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Education and Economic Mobility: How Schools Shape Peer Composition and Student Trajectories
Get PDFThe potentially equalizing role of schools is called into question when lower-income students increasingly attend different schools—and, within schools, different classrooms—than their higher-income peers. My dissertation examines how schools shape lower-income students’ peer composition and the implications for long-term outcomes.
In the first paper, using data from Texas, a large and nationally representative state, I find that the median lower-income student experiences schooling with nearly ten times fewer upper-income classmates than their wealthier peers. To understand why exposure to upper-income peers may matter for long-term outcomes, I isolate peer effects from resource access using within-school, between-cohort variation in the share of upper-income students, controlling for school trends. I find that lower-income students in cohorts with more upper-income peers are marginally more likely to enroll in four-year colleges and earn higher wages. These effects do not appear to operate through changes in access to school resources; the increase in college enrollment seems to be driven by exposure to lower-achieving upper-income peers.
The second paper bridges research on school choice and academic tracking by examining how the addition of advanced courses affects classroom and school peer composition. Public schools may introduce academic tracks to attract or retain upper-income and higher-achieving students. However, tracking can also exacerbate sorting by income and achievement within schools. Exploiting variation in the timing of Advanced Placement (AP) course additions within subjects, I find that adding an AP course increases lower-income students’ exposure to upper-income classmates. This increase is driven by a rise in the overall share of upper-income students at the school following the course addition, offsetting the increase in within-school sorting.
In the third paper, my co-authors and I study the expansion of alternative schools for lower-performing students in Chicago. These schools offer tailored curricula and flexible scheduling, potentially improving graduation rates among students at high risk of dropping out. However, they may also segregate vulnerable students who otherwise may have graduated from traditional public schools. Using variation in the timing and proximity of school openings, we find that alternative schools increase high school persistence and reduce student arrests but reduce the likelihood of college enrollment.Educatio
Elucidating novel chemical and genetic mechanisms of LSD1-HDAC1/2-CoREST complex regulation
Get PDFProtein complexes have a wide range of functions that can be modulated through both enzymatic activity and protein-protein interactions. In efforts to design small molecule therapeutics that target specific protein functions, molecules with diverse mechanisms of action have been developed. Traditionally, drug design has focused on inhibiting an enzyme’s catalytic activity, either by directly blocking its active site or by designing an allosteric modulator. However, beyond catalytic function, enzymes often serve as scaffolds that mediate interactions with other proteins—interactions that influence the overall function of a protein complex within cells. Discovering new small molecule modalities that selectively target one function of a protein can optimize therapies for various disease indications, while also offering insight into novel mechanisms of protein regulation and disease pathogenesis.
In this thesis, I investigate the mechanisms of action of two recently developed small molecule modalities targeting the LSD1-HDAC1/2-CoREST (LHC) complex and uncover how mutations in an E3 ligase substrate adaptor lead to a new mode of LHC complex dysregulation in cells. In Chapter 1, I provide an overview of the LHC complex and key structural studies that have elucidated its fundamental functions and biological roles in cells and human development. I then review its involvement in disease and therapeutic applications, which has driven efforts to identify small molecules that target the complex. Finally, I introduce the concepts of targeted protein degradation—a therapeutic strategy recently applied to targeting the LHC complex—and genomic screening methodologies that we have used to evaluate novel mechanisms of protein regulation.
In Chapter 2, I describe our work elucidating the mechanism of action of the small molecule T-448, an LSD1 inhibitor that selectively targets enzymatic activity while preserving LSD1’s interactions with transcription factors. Through mass spectrometry and structure-activity relationship studies with T-448 analogs, we found that T-448 forms a covalent drug-FAD adduct in LSD1’s active site, which subsequently undergoes Grob fragmentation to yield a compact formyl-FAD adduct. This adduct preserves LSD1’s scaffolding function with transcription factors such as GFI1/GFI1B, thereby reducing hematological toxicity and making T-448 a more promising candidate for treating neurological disorders. Additionally, we show that this conversion from drug-FAD to formyl-FAD can serve as a resistance mechanism in AML cells. Using CRISPR suppressor scanning, we previously identified a loop deletion mutation distal to the catalytic site that confers resistance to certain LSD1 inhibitors through this mechanism. Altogether, this work highlights how small molecule design can target specific LSD1 functions and how distal loop mutations can impact drug mechanism of action.
