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Ultracold Atom-Polar Molecule Interactions: Discoveries, Surprises and Puzzles
Get PDFStudying ultracold chemical reactions with quantum state resolution reveals details of the reaction processes, especially with single quantum state preparation of the reactants and state-selective detection of reaction products. In this thesis, we investigate two main processes: KRb + KRb → K2 + Rb2 reactions, and Rb and KRb atom-molecule collisions.
In the KRb bimolecular reaction, we demonstrate the preservation of quantum coherence in bimolecular reactions for the first time, which is surprising in a reaction considered to be largely chaotic. Additionally, we proposed a coherent control scheme to manipulate product yields across different product channels. These results represent a critical step toward probing quantum coherence and entanglement in the chemical reaction.
In atom-molecule collisions between Rb and KRb, we discovered an exceptionally long-lived intermediate complex, KRb2, which can be photo-excited by trapping light. The observed complex lifetime was orders of magnitude longer than theoretical
predictions, underscoring the limitations of the current theory. We further explored the dependence of complex lifetimes on the initial quantum states and external electric and magnetic fields, providing additional experimental benchmarks to guide future theoretical work.
Separately, we found that inelastic collisions between hyperfine-excited Rb atoms and KRb molecules can lead to rotation excitation of KRb post-collision. By probing the product state distribution, the result suggests that mechanical angular
momentum is coupled to the spins. Such couplings are too weak in the current theory models to explain the result. Moreover, our result contradicts state-of-the-art coupled-channel calculations. These suggest that some subtle effects, such as molecular vibration and conical intersections, play a critical role in the reaction dynamics.
The final piece of the thesis describes the observation of resonant interaction between a Rydberg atom and an ensemble of polar molecules. Such hybrid quantum systems have been proposed for a wide range of applications. Our work provides an
experimental demonstration of resonant dipolar interactions between Rydberg atoms and ultracold polar molecules, paving the way for the realization of hybrid systems for quantum computation and simulation.Chemical Physic
A Multi-Wavelength Perspective of Volatiles Across Protoplanetary Disk Regions
Get PDFThis thesis investigates the spatial distribution, excitation, and chemical evolution of volatiles in protoplanetary disks through a combination of submillimeter interferometry and mid-infrared spectroscopy. Leveraging high-resolution ALMA observations and recent JWST-MIRI data, we characterize how the molecular composition varies across disk regions and with disk properties. The work aims to constrain both physical conditions and chemical processes relevant to planet formation, with particular focus on deuterium fractionation, snowline physics and chemistry, and the role of pebble drift in enriching inner disk gas.
In Chapter 2 we carry out multi-line ALMA observations of deuterated organics in TW Hya, demonstrating that \textit{in-situ} deuterium fractionation occurs near the CO snow-surface, consistent with H2D+-driven chemistry. In Chapter 3, we perform JWST-MIRI spectroscopy of the AS 209 disk, revealing rich water and organic emission, with notable temporal variability relative to archival Spitzer data. In Chapter 4, we develop a retrieval framework for inferring radial water vapor distributions from unresolved JWST spectra, finding that the observable cold water masses anti-correlate with disk size, likely due to efficient icy pebble drift. In Chapter 5, we analyze the transition disk GM Aur with JWST, where volatile depletion in the inner-disk is accompanied by strong OH emission from photodissociation, pointing to irradiation-driven chemical evolution. Finally, in Chapter 6 we extend the prior analyses to a 40-disk sample from the IDECO JWST survey, confirming and revealing new links between disk structure, stellar properties, and water vapor emission. Together, these studies provide new empirical constraints on how volatile chemistry in disks is actively reshaped by local thermodynamic conditions, dynamics, and stellar irradiation.Astronom
Regulation of CD8+ T cell tissue residency following influenza infection
