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Quantum Black Holes and the Primordial Universe
No full textTwo central challenges of twenty-first century physics are to understand the quantum nature of regions of spacetime with strong curvature, such as black holes, and to uncover the composition and physical laws of the universe's dark sector, especially during the primordial era. This dissertation presents new theoretical results and experimental tools aimed at advancing our understanding of these fundamental problems.
When quantum field theory is combined with classical black hole models, it predicts that black holes emit radiation and lose mass over time, potentially evaporating completely. However, there are unresolved questions about the origin of this radiation and its behavior near the event horizon. I present the most detailed numerical study to date of the quantum state near the horizon of a semi-classical Schwarzschild black hole, helping resolve conflicting ideas from previous research and offering new insights into the local temperature near the horizon.
There are currently no observational data on evaporating black holes, or even any direct evidence that they evaporate at all. I explore the prospects of detecting warm, dark-sector relic particles emitted from evaporating primordial black holes through their impact on the large-scale structure of the universe. I show that these relics can be detected by current and future cosmological surveys and can be distinguished from thermally-produced relics. Additionally, I provide the strongest constraints on these relics to date, demonstrating that they can account for no more than about 2% of the dark matter across a broad region of their viable parameter space.
Exploring the dark-sector of the universe and its primordial state requires reconstructing its early-time conditions from present-day observations. I present a novel method for reconstructing the initial matter density field from the late-time density field using convolutional neural networks. This method expands the range of high-fidelity reconstruction to much smaller scales than existing techniques, showing promise for exploring the properties of the primordial universe at smaller scales than ever before.Astronom
Famous Views of Economics: An AI-Based Analysis of Japanese Woodblock Print Subject Matter and Economic Circumstances
No full textHow do socioeconomic conditions influence what artists depict in their artworks? More concretely, how do artists react to trade shocks and technological innovation? To answer these questions, I leverage novel artificial intelligence (AI) methods to construct and study a bespoke dataset of Japanese woodblock prints, artist biographies, and international trade records from 1830-1939. I first detail how this novel AI methodology can unlock previously unavailable insights into contemporary culture and economy. Then, through regression discontinuity analysis, I show that artworks reflect "hype cycles" in specific object depictions around technological innovations and Japan's opening of trade in 1854 which precede the widespread proliferation of these novel objects. I then point to a potential mechanism of the artist's decision process as artists' depictions of foreign objects are correlated with their educational background and their geographic locale. Then, I connect artistic subject matter with economic variables to show that lagged artistic depiction of objects can be predictive of future imports, evidence that may suggest artworks could be proxies for consumer interest and eventual demand. Finally, I conclude by noting potential extensions of my AI-based approach.Applied Mathematic
Exploring 2D Quantum and Acoustic Systems Using Scanning Probes
No full textThe world of quantum materials is made rich by the coexistence of many, many interacting electrons, giving rise to complex and fascinating phases of matter such as topological superconductivity. Such emergent quantum phenomena are associated with small interaction energy scales, appearing only in specific materials at ultra low temperatures. In this thesis I will address two distinct pathways towards studying strongly correlated materials: 1) creating better instrumentation and 2) discovering new materials.
In order to study already existing quantum materials, and more specifically topological superconductors, I will present the design and construction of a mK-base temperature scanning probe microscope. This system is the first of its kind to support simultaneous scanning tunneling microscopy and optical detection pendulum atomic force microscopy at mK temperatures. Such a combination opens the door for the realization of my proposed topologically protected quantum logic operation in the topological superconductors.
An alternative approach is to discover new systems that are potential hosts for strongly interacting phenomena. Discovering new quantum systems can be laborious and expensive; however, the dispersion of electrons can accurately be mimicked by classical waves, such as sound. The ability to quickly and cheaply 3D print acoustic metamaterials allows for rapid iterations and the discovery of novel lattice geometries which can then be brought to the quantum regime. I will present the experimental measurement and simulation of macro-scale acoustic metamaterials to prototype new flat band lattices. Additionally, I will discuss the development of a novel platform for designing arbitrary dispersions of surface acoustic waves in piezoelectric crystals using metamaterials.Physic
Unearthing Waters: River Heritages of Amazonia
No full text“Unearthing Waters” challenges the failures of heritage preservation in landscape architecture, exposing how its conventions uphold systems of exclusion instead of dismantling them. Placed as both a spatial archive and counterfactual speculation, it foregrounds traditional river heritages as counter-frameworks for land back initiatives in Brazil’s Amazon River basin, envisioning alternative pathways toward territorial justice. Rooted in site-specific ecologies of repair, this initiative structures a new communal program: The Amazon River Reparation Complex.