In Chapter 3, I detail our investigation into the mechanism of action of another LSD1-targeting molecule, UM171. It was initially identified in a phenotypic screen and later shown to induce degradation of LSD1 and CoREST via the E3 ubiquitin ligase substrate adaptor KBTBD4, however the direct binding partners of UM171 remained unknown. Using fluorescence-based cellular assays and biochemical binding studies, we determined that HDAC1/2 is the direct binding partner of UM171 within the LHC complex. UM171 acts as a molecular glue and increases the affinity between LHC and KBTBD4. We validated this by solving a cryo-EM structure of the KBTBD4-UM171-LHC complex and unexpectedly identified a second molecular glue—inositol hexakisphosphate—at the binding interface. The structure revealed that the KBTBD4 dimer engages a single copy of the HDAC1/2-CoREST complex asymmetrically. Additionally, base editing scanning was performed and confirmed UM171’s binding sites. This was the first study to elucidate the binding mode of a molecular glue that engages a Cullin3 E3 ligase substrate adaptor, revealing the mechanism behind LSD1 and CoREST degradation.
In Chapter 4, I move beyond small molecule regulation to explore how mutations can also modulate protein-protein interactions. In medulloblastoma, complex insertion-deletion and substitution mutations have been found in a single loop in the Kelch domain of KBTBD4. In patient-derived xenograft models harboring these mutations, CoREST and LSD1 levels are depleted and knockout of mutant KBTBD4 rescues these protein levels. Through a series of biochemical assays, we also discover that the mutant KBTBD4 have increased binding affinities to LHC. To understand the scope of these gain-of-function mutations, we performed a deep mutational scan of the loop mutated in medulloblastoma. Surprisingly, a wide array of mutations promoted CoREST degradation and further analysis was performed to determine the types of mutations that had the strongest phenotype. Structural studies were performed to determine how these KBTBD4 variants were engaging the LHC substrate and revealed that mutant KBTBD4 mimics the UM171-induced binding mode observed in Chapter 3. This structural insight prompted us to test known HDAC active-site inhibitors as a potential therapeutic strategy to disrupt the mutant KBTBD4-LHC interaction. Through this study, we show that KBTBD4 cancer mutations chemically and functionally mimic UM171 and that deep mutational scanning can identify mutations that drive substrate degradation. We also demonstrate that active-site inhibitors can be repurposed to disrupt pathogenic protein-protein interactions.
Overall, this thesis showcases multiple ways to perturb the LHC protein complex, via distinct small molecule modalities and neomorphic mutations that induce novel protein interactions leading to degradation. These studies not only teach us how we can differentially regulate the LHC complex for different therapeutic applications but also serve as an instructive example of how we can use both chemical and genetic methodologies to induce similar phenotypic effects. This work opens the door to applying high-throughput genomics to discover novel modulators for other protein complexes and cellular pathways in various disease contexts.Chemistry and Chemical Biolog
Structural Characterization of Outer Membrane Protein Folding Intermediates
No full textTransmembrane proteins with a β-barrel topology are found in the outer membranes of mitochondria, chloroplasts, and Gram-negative bacteria. These proteins are folded by a conserved protein complex termed the β-barrel assembly machine (BAM). Structural evidence has demonstrated that the central component of the complex, BamA – itself a β-barrel, interacts with substrates via β-augmentation. However, the mechanism by which BAM allows a substrate to fold is unclear, and what features of the machine allow it to effectively fold many different substrate barrels of varying size and shape is unknown.
First, we develop a disulfide crosslinking assay that we use to identify folding intermediates of substrate barrels as they are assembled on BAM. We use this assay to show that two β-barrel substrates, BamA and LptD, pass through multiple shared intermediates during their folding on the BAM complex.
Next, we structurally characterize three of these sequential folding intermediates of a BamA barrel substrate folding on BAM using cryo-electron microscopy. This “movie” of snapshots shows that β-strands are added to the nascent substrate barrel from a disordered state within the machine BamA lumen. The snapshots also show how the machine BamA barrel variably distorts according to the stage of folding of a single barrel, and suggest that a substrate’s efficient release from the machine requires a properly ordered global substrate architecture.