No full textDurable CD8+ T cell memory is a defining feature of adaptive immunity to pathogens. Among memory CD8+ T cell subsets, tissue-resident memory (TRM) cells are locationally positioned within nonlymphoid tissues to respond rapidly to secondary antigen encounter. The generation of CD8+ TRM is known to require antigen and specific cytokine cues. Although CD8+ TRM constitutively express the coinhibitory receptor PD-1 in the absence of antigen stimulation, the functional significance of PD-1 in regulating CD8+ TRM differentiation and function remains unclear. Here, we investigated the regulatory role of PD-1 in CD8+ T cell differentiation into TRM following infection with influenza virus, which targets the lungs and nasal cavity. Genetic deletion of PD-1 in virus-specific CD8+ T cells resulted in significant expansion of virus-specific effector CD8+ T cells, yet compromised the establishment of durable, functional CD8+ TRM in the lungs and nasal mucosa following infection. Transcriptional studies suggest that PD-1 loss altered CD8+ T cell differentiation in the lymph node by altering the duration of the G1 phase of the cell cycle and modifying the utilization of pioneer transcription factors (TFs) that regulate chromatin accessibility. Loss of PD-1 impaired the ability of effector CD8+ T cells to express the adhesion molecule CD103 in response to TGF-β signaling. In addition, PD-1 KO CD8+ T cells had a reduced ability to downregulate the tissue egress receptors S1PR1 and CCR7 following entry into infected tissue. During the memory phase, PD-1 KO CD8+ T cells in the lung expressed TFs that antagonize tissue residency, including Klf2 and TCF-1/Tcf7. The deleterious impact of PD-1 deletion on TRM formation was partially tissue-dependent, with a more profound reduction in TRM accumulation in the lungs than the nasal mucosa. These two tissues display distinct viral infection kinetics, differing requirements for TRM formation, and distinct capacities to support life-long CD8+ TRM. These factors, individually or in combination, may determine the impact of PD-1 deletion on CD8+ T cell fate in each tissue. Collectively, these findings support a model in which PD-1 deficiency enhances CD8+ T cell proliferation in draining lymph nodes but compromises their adaptability within infected tissues. However, the consequences of PD-1 loss are also shaped by the specific characteristics of the infected tissue microenvironment.Immunolog
Contextualizing the Environmental Crisis through Narrative in Richard Powers’ The Overstory
Get PDFRichard Powers’ 2018 novel The Overstory confronts an uncertain planetary future in the face of a world ravaged by climate change. While many recent works of environmental-based literature employ elements of science fiction—dystopian settings in a not-so distant future—Powers’ novel mirrors the contemporary United States and rooted in applicable ecology. The following analysis explores how The Overstory and selected precedent works of fiction use narrative to contextualize complex ideas, particularly the climate crisis. While data and science can be instructive, they often fail to grab public attention to the degree necessary to inspire appropriate reactions and behaviors, as underscored by many actions of the American government. Climate crisis skeptics are unlikely to care more about the environment through a bombardment of data, but those nonbelievers might be moved by a well-told story they can connect with. Drawing on the literary field of eco-criticism—particularly the work of Ursula K. Heise and Richard Nixon—this paper explores how fiction can shape the conversation around climate change in ways that account for both the human and natural world.Extension Studie
Beyond Intention-to-Treat Analyses in Randomized Trials: Utilizing Per-Protocol Estimands and Observational Data to Investigate Strategies for Cardiovascular Disease Prevention
No full textRandomized trials are considered the gold standard study design for conducting comparative effectiveness research. Yet, evidence from randomized trials to inform cardiovascular disease (CVD) prevention efforts remains scarce for some patient populations, partly due to restrictive eligibility criteria and shorter follow-up of surrogate outcomes. Emulating target trials in observational data can provide insights into the effects of existing medications for CVD prevention in new target populations and on longer-term clinical endpoints. Regardless of study design, that is, whether we use data from randomized trials or emulate target trials in observational data, complementing intention-to-treat analyses, which estimate the effect of the assigned treatment strategies, with appropriate per-protocol analyses, which estimate effects that would have been observed had there been full adherence to the assigned treatment strategies, can be important to facilitate informed clinical decision-making. In this dissertation, I estimate both intention-to-treat and per-protocol effects using data from a large-scale, pragmatic randomized trial and from electronic health records and health insurance claims to elucidate the impact of medications important for CVD prevention in populations for whom evidence has been limited based on existing intention-to-treat analyses of randomized trials.
