and enabling environments to improve ECD outcomes, emphasizing the need for multisectoral collaboration that aligns with cultural and social contexts.
Recommendations include developing culturally appropriate measures of women’s empowerment, adopting flexible program designs to accommodate caregiver variability, and enhancing primary care services and multisectoral collaboration to support early childhood development (ECD). This research underscores the importance of an integrated approach to child health that not only supports survival but also fosters children’s holistic development within their broader social and cultural ecosystems.Population Health Science
Discovery of a Broad-spectrum, Fluorinated Lincosamide Antibiotic Through Chemical Synthesis
No full textThis dissertation presents an investigation of next-generation lincosamide antibiotics which led to the discovery of a fluorinated, macrobicyclic antibiotic candidate (BT-33) with best-in-class activity metrics in antibacterial potency, metabolic stability, and in vivo efficacy against multidrug-resistant bacterial pathogens.
I report the discovery of BT-33 using a modular synthetic route designed to access substituted macrobicyclic thiolincosamines. Adaptations of this discovery synthesis delivered >60 macrobicyclic lincosamide analogs, more than half of which possessed antibacterial activity. The structure-activity relationships elucidated in this investigation showed that each structural feature within the macrobicyclic residue of BT-33 is essential to its potent antibacterial activity and enhanced metabolic stability. These conclusions were supported by conformational analysis and X-ray crystallography which revealed the 11-membered macrobicyclic residue of BT-33 to be rigidified in a conformation optimal for binding to the bacterial ribosome. Further investigation of this chemical series provided analogs which were unaffected by mechanisms of lincosamide resistance (namely erm and cfr methyltransferases), likely by engaging an additional binding pocket in the nascent peptide exit tunnel.
I present a distinct, scalable synthesis of BT-33 that enabled its preparation on >5-g scale, an amount which was required to support an early preclinical profiling campaign. This new synthesis relied on a highly diastereoselective coupling reaction between a sulfinimine intermediate and a putative allenylzinc reagent formed in situ. Macrocyclization of the coupled product by C–S bond formation (rather than by C=C bond formation, as was used in the discovery route) followed by semireduction of the resultant cyclic alkyne intermediate set the key stereochemical features within BT-33 in an operationally simple and high yielding reaction sequence. This route was adapted to synthesize another structurally distinct, fluorinated antibiotic (11-fluoromethyl-cresomycin, a lead candidate in its own right) and synthetic analogs of BT-33 which were not accessible by the discovery route.
I detail the results of an early preclinical profiling campaign to evaluate oxepanoprolinamide (OPP) antibiotics (including BT-33 and 11-fluoromethyl-cresomycin) for use in the treatment of community-acquired bacterial pneumonia. In vitro assays determined that the lead OPP molecules exhibit a highly favorable microbiological profile, acceptable physicochemical properties, and no apparent liabilities for off-target toxicity. In vivo assessments showed that BT-33 was efficacious in multiple models of infection using multidrug-resistant bacterial strains. Considering this highly promising profile, we are optimistic that one or more molecules from this class will be advanced further in preclinical development and may one day reach the clinic.
Finally, I report an investigation of new lincosamide derivatives inspired by the rigid oxepanoproline residue of the prototypical OPP antibiotic, iboxamycin. Rational, structure-based design guided the synthesis and assessment of >40 lincosamide analogs with substituted, heterobicyclic amino acid residues. Ultimately, this investigation confirmed the strict steric and physicochemical requirements for a lincosamide derivative to effectively overcome antibiotic resistance in bacteria and supported the conclusion that the oxepanoprolinamide is a privileged scaffold.Chemistry and Chemical Biolog
Engineering Asymmetry: Geometric Design of Nanoscale Lipid Vesicles for Uptake-Optimized Drug Delivery
No full textIt is often the case that therapeutics needed to treat particular diseases or ailments cannot be administered directly into the bloodstream or digestive system. Due to problems like toxicity in non-targeted environments or requirements for higher uptake by target cells, they often need to be transported by drug delivery vehicles. Today, a broad range of such vehicles are used, including Lipid NanoParticles (LNPs) and Viral Vectors, but they all face significant shortcomings (in this case, limited parameter space for packaging only negatively charged molecules, and size constraint of packages respectively). We explore a new type of drug delivery system, namely nanoscale bi-leaflet lipid vesicles, which have shown promise in encapsulating a large set of drugs without size or charge constraints. The biggest challenge currently facing lipid vesicles is limited cellular uptake, which we explore in this thesis through a geometric and symmetric lens. We show that asymmetry between the inner and outer leaflet of the vesicles enhances uptake by up to 9-fold in some cases, while showing that higher magnitudes of zeta potential and greater membrane fluidity enhance uptake as well. We also relate these empirical findings to geometric theory to synthesize our learnings and move toward an optimization model to maximize vesicle uptake by cells.This research hopes to contribute to forming more efficient, universal drug carriers and make it possible to transport therapeutics never delivered before, including the CRISPR Cas-9 gene-editing protein among other large, complex proteins and drugs.Biomedical Engineering A
Multidimensional Attention Masks: Towards Performant and Provable Order Independence in LLMs