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Finally, we structurally characterize two large substrate barrels, LptD and FimD, in the process of folding on the BAM complex. These structures suggest that BamA barrel distortion and β-templating of substrate strands from the BamA lumen are general folding features. They also present twists on this general folding mechanism, and allow us to propose models for how BAM folds large barrels which contain soluble plug domains.
Together, these results provide a detailed structural picture of outer membrane protein folding, show how substrates grow via sequential addition of β-strands, and suggest that BAM’s ability to fold many different barrels is rooted in its ability to variably distort, allowing a substrate to find its thermodynamic minimum structure no matter the substrate barrel’s ultimate shape.Chemistry and Chemical Biolog
Decoding DUB regulation in Golgi reassembly and protein degradation
No full textThe ubiquitin proteasome system (UPS) plays a critical role in maintaining protein homeostasis in cells – regulating both protein synthesis and protein degradation. Embedded in the UPS are proteins that (1) add ubiquitin enabling different signals, (2) remove ubiquitin signals allowing for substrate rescue and (3) recognize poly-ubiquitin signals for subsequent proteasomal degradation. Targeting different components of the UPS is of high interest for drug discovery in hopes to uncover novel therapeutic targets for regulating protein homeostasis for a wide range of diseases. My thesis work investigates interactions of deubiquitylating enzymes (DUBs) to various players in the UPS to explore the possibility of targeting specific DUBs, with in-house DUB inhibitors, to regulate substrate fate. In Chapter 2, I utilized structural biology, biochemistry and cellular biology to elucidate the interaction between VCPIP1, a DUB of interest, with VCP, a key player in the UPS, and p47, a VCP adaptor protein, in the context of Golgi reassembly. In Chapter 3, I employed biochemistry to understand the function of VCPIP1 at the C-terminal end of VCP in the context of the UPS. In the presence of a poly-ubiquitylated substrate, we used fluorescence-based assays and SDS-PAGE gels to assess the effect of VCPIP1 domain truncations as well as VCPIP1 and p97 inhibitors on VCP and VCPIP1 function. We provide initial structural analysis of a substrate-engaged VCP-VCPIP1C219A-UN complex. In Chapter 4, I applied mass spectrometry proteomics and structural biology to characterize the structural features of USP family of DUBs, specifically USP7, USP25 and USP48, and explored their interactome to discover unknown binding partners for the DUBs. The multi-faceted discoveries from my thesis work provide new structural and functional understanding of a few DUBs of interest using cryo-EM, biochemistry, cellular biology and proteomics. Taken together, this unveiled new binding regions for inhibitor development demonstrated by the newly characterized bivalent interaction of VCPIP1 to VCP and/or revealed novel interactions with binding partners between DUBs and E3 ligases observed in the proteomics data that can be leveraged for targeted protein degradation.Biological and Biomedical Science
Intimately Bound: Injustice and the Foster System
No full textPolitical theorists have not paid sustained attention to the foster system or treated it as a political institution. Despite this, scholars in law and the social sciences, as well as a growing number of social movement advocates, have suggested that the U.S. and English foster systems are unjust. This dissertation characterises injustice in the widespread but relatively understudied institution of the foster system, proposes action-guiding ethical and policy principles to address these injustices, and suggests new normative ideals to govern the state’s intervention into intimate life.
To properly characterise injustice in the foster system, I argue that we must correct a conceptual oversight about the definitive power of the system and how it is typically employed. The foster system is an institution that engages in coercive relational intervention. More specifically, it enacts violence on our intimate relationships when it exercises its power to remove children from their caregivers. Much of the injustice in the system pertains to the misuse of this power, or, what I call, the capacity to employ relational violence.
Chapter one proposes the novel concept of relational violence which provides an ethical framework for evaluating moral harms to intimate relationships. Relational violence occurs when an external party damages an intimate bond by substantially disrupting an intimate relationship. Relational violence, I argue, is generally morally wrong and we have moral reasons to minimise its use where possible. In the foster system, however, poverty, housing insecurity, and racial prejudice can lead to unnecessary relational violence through child removals. The foster system thus emerges as an unjust institution that can compound the existing harms of racial and economic inequality with painful relational injustices.