In Chapter 1, I estimated the effect of adhering to assigned treatment strategies of pravastatin or usual care on death and CVD in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack – Lipid-Lowering Trial. The high initiation of lipid-lowering therapy in the usual care comparator group has been previously suggested to explain the null intention-to-treat findings. I demonstrate that deviations from the pravastatin treatment strategy may better explain the intention-to-treat results, showing that pravastatin reduced the risk of death and CVD even when allowing individuals in the usual care group to initiate lipid-lowering therapy. In Chapter 2, I estimated the effect of statin therapy versus usual care on the 5-year risk of CVD among women with breast cancer. I first specified the target trial and then emulated the trial using electronic health record data from a large cohort of patients at several Kaiser Permanente networks. While intention-to-treat findings showed no difference in risk of CVD over five years, the risk of CVD was lower for the statin therapy group compared to usual care in per-protocol analyses, though estimates were imprecise. In Chapter 3, I estimated the effects of adding GLP1-RA to SGLT2i and adding SGLT2i to GLP1-RA on glycemic control and intermediate cardiovascular risk factors at one-year, and risk of CVD over three-years among persons with inadequately controlled type 2 diabetes. I outlined the protocol of two target trials, then emulated them using electronic health records and claims data from 12 insurance/healthcare systems in the US. Regardless of initial background treatment, adding SGLT2i to GLP1-RA reduced HbA1c, systolic blood pressure, and body mass index after one-year. Estimates for the effect of combination therapy on cardiovascular events were imprecise, and additional data are needed to confirm whether adding SGLT2i or GLP1-RA leads to long-term protection against cardiovascular disease.
In conclusion, when evidence from intention-to-treat analyses of existing randomized trials is insufficient to guide clinical decision-making alone, using per-protocol effects and pragmatic trials as a framework for conducting comparative effectiveness research in observational data can help inform future CVD prevention efforts for populations at high risk, such as breast cancer survivors and patients with type 2 diabetes.Population Health Science
New Tools, New Challenges: Navigating the Complexities of Digital Healthcare Delivery
No full textEmerging digital tools – such as telemedicine visits, remote monitoring, and patient portal messages – hold immense promise for improving healthcare access, quality, and efficiency. At the same time, they also introduce new challenges for healthcare organizations and policymakers. My dissertation sheds light on new dynamics brought about by three forms of digital care, providing practical guidance to managers on how to navigate them and policymakers on how to incentivize and enable effective use.
In Chapter 1, titled “From Rooms to Zooms: The Hidden Costs of Hybrid Work in Primary Care”, my co-authors and I examine hybrid primary care practices that offer both in-person and telemedicine care. My findings highlight new frictions that arise when virtual visits are incorporated into still predominately in-person clinic schedules. Intermixing the two modalities can lead to costly “modality switch” transitions that can negatively impact subsequent visits. Telemedicine visits following an in-person visit often see delayed starts; patients are 75% more likely to abandon the visit before being seen, and the visits that do occur are 25% less likely to begin on time. These disruptions also result in less comprehensive visits and a higher likelihood of after-hours work. Dedicated telemedicine-only blocks in provider schedules help avoid these costly transitions but can also lead to reduced capacity utilization when there is insufficient demand for telemedicine visits in that time window. Indeed, we find that telemedicine-only slots see a 10% lower booking rate relative to similar slots without such restrictions. Telemedicine visits are often framed as a useful tool for improving patient care access. However, we show that, depending on how they are incorporated into hybrid schedules, they can lead to negative care experiences, chaotic clinic days, and ironically even reductions in patient access. Our findings also demonstrate the tradeoffs of dedicated telemedicine blocks and highlight potential changes to managerial practices and clinical workflows to improve performance of hybrid practices.
In Chapter 2, titled “Practice-level Effects of Remote Physiologic Monitoring Adoption”, my co-authors and I leverage a 100% sample of Traditional Medicare claims data to study the practice level impacts of RPM adoption. Use of remote physiologic monitoring (RPM), the remote transmission of patient physiologic measures (e.g., blood pressure) to care teams, has grown rapidly in recent years. For practices, establishing an RPM program can increase revenue and improve patient care, but may also require substantial reorganization within the practice. No prior work has quantified the impact of RPM on practices. Using our Medicare claims dataset, we identified 754 primary care practices that began billing for RPM from 2019-2021. We find that, after these practices adopted RPM, Medicare revenue increased by 20.1% relative to similar matched non-adopting practices. This was driven by RPM billing as well as more outpatient visits and care management. While adopting practices had a 3.0% increase in their number of billing providers, the increase in revenue was predominantly driven by increased activity per provider. Adoption of RPM and resulting increases in visits for patients receiving RPM did not seem to come at the expense of other patients. Our results suggest that RPM holds promise as a tool for strengthening primary care and improving chronic disease management but also has the potential to substantially increase Medicare costs.