No full textThe development of generative language models that can create long and coherent textual outputs via autoregression has led to a proliferation of uses and a corresponding sweep of analyses as researchers work to determine the limitations of this new paradigm. Unlike humans, these ‘Large Language Models’ (LLMs) are highly sensitive to small changes in their input, leading to unwanted inconsistency in their behavior. One problematic inconsistency when LLMs are used to answer multiple-choice questions or analyze multiple inputs is order de- pendency: the output of an LLM can (and often does) change significantly when sub-sequences are swapped, despite both orderings being semantically identical. In this paper we present Multidimensional Attention Mask, a technique that guarantees the output of an LLM will not have order dependence on a specified set of sub-sequences. We show that this method provably mitigates order dependency, and that it can be applied to any transformer-based LLM to enable text generation that is unaffected by re-orderings. Delving into the implications of the method, we show that, despite our inputs being out of distribution, the impact on expected accuracy is small, where the expectation is over the order of the candidate responses. Thus, Multidimensional Attention Mask can be used as a ‘dropped-in’ method on fully trained models. Finally, we introduce a fine-tuning strategy that integrates SBP into the training process, “pulling” these set-formatted prompts closer to the model’s training manifold in order to address the performance degradation induced by the drop-in Multidimensional Attention Mask approach. Experiments demonstrate that SBP fine-tuning significantly improves accuracy and robustness to answer-order permutations, all while preserving broader language modeling capabilities. We discuss the broader implications of order-invariant modeling and outline future directions for building fairer, more consistent LLMs.Computer Scienc
The Effect of Changing Medicaid Dental Benefits Type on Dental Services Utilization Among the Adult Population
No full textIntroduction: In 2021, Medicaid invested approximately $18 billion in dental care, yet studies show that access remains limited for many low-income adults. One key strategy that states can use to enhance dental care and reduce disparities among low-income adults is increasing the number of covered dental services. However, few studies have explored the impact of changing the Medicaid dental benefit type on dental services utilization among the low-income adult population at the state-level. Additionally, including the perspectives of Medicaid dental offices in each state would deepen our understanding of Medicaid dental benefits for adults. Objectives: 1) to understand the attitudes of state Medicaid dental offices toward the importance of different types of dental benefits on dental care use among Medicaid beneficiaries, and 2) to explore the impact of changing the Medicaid dental benefit type on adult dental service utilization within each state, considering the year of these changes. Hypothesis: upgrading Medicaid dental benefit type would improve dental services utilization. Approach: This cross-sectional study distributed a survey to all 50 states and the District of Colombia (DC) Medicaid dental offices. Also, we used nationally representative Behavioral Risk Factor Surveillance System (BRFSS) data from 2010 to 2020. Our study population included low-income (household income below 138% FPL) adults aged 18 to 64 years. Statistical analysis: Univariate and bivariate analysis using Fisher's exact test were conducted to analyze the survey data. While difference-in-differences (DID) and regression discontinuity (RD) designs were employed to evaluate the association between Medicaid dental benefit changes and dental care utilization, accounting for individual-level and state-level covariates. Results: The survey, with a 65% response rate, revealed strong agreement on the importance of offering more dental services for Medicaid adult beneficiaries, particularly preventive care, and on the importance of expanding Medicaid eligibility criteria. Moreover, all states expressed a positive attitude toward the importance of including various types of dental services, except for teledentistry, which was less prioritized. Regarding Medicaid dental office satisfaction with the provided dental services, a direct relationship was observed: where an increase in the level of dental benefits offered was associated with higher satisfaction levels reported by Medicaid dental offices. For the BRFSS data analysis, eight states were included based on the year and type of dental benefit change (Emergency to Limited: 1 state; Emergency to Extensive: 4 states; and Limited to Extensive: 3 states). The results of DID and RD analyses suggest that, in general, expanding dental benefit type for Medicaid adult beneficiaries would increase the probability of dental service utilization among low-income adults. However, the magnitude of this increase varied by state. Conclusion and future direction: expanding dental benefits for low-income adults seems to be effective. However, other strategies and state-specific factors should be carefully considered when designing interventions aimed at increasing and sustaining dental service utilization. We recommend gaining a deeper understanding of these state-specific factors, by integrating both quantitative and qualitative approaches, to develop a tailored plan for creating targeted and effective interventions.Dental Public Healt
Profiling the molecular and cellular consequences of microtubule drug perturbations
No full textMicrotubules are dynamic polymers integral to cellular processes such as division, signaling, and maintenance of cell shape. Microtubule-targeting agents are crucial in the treatment of cancers, inflammatory diseases, and parasitic infections. They achieve this broad therapeutic effect by either inducing cytotoxicity or inhibiting maladaptive responses, resulting in narrow therapeutic indices that can leave patients vulnerable to toxic side effects. This dual functionality raises important questions about the factors driving their clinical efficacy. Additionally, the development of specialized microtubule-destabilizing drugs, such as those that target tumor vasculature or reduce chemotherapy-induced neutropenia, highlights the complexity of these treatments and the need for further investigation into how these clinical outcomes are achieved.