Chapter two expands on how racism in the contemporary foster system damages intimate relationships. I argue that racial ideology specifically targets black parents in their capacities as parents. Racial ideology can suggest that the intimate bonds within black families are worth less than those within other families–or even that black intimate bonds are worth nothing at all. Critics have suggested that the foster system violates a “right to parent” or the family autonomy of black parents and families, and that it can violate a black child’s right to be raised in their racial group. Alternatively, some have even suggested that the system may under-intervene into black families. I show that my account of racial ideology as undervaluing, or totally devaluing, black intimate bonds complements some critiques of racism in the system while also addressing important counterarguments raised against others.
In chapter three I argue that despite the system’s purported goal of safeguarding children, the foster system’s demonstrable function–how it effectively operates in social and political life–is in fact a kind of poverty intervention. This poverty intervention can be direct or indirect. By this I mean that the foster system may intervene based on factors that impair parenting capacities but that may be either directly or indirectly caused by poverty. That the demonstrable function of the foster system is poverty intervention is itself concerning for theories of justice since poverty is a form of systemic injustice. But despite our moral obligations to correct for systemic injustice in society, state intervention within the foster system, I argue, should be determined primarily by our obligation to minimise damage to intimate bonds.
Finally, chapter four argues that our response to injustice in the foster system requires that the system aim to protect, where possible, the integrity of our intimate relationships. The concept of relational violence implies that we must aim to equally respect the moral value of other’s intimate bonds. This requirement is, I suggest, a necessary condition for the integrity of our intimate relationships. Nevertheless, respecting even this minimal account of intimate integrity requires substantial changes to law, policy, and practice in the foster system. It also demands that we clarify the extent and bounds of coercive relational intervention through the system, and that we work to make decision-making about intervention in the system more democratic. I conclude the chapter and the dissertation with some suggestions about what respect for intimate integrity would demand of the foster system.Governmen
Bioinspired Engineering: From Medical Devices to e-Nose Sensors
No full textNature rarely solves one problem at a time. It designs systems—delicate yet resilient, selective yet responsive—that operate under multiple constraints in complex environments. This dissertation draws from that ethos, presenting a body of work that bridges implantable medical devices and electronic chemical sensors, unified by a central theme: bioinspired engineering at the intersection of materials science, fluid dynamics, and computation.
In the first half of this work, I tackle long-standing challenges in biomedical implants—devices that must remain open yet resist fouling, deliver therapeutics yet prevent contamination, function reliably yet disrupt the body as little as possible. Using tympanostomy tubes as a case study, I develop subcapillary-scale conduits with curved geometries derived from capillary transport models, paired with liquid-infused surfaces that mimic the self-cleaning skins of pitcher plants. These tubes selectively transport desired fluids (e.g., therapeutics) while passively rejecting undesired ones (e.g., water, pathogens), with performance validated in vitro and in vivo. I extend these concepts to hydrocephalus catheters, where shear-driven self-cleaning and geometry-guided antifouling design prevent occlusion from cellular debris—a leading cause of implant failure. In both systems, I combine computational fluid modeling, materials engineering, and biological analogy to build devices that work with the body, not against it.
The second half of the thesis turns to the invisible world of chemical vapors, where biological olfaction offers a blueprint for high-dimensional, real-time sensing. Inspired by the sniffing behavior of mammals and the diverse receptor arrays in biological noses, I construct cross-reactive metal oxide sensor arrays integrated with machine learning models capable of classifying complex vapor mixtures. These e-nose platforms are deployed across domains—from food spoilage and air quality to breath-based diagnostics—achieving high specificity and adaptability by incorporating temporal signal processing, fluid-guided delivery, and adaptive sampling schemes. I postulate how feedback from flow simulations and physics-informed neural networks can guide sensor calibration and improve robustness, mimicking how natural systems sense dynamically and respond in real time.