In Chapter 3, titled “The Doctor Won’t See You Now: Examining Drivers of Care Team Response to Patient Portal Messages”, my co-authors and I investigate the drivers of provider engagement with patient portal messages. Prior work has shown that when patients from historically disadvantaged groups (e.g., racial and ethnic minorities, those with lower socioeconomic status) send messages to their care teams, they are less likely to receive responses from physicians, seemingly driven by lower prioritization in the message triaging process. In this study we leverage natural language processing (NLP) tools to analyze the text of patient portal messages from a large academic health system. Our goal is to understand what drives these differences in care team response, enabling us to separate three potential mechanisms: differences in message content and the underlying request of the message (e.g., medication question, referral request), differences in the way the messages are written, and non-clinical bias. We find that, while message content is a significant predictor of care team response, it cannot explain observed differences across demographic groups. On the other hand, the way the message is written – including writing style characteristics such as length and formality – accounts for nearly half of the observed differences. Our findings identify a clear mechanism underlying disparities in care team response, highlighting avenues for mitigating them and deepening our understanding of care disparities more broadly.Health Polic
Neuroanatomical Asymmetry Across Species: From Mice to Macaques to Human Insights
Get PDFHow left-right anatomical asymmetry is established in the human brain is a major unanswered question in the field of laterality. Efforts to address this area of brain development are limited by the scarcity of animal models with such asymmetries, particularly for mammals whose brain structure and development are most similar to that of humans. Identifying patterns of anatomical brain asymmetry in other mammalian species would lay the groundwork for pursuing mechanistic studies of the molecular and cellular processes underlying its generation. Here, I led two studies using automated image analysis to perform extensive characterization of anatomical brain asymmetry in two key mammalian species of interest: mice (M. musculus) and rhesus macaques (M. mulatta).
Using seven separate mouse datasets totaling over 3500 animals, I identified a global anterior-posterior asymmetry pattern in the mouse brain but the absence of regional asymmetries at individual structures. Anterior regions in the mouse brain are greater in volume and surface area on the right compared to left and are shifted anteriorly on the right compared to left. Posterior regions are greater in volume and surface area on the left compared to right and are shifted anteriorly on the left compared to right. In macaques, using seven datasets totaling nearly 700 animals, I identified 80 regional asymmetries, including a right hemisphere frontal lobe expansion and right-larger auditory regions, which are present as early as 1 month after birth and persist into adulthood. Yet, in contrast to mice, I observe no global asymmetry pattern in macaques. Extensive use of cross-validation demonstrates the results to be reproducible across independent datasets, across two different image modalities in mice, and across two different image registration software.
Together, my studies establish high-confidence, atlas-based patterns for studying neuroanatomical asymmetry in both mice and macaques, robust to numerous biological and technical variables. These atlas-based patterns can serve as a foundation for future studies examining the action of genetic factors in neuroanatomical asymmetry, characterizing the underlying cellular architecture, or further probing the relationship between anatomical and functional brain asymmetries. Yet, interrogating these patterns also reveals three significant observations that advance our understanding of brain laterality. 1) The presence of human-like regional asymmetries in macaques but not mice suggests this aspect of laterality may have emerged within the primate lineage. 2) The mouse results show no relationship between anatomical asymmetries and known mouse functional asymmetries, indicating that functional asymmetry can be decoupled from macro-anatomical asymmetry. 3) The regional pattern of anatomical asymmetry in macaques is not correlated at all with that seen in humans, suggesting that, although some instances of consistent asymmetries may exist across species, the regional patterns are generally not evolutionarily conserved. Finally, my findings in mice reconcile two previously published studies on the question of neuroanatomical asymmetry in mice which on their surface, appeared to show major differences in their findings but which co-exist within the results of my analysis. Overall, my thesis research has provided a foundation for future cellular-level studies and advanced evolutionary understanding of anatomical left-right asymmetry.Medical Science
Characterization of Factors that Regulate Cell Envelope Synthesis in Staphylococcus aureus
No full textBacteria are separated from their environment by a cell envelope, an essential structure
composed of multiple polymers and proteins. To grow and divide, the existing structure needs to
be remodeled then expanded with new material. These processes are inextricably linked: the
degradation and synthesis of the cell envelope must be balanced to maintain its integrity. To
accomplish this, cells have evolved a series of regulators in the cell envelope which can (i) directly
modify the activities of cell envelope synthesis proteins or (ii) signal transduction proteins that can
direct intracellular processes to respond to extracellular events. This thesis is split across two
projects, each elucidating a regulatory complex in the membrane of S. aureus.