Unlike regional conservation and industrial complexes, this endeavor unfolds as an active counter-archeology, unearthing historical land trauma through mobilized local insurgencies set in 2035. These acts retrace the submerged histories and contested geographies of the region, critiquing how extractive infrastructures have erased cultural landscapes and land rights across three conflict sites — from Indigenous settlements flooded by hydropower reservoirs in Amazonas, to archeological sites buried beneath transportation ports in Santarém, and riverine communities mined near the Xingu River.Department of Landscape Architectur
Comparative Outcomes in Cervical Spine Surgery: A Dual Analysis of Revision Surgeries and Adjacent Segment Degeneration
No full textBackground
Cervical disc arthroplasty (CDA) is increasingly favored over anterior cervical discectomy and fusion (ACDF) for its motion-preserving capabilities and theoretical advantage in reducing adjacent segment degeneration (ASD). While evidence on revision surgery rates between CDA and ACDF remains inconsistent, the performance of individual CDA implants concerning ASD and related complications has received less comparative scrutiny. This study aimed to (1) compare the hazard and predictors of revision surgery between ACDF and CDA, and (2) evaluate the risk of ASD and complications across three commonly used CDA implants: Prodisc-C, Mobi-C, and M6-C.
Methods
We conducted a two-part retrospective cohort study at a single academic medical center. First, using propensity-score matching (2:1), 312 patients who underwent ACDF or CDA between January 2008 and June 2023 were analyzed to compare revision surgery rates and identify associated risk factors. Second, 70 CDA cases (17 M6-C, 21 Prodisc-C, 32 Mobi-C) performed by a single surgeon between 2008 and 2024 were reviewed for ASD development and implant-specific complications. Multivariable Cox regression was used to assess hazard ratios (HR) for revision surgery and ASD, adjusting for demographics, comorbidities, and operative characteristics.
Results
CDA was associated with a significantly lower hazard of revision surgery compared to ACDF (HR 0.36; 95% CI 0.017–0.77; p=0.01). Age, gender, diabetes, hypertension, heart disease, chronic steroid use, and opioid dependence were not significant predictors of revision risk. Two-level surgeries were not associated with increased revision hazard relative to one-level procedures (HR 0.78; 95% CI 0.48–1.53; p=0.48). Among CDA implants, the risk of developing ASD was not significantly different for M6-C (HR 1.94; 95% CI 0.19–20.14; p=0.58) or Mobi-C (HR 1.69; 95% CI 0.26–10.77; p=0.58) when compared to Prodisc-C. No demographic, lifestyle, or operative variables were associated with ASD risk, and no implant-specific complications showed statistically significant differences across implant types.
Conclusion
CDA is associated with a lower risk of revision surgery relative to ACDF, with no significant predictors identified among common clinical variables. Among CDA implants, Prodisc-C, Mobi-C, and M6-C demonstrated similar performance in terms of ASD risk and implant-related complications. These findings support the long-term durability of CDA over ACDF and suggest comparable outcomes across commonly used CDA implant designs.Medical Scienc
Techniques for High-Throughput Directed Enzyme Evolution
No full textEnzymes are versatile biological catalysts that play crucial roles in numerous industrial processes, including the production of biofuels, pharmaceuticals, and fine chemicals. However, natural enzymes often face limitations in stability and efficiency under industrial conditions, necessitating their evolution for enhanced performance. High-throughput directed evolution schemes typically involve four key steps: mutagenesis library construction, library screening or selection, variant sequencing, and variant characterization. In this thesis, we present a series of techniques relevant to enhancing the efficiency and effectiveness of high-throughput directed evolution.
In Chapter 2, we introduce a platform that utilizes nCas9 and mutagenic polymerase to achieve autonomous gene diversification. This platform, combined with a customized lab-on-chip device, enables continuous screening and thus facilitates controlled continuous evolution.