While these domains may seem disparate—an ear tube and a chemical sensor—their design challenges and solutions are strikingly parallel. Both demand selectivity without complexity, resilience without rigidity, and the capacity to navigate the messy gradients of biology and the environment. By pairing natural design principles with modern fabrication, modeling, and data tools, this dissertation offers a cohesive framework for engineering systems that are not only inspired by nature, but perform with nature’s elegance and efficiency.
Ultimately, this work illustrates that the future of biomedical and environmental technologies will not come from any single field—but from the harmonious convergence of materials, computation, and mechanics, guided by the silent logic of biology. From implant to e-nose, this is a vision of devices that sense, respond, and endure—because they are designed like life itself.Engineering and Applied Sciences - Engineering Science
Stromal-immune cell crosstalk in the developing brain borders
No full textCentral nervous system (CNS) border tissues including the meninges serve as key immune interfaces between the brain and the periphery. The three meningeal layers – the pia mater, the arachnoid mater, and the dura mater - each host a unique landscape of immune lineage cells that continuously shape healthy adult brain function and provide a firewall against invasion of pathogens into the central nervous system. However, much less is known about how the meningeal immune compartment develops in early life or how meningeal immune cells may interact with or protect the brain during critical developmental windows. Emerging evidence also suggests that meningeal stromal cells critically shape the adult meningeal immune landscape. How meningeal stromal cells contribute to establishment of this compartment in the early life window is an outstanding question.
To better understand the how the meningeal immune compartment is established, we profiled changes in the composition of meningeal immune cells from early postnatal life through adulthood. Unexpectedly, we uncovered a role for the meninges as a niche for B lymphopoiesis in the early postnatal window. B cells appear in the dura mater and other meningeal compartments as a wave spanning the first month of life in mice. Meningeal B cells undergo lymphopoiesis locally but in concert with other waves of extramedullary lymphopoiesis across the body that fuel generation of the B2 B cell compartment. Developing B cells in the dura are seeded by a common pool of hematopoietic progenitors as are B cells in other early life organs but diverge in the perinatal window and establish local hematopoietic foci in microanatomical niches near the dural venous sinuses. To elucidate the niches that support meningeal lymphopoiesis and their relationship to bone marrow niches, we profiled stromal and endothelial cells from the early life dura mater and bone marrow. This data revealed that dura and bone marrow niches are fundamentally distinct in composition. Indeed, the early life dura mater lacks canonical mesenchymal stromal cell populations known to regulate B cell development and instead comprises a heterogenous landscape of fibroblast-like cells (FLCs) enriched for the transcription factor Foxd1. Lymphopoietic foci associate with a unique network of dural sinus-associated (peri-sinus) FLCs that express the pro-hematopoietic chemokine Cxcl12, and ablation of Cxcl12 from Foxd1-expressing FLCs profoundly impairs local B lymphopoiesis. These data suggest that CNS border tissues contribute to generation of the postnatal B cell compartment and provide a model for how extramedullary stromal niches may regulate lymphopoiesis across the body in early life.
Separately, we have undertaken broader efforts to define functional roles for CNS immune cells in health and disease. One of these includes a collaborative effort to develop FEAST (Flow cytometric Engulfment Assay for Specific Target proteins) - a robust, in vivo assay to quantify engulfment of neuronal and myelin substrates by brain and brain border macrophages. This approach will be useful for studying the role of CNS phagocytes in tissue development, infection, and other neurological diseases across the lifespan.Immunolog
Probing Muon + b-Jet Resonances in pp Collisions with the ATLAS Detector
Get PDFProbing heavy resonances in collider physics has been a longstanding and fruitful endeavor. Despite well-motivated candidates like leptoquarks and their role in grand unified theories, direct experimental searches for lepton–quark resonances in proton–proton collisions are relatively scarce. Cross-generational lepton–quark resonances have received even less experimental attention. This thesis presents an ATLAS search for one such under-represented resonance: the muon and b-jet resonance. The search leverages the full Run 2 and partial Run 3 datasets at √s = 13 TeV and √s = 13.6 TeV, respectively. For a measure of sensitivity, a benchmark leptoquark model with only muon and b-quark Yukawa couplings is used. Using the CLs statistical method, the analysis improves upon prior leptoquark mass exclusion limits for couplings above ~1.Physic
Evaluation of the Immunogenicity of Novel HIV-1 gp160 Env mRNA Vaccines in Pre-clinical Mouse and Guinea Pig Models
No full textHuman immunodeficiency virus (HIV) is one of the biggest healthcare challenges that humans have ever faced, with millions of people living with HIV and new cases of infections each year. Despite advances in HIV treatments, an example being antiretroviral therapies (ART), there is still no cure. Individuals with HIV are required to take lifelong treatment for virologic control. As a result, developing a safe and effective HIV vaccine is needed to reduce new infections and protect the public. In this study, we explored the immunogenicity of structure-based, epitope-targeted HIV-1 nanoparticle enclosed messenger RNA (mRNA) vaccines targeting V2 apex of HIV Envelope (Env) glycoprotein. The vaccine encodes three engineered Env glycoproteins as immunogens: Wildtype (WT), Optimized (OPT), and Alternative (ALT). All immunogens build on HIV clade C serotype 459C backbone and are informed with broadly neutralizing antibody (bNAb) signatures. Key modifications such as stabilizing mutations, glycan hole mutations, antigenic diversity set mutations, and cleavage site linkers were introduced to improve trimer stability, immunogenicity, and the breadth of antibody responses.