In the first project, I describe a physical and genetic interaction between SpsB and SpbR
(backgrounds for each protein are provided in Chapter 1.3). This project was undertaken with two
other graduate students, Madeleine Stone and Youngseon Park, and together we describe how
SpbR controls processing of LtaS to terminate lipoteichoic acid synthesis and maintain
appropriate length LTAs in the membrane.
In the second project, I describe a physical and genetic interaction between AuxB, PknB,
and GpsB (backgrounds for each protein are provided in Chapter 1.4, Chapter 1.6, and Chapter
1.7). I show that AuxB forms independent interactions with GpsB and PknB; by altering the
interaction between AuxB and PknB, I induce phenotypes that indicate the former regulates the
latter. I also describe how the features of PknB and AuxB confer intrinsic resistance to various
antibiotic compounds and have unique genetic relationships to cell envelope polymers. Finally, I
present models for the possible physiological roles of AuxB in complex with PknB and GpsB.
In Chapter 2, I characterize SpbR as an interacting partner of the signal peptidase SpsB
and show that it regulates lipoteichoic acid synthesis by controlling cleavage of lipoteichoic acid
synthase. In Chapter 3, I report and characterize AuxB-GpsB and AuxB-PknB interactions and
present evidence that AuxB antagonizes PknB through its direct association. I further show that
S. aureus becomes sensitive to various disruptions in cell envelope synthesis when the AuxBPknB
complex is too abundant or lacking from the cell. In Chapter 4, I discuss unpublished work
on AuxB and PknB that provides exciting hypothesis for future work. In Chapter 5, I discuss future
directions and implications for this workChemical Biolog
Studies of Ubiquitin Activation and Chain Synthesis
No full textThe Ubiquitin Proteasome System (UPS) is among the most extensive cellular pathways, with over
1200 components, and it has profound implications for cellular homeostasis and disease. In this
dissertation, we will discuss in vitro studies of its mechanism. We will begin in Chapter Two by characterizing
a computationally derived small molecule library to target the ubiquitin fold domain of UBE1 for enzymatic
inhibition. This work will describe a screen conducted to test a library generated in silico and discuss
alternative methods for targeting E1. Next, we will transition to investigating free ubiquitin chain formation
by the E3 ligase Hul5 in Chapter Three. We will describe rapid di-ubiquitin formation by Hul5 and the
suppression of this reaction by calcium, which is mediated by calcium binding to calmodulin.
Characterization of di-ubiquitin identified a preference for K48-linkages and formation by an acceptor site
on Hul5. Lastly, we will conclude by discussing the role of Hul5 as the only identified processivity factor of
the proteasome. In Chapter Four, we will establish a framework and method for the in vitro characterization
of Hul5 as a processivity factor to uncover its mechanism of action. Together, this body of work elucidates
therapeutic and mechanistic features of the UPS to contribute to our biological understanding of the
pathway.Chemical Biolog
Erosion of Democracy: Viktor Orban, Hungarian Voters, and the Desire for Autocracy
Get PDFThe rise of illiberal democracies within the European Union presents a profound
challenge to the post-Cold War liberal democratic order. This thesis examines the case of
Hungary under Prime Minister Viktor Orbán, investigating the erosion of democratic
values in an EU member state. It argues that the longevity of Orbán and the Fidesz party
is not merely the result of political maneuvering but is deeply rooted in a significant
segment of the Hungarian electorate’s desire for autocracy, a desire borne from historical
trauma, post-communist disillusionment, and economic anxiety.
This paper analyzes the historical and socio-economic factors, including the
Treaty of Trianon and the failures of the post-1989 transition to democracy, that created
pathway for a leader such as Orbán to gain support for a national shift towards autocracy.
Furthermore, it details specific mechanisms of state level mass mobilization employed by
Orbán and the Fidesz party to consolidate control of state media, rewrite the constitution,
and isolate Hungary from the EU. The thesis concludes that Hungary is a successful
model of an electoral autocracy which has consistently gained the support of Hungarian
voters and therefore represents a significant challenge to the normative foundation of
European integration and the broader liberal democratic order.Extension Studie