Chapter 3 discusses the development of Random Saturation Mutagenesis (RSM) libraries. This method allows for the generation of chemically diverse libraries with minimal bias, broadening the exploration of the enzyme fitness landscape. We demonstrate the design, construction, and superiority of these libraries over traditional error-prone PCR techniques in terms of diversity and efficiency.
In Chapter 4, we address the challenge of maintaining functional conditions in complex droplet environments by developing a hydrogel-bead based method for high-throughput screening of IVTT-expressed enzymes in each droplet.
And finally in Chapter 5, we present an economical method for sequencing mutagenesis libraries at full gene length using Illumina sequencers, significantly reducing costs for validating mutations in large libraries.Engineering and Applied Sciences - Engineering Science
Disambiguating Large Language Model Performance on the Ambiguities of Law, Reasoning, and the Future
No full textOver the past year, two separate cases of legal actors using LLM-based products to submit fictitious materials to American courtrooms have raised significant concern. In this thesis, I tackle one facet of this legal LLM usage problem, in arguing normatively for the need to teach LLMs legal reasoning. Drawing from legal theory but developing new definitions for the LLM context, I establish that legal reasoning requires reasoning over a central ambiguity in the application of general statutes to specific fact patterns — an inescapable ambiguity that I find traditional LLM reasoning research paradigms unequipped to handle. Thus, I contribute back to LLM reasoning research an experimental methodology that directly targets this central ambiguity and intuition in reasoning, as well as an evaluative framework that holistically captures true reasoning ability. I rework two prior legal ML datasets into benchmarks for a novel legal ambiguity identification task (available on HuggingFace). Conducting a preliminary experimental exploration of GPT-3.5 and GPT-4 models on this task, I discover some true ability at identifying legal ambiguity. Though it is currently weak and somewhat misaligned with legal practice, this ability shows promise for improvement, especially through model milestoning and fine-tuning. Overall, this thesis analyzes one component of ideal legal LLM usage from an interdisciplinary legal theory and computational perspective, toward progress in principled legal LLM implementations and more productive law and CS collaboration.Computer Scienc
Identification and characterization of unique enzymatic transformations by gut microbes
No full textThe human gut microbiome is a diverse community of microorganisms that catalyze millions of unique biotransformations of both endogenous and exogenous compounds. The production and modification of these microbial products can influence both other gut microbes and the human host, having impacts on health and disease. Characterizing these biotransformations is an important part of understanding the functions of the gut microbiome and a key step in the development of microbiome-directed therapies.
In this thesis, I describe my work identifying and characterizing several unique microbial enzymes and the conditions necessary for their activity. In chapter 2, I describe our identification of a steroid 21-dehydroxylase present in gut microbial species Eggerthella and Gordonibacter that transforms glucocorticoid steroids into progestins. My work in this chapter focuses on understanding the role of hydrogen production by E. coli and other bacteria in facilitating this reduction, characterizing the genetic and metabolic regulation of the steroid 21-dehydroxylase, and developing protein purification parameters both to confirm our identified enzyme and to provide a framework for subsequent mechanistic studies.
In chapter 3, we introduce a new biochemical transformation for microbiome— sulfonation. Sulfonation is an important biochemical transformation that has long been attributed solely to host metabolism. We showed that the gut commensal Bacteroides thetaiotaomicron encodes for a sulfotransferase (SULT) enzyme capable of catalyzing the sulfonation of cholesterol and structurally related steroidal molecules (BT0416 or BtSULT). Our discovery and characterization of this enzyme revealed that it is structurally selective for substrates with a “planar” 5α-trans or 5-ene A/B ring structure within the steroidal core. Additionally, accompanying in vivo studies in monocolonized germ free (GF) mice showed that the presence of this bacterial gene increased cholesterol sulfate (ChS) levels and reduced T cell migration to the mesenteric lymph nodes, showing the potential for sulfated products of the gut microbiome to influence host biology.