mRNA encoding these immunogens was formulated into lipid nanoparticles (LNPs) for delivery. Mice and Guinea pigs were immunized, and sera were collected at regular intervals. Binding antibody responses were monitored by endpoint ELISA, demonstrating that SOSIP-stabilized gp160 constructs induce significantly higher IgG titers than non-SOSIP gp160 or SOSIP gp140 constructs. Moreover, incorporating fusion peptide (FP) bNAb signatures into V2-SET designs might further improve immunogenicity in both models. These findings highlight that stabilizing full-length Env in a native-like conformation and targeting multiple vulnerable epitopes enhances vaccine-induced antibody responses.
For future studies, serum collected a month after the third boosting immunization would be tested with neutralizing antibody (NAb) assays against heterologous panels of select tier 2 V2-sensitive and/or FP-sensitive HIV-Env pseudoviruses. Additional boosts and longer-term follow-ups will be performed to evaluate durability and breadth of the antibody responses. After completion of these studies in mice and guinea pigs, select candidate vaccines would finally be tested in non-human primates in the future.
This study highlights the potential of mRNA-LNP vaccine platforms to elicit broad and robust immune responses against HIV. Our findings provide valuable insights into epitope-targeted immunogen design and could further inform the development of next-generation HIV vaccines capable of inducing broadly neutralizing antibodies.Graduate Educatio
Building Resilience Out of Air: Reimagining a Typology of Thin Shell Air-formed Shelters
Get PDFIn recent decades, a novel form of disaster architecture has emerged on grade-school campuses across the U.S. Midwest and Gulf Coast as thin-shell concrete monolithic domes. Constructed using pneumatic formwork, these FEMA-rated domes possess exceptional structural capacity to resist catastrophic loads, serving an everyday function for schools, most often as gymnasiums, while doubling as public shelters during high-wind events. This typology demonstrates a form of resilient architecture that is anticipatory rather than reactionary, permanent rather than temporary, and multipurpose rather than single purpose. However, structural optimization has overshadowed all other possibilities, producing spaces that privilege performance at the expense of experience.
Historically, pneumatic and surface structures pushed the limits of architectural imagination, yet these structures have fallen into banal repetition. Heavy, bunker-like, and spatially austere, contemporary disaster shelters are more often utilitarian than visionary. While windowless hollow forms are an effective approach as a brief reactionary response, anticipatory architecture has an untapped potential to create shelters that provide dignity and comfort to a community in and beyond crisis. This thesis explores the possibility of building resilience out of air by reimagining FEMA-rated dome shelters through the experimental spirit of Frei Otto, Dante Bini, and Heinz Isler. Through a physical form-finding process that employs strategically restrained pneumatic forms to create solid casts, it investigates the unrealized formal and spatial potential of pneumatic formwork construction. Maintaining the community-scale and construction logic of existing FEMA domes, this research challenges the typology’s structural and programmatic conventions, proposing imaginative shelters that unite daily use and disaster preparedness with the aim of fostering resilient communities.Department of Architectur