This dissertation profiles molecular responses to microtubule-targeting agents and investigates whether microtubule depolymerizers, despite their diverse clinical applications, share common pathways. Using primary endothelial cells from three human donors and one immortalized cell line, I employ dose-response assays, RNA-sequencing, and phosphoproteomics to analyze the effects of these compounds.
In Chapter 1, I compare transcriptional and phosphoproteomic responses that microtubule depolymerizers elicit and propose a model that links microtubule depolymerization to complex downstream cellular responses. Chapter 2 delves into specific pathways activated by microtubule polymerization and depolymerization, with a focus on their intersection with inflammatory signaling.
Collectively, these findings reveal that while microtubule depolymerizers induce complex molecular responses, they do not exhibit significant differences in their mechanisms of action. This reinforces the direct link between microtubule perturbation and cellular response. Furthermore, this study also illustrates the value of multi-omics approaches in validating existing knowledge and uncovering new insights into microtubule biology.Medical Science
Marginal Development: Japan, Taiwan, and the Tropicalization of the Yaeyama Islands, 1880s to 1970s
No full textLocated 491 kilometers south of Okinawa’s main island and 111 kilometers east of Taiwan, the Yaeyama Islands consist of 23 islands and represent Japan’s only tropical region. During the Japanese colonial period (1879-1945) and the American Occupation (1945-1972), scientists, capitalists, and bureaucrats idealized the archipelago as a “treasure trove” of unique natural resources. Japanese and American metropolitan demands for tropical products not only drove the exploration and exploitation of the islands’ resources but also transformed the environmental landscape to create a specific form of tropicality modeled after Taiwan. The process of tropicalization included the transplantation of hybridized varieties of pineapple and sugarcane, as well as the resettlement of other colonial populations, particularly Taiwanese and Okinawans, to work on large-scale land reclamation projects. These development efforts established new connections between the Yaeyama Islands and other islands in the region, while also reinforcing the economic structures that positioned the archipelago as internal colonies within the Japanese empire and American-occupied Okinawa. Through examination of the tropicalization of the Yaeyama Islands, this dissertation highlights the roles of scientific expertise, inter-imperial technological exchange, and labor migration networks in shaping the agricultural development of the islands within a broader global context.East Asian Languages and Civilization
Hollowed Ground: Reconstructing an Abandoned Catholic Space Through a Queer Lens
No full textIn the United States, the share of Americans who identify as Catholic has been on the decline over the last fifty years. Many young people today cite differing views on gender and sexuality from organized religion as their reason for leaving. The continued alienation of queer and female populations, further exacerbated by the COVID-19 pandemic, has led to the closing of churches, monasteries, and convents across the country, as well as other vital services often provided by organized religion such as schools and hospitals.
Catholicism, as a religion with a deep-rooted history in architecture and the arts, inevitably leaves behind many historical buildings imbued with tradition vacant though difficult to repurpose. There remains a certain reverence for sites of worship – as such, any reuse of a spiritual building forces us to question what constitutes a sacred space, and for how long sacrosanct veneration should be upheld. Despite the socially imposed moral odds, can queer and feminist theory be used to reclaim and recreate spiritual spaces for new communities?
Using a former Catholic Church in Hell’s Kitchen, New York, a neighborhood that presently draws in the queer community, this thesis first explores the history of the neighborhood’s demographics to gain clues on how different groups have used and repurposed the same space. Through deconstructing and reevaluating the spiritual space of a Catholic church this thesis offers a new, queer understanding of spaces of worship. By re-using, and existing in the shell of organized religion’s past this project provides a broader understanding of spirituality and community.Department of Architectur
Effect of exposure energy dose on lateral resolution and flexural strength of three-dimensionally printed dental zirconia
No full textPURPOSE
This study aims to evaluate the effects of exposure energy on the lateral resolution and mechanical strength of dental zirconia manufactured using digital light processing (DLP).
MATERIALS AND METHODS
A zirconia suspension and a custom top-down DLP printer were used for in-office manufacturing. The viscosity of the suspension and uniformity of the exposed light intensity were controlled. Based on the exposure energy dose delivered to each layer, the specimens were classified into three groups: low-energy (LE), medium-energy (ME), and high-energy (HE). For each energy group, a simplified molar cube was used to measure the widths of the outline (Xo and Yo) and isthmus (Xi and Yi), and a bar-shaped specimen of the sintered body was tested. A Kruskal–Wallis test for the lateral resolution and one-way analysis of variance for the mechanical strength were performed (α = .05).
RESULTS
The zirconia green bodies of the ME group showed better lateral resolution than those of the LE and HE groups (both P .001). Regarding the flexural strength of the sintered bodies, the ME group had the highest mean value, whereas the LE group had the lowest mean value (both P .05). The ME group exhibited fewer agglomerates than the LE group, with no distinctive interlayer pores or surface defects.
CONCLUSION
Based on these findings, the lateral resolution of the green body and flexural strength of the sintered body of dental zirconia could be affected by the exposure energy dose during DLP. The exposure energy should be optimized when fabricating DLP-based dental zirconia.Prosthodontic