In chapter 4, we follow up on our discovery of BtSULT, seeking to identify and study new sulfotransferases across the microbiome. Sulfated metabolites have important roles in regulation of metabolism, immune cell function and migration, and disease phenotypes; therefore, understanding the role of the microbiome in producing sulfated metabolites is an important area of study. To identify and study SULTs across the microbiome, we leveraged PAPS biosynthesis to integrate a stable isotope labeled sulfate moiety into sulfated metabolites both in bacterial monoculture and in vivo mouse samples. Using a combination of comparative methods and high-resolution mass spectrometry, we identified hundreds of sulfated features in mouse tissues and several new chemical classes from bacterial cultures. We identified sulfated hydroxy fatty acids as a new type of microbiome-derived sulfated metabolite and identified a candidate sulfotransferase enzyme encoded in the genome of Eubacterium ramulus ATCC 29099. The data from these exploratory studies will inform future investigations of other classes of sulfated metabolites and provide a framework for studying their SULTs.
In all, these studies contribute to our understanding of gut bacterial enzymes, their metabolic and genetic regulation, and the biological activities of their products. The tools used in these studies will facilitate future studies of gut bacterial enzymes and the small molecule metabolites that they produce.Chemical Biolog
Intraoperative Feedback System to Predict Long-Term Pedicle Screw Fixation using Modal Analysis
No full textThis thesis presents a novel intraoperative feedback system designed to predict long-term pedicle screw fixation in spinal fusion surgeries by leveraging modal (vibrational) analysis. Spinal fusion is a prevalent procedure aimed at stabilizing vertebrae in cases of degenerative disease, trauma, or deformity; however, current intraoperative methods for assessing pedicle screw stability largely rely on subjective tactile feedback. To address this gap, we developed a compact, single-handed device that excites the screw–bone construct with a controlled vibrational input and measures the response via an embedded sensor. Through fast Fourier transforms and resonance frequency detection, the system quantitatively gauges screw anchorage quality in real time.
Finite element analysis (FEA) of pedicle screws in bone analogs demonstrated that resonance frequency shifts reflect changes in bone–screw interface stiffness. Bench-top experiments with polyurethane foam blocks of varying densities confirmed strong correlations between resonant frequency and mechanical pull-out strength, validating the approach in a controlled environment. Further testing on cadaveric vertebrae reinforced the device’s clinical relevance, showing it can differentiate securely anchored screws from those at higher risk of loosening.
Designed for seamless integration into the surgical workflow, the tool displays a simple color-coded readout (green/yellow/red) to guide intraoperative decision-making. User feedback from orthopedic surgeons highlights the system’s potential to reduce revision rates and hardware failures by enabling immediate identification of suboptimal fixation. Future work will focus on extending compatibility to polyaxial screws, refining signal processing algorithms for greater robustness, and undertaking large-scale clinical studies to establish the device as a standard instrument for spinal fusion procedures.Engineering Sciences A
A novel biomarker to identify atherosclerotic cardiovascular disease in people with HIV and assessment of clinical and ECG features associated with incident sudden cardiac or undetermined death: Insights from the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE)
No full textThe two manuscripts presented for this thesis have both analytical and thematic content
links that are consistent with: 1. addressing important scientific questions in a historically
underserved/under recognized high cardiovascular risk primary prevention population, and
2. Demonstrating the student’s facility with analysis and interpretation of clinical trial data
using dieerent study designs for these secondary analyses. These analyses of the
Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) also utilize the clinical trial
expertise of the student’s mentors, one who is the study principal investigator (SG) and the
other who was the study endpoint committee chairman (SW) who also serves in this
capacity for many phase III cardiovascular clinical trials managed through the Harvard
based academic research organization, the TIMI study group.
The overarching theme is that people with HIV (PWH) are at increased risk of
cardiovascular disease even in the present era of excellent viral suppression with antiviral
therapy.(1) The first manuscript utilizes a cross-sectional design to evaluate the
associations of “high-risk” coronary atherosclerosis imaged by CT coronary angiography
(CTCA) in a REPRIEVE sub study with the cardiac specific circulating protein, cardiac
troponin T (cTnT) measured by high-sensitive assay.(2, 3) We further sought to understand if
this biomarker could augment discrimination between those participants with and without
these plaque features.(3) Next utilizing a longitudinal study design we investigated clinical
and ECG features associated with carefully adjudicated sudden cardiac and undetermined
deaths highlighting the importance of meticulous adjudication to characterize the
dieerences in the clinical phenotypes in participants with these outcomes.Medical Scienc