VictorJuiz/thesis huggingface dataset:
Elucidating anti-cancer mechanisms using chemoproteomic platforms

Historically, in the early 20th century, drug discovery efforts started off using natural products that were isolated from microbes, plants, and other living organisms. Natural products have been a major source of therapeutics and constituted 50-70% of the marketed drugs used for bacterial and fungal infections, inflammation, diabetes, and chemotherapy1-3. However, due to the limitations of natural products—synthetic complexity, difficult to isolate, and lack in understanding in mechanistic action—pharmaceutical companies slowly reduced their natural product drug discovery efforts and put their emphasis in using small molecules. What originally made natural products exciting to explore were the subset of covalently reactive molecules that possess reactive electrophilic centers that irreversibly reacts with proteins’ nucleophilic amino acid hotspots to modulate their therapeutic activity5. By taking full advantage of the natural products’ bioactive and covalent properties, chemoproteomic approaches can use these reactive moieties to map out nucleophilic hotspots, such as cysteines and lysines, to identify the natural product’s binding pockets and protein target engagement./nThis dissertation explores the natural product Ophiobolin A’s (OPA), nanomolar anti-cancer properties and mechanism of action (MOA). OPA is a sesterterpenoid fungal metabolite that has demonstrated anti-proliferative properties across various cancer cell types7. Similar to other natural products, OPA’s MOA remains elusive with various groups proposing various explanations. Like other natural products, OPA is a covalently reactive molecule that possess reactive electrophilic centers that irreversibly reacts with proteins’ nucleophilic amino acid hotspots to modulate its therapeutic activity. Using chemoproteomic platforms, we identified OPA’s direct protein targets and mechanism of action (MOA) in squamous, non-small cell lung cancer cells (NCI-h1703): HIG2DA C53 and COX5A K72. Using activity-based protein profiling (ABPP) chemoproteomic platforms, we determined that OPA confers its anti-cancer activity through targeting cysteines and lysines in NCI-h1703 through covalently targeting HIG2DA C53 and/or COX5A K72, leading to cytochrome c oxidase activation, and altering the cancer cells’ metabolism.

Advisor: Nomura, Daniel K
Essays on Industrial Organization

We study the question of whether women, on average, pay a price premium — a so-called“pink tax”—for the products they buy. A particular concern facing policy makers is whether such differences are a form of gender based price discrimination. Using scanner data, we find that averaged across the entire retail grocery consumption basket, women pay 4% more per unit for goods in the same product-by-location market as do men. This price differential is generated by a 15% higher average per unit price paid by women on explicitly gendered products, like personal care items, as well as a 3.8% higher average per unit price paid by women on ungendered products, like packaged food items. Higher prices paid by women could be the result of differences in demand elasticity, competitive structure, or sorting into goods with differing marginal costs. To disentangle these mechanisms, we estimate demand differences between men and women and structurally decompose price differences into markups and marginal costs. We find that women are, on average, more price elastic consumers than men, suggesting that as a consumer base women are not likely to be charged higher markups under price discrimination. Overall, we find that the pink tax is not sustained by higher markups charged to women, but by women sorting into goods with higher marginal costs and lower markups. Medical provider price transparency is often touted as a key policy for efficiently lowering health care spending, which is nearly 20% of GDP. Despite its many proponents, the impact of price transparency is theoretically ambiguous: it could lower health care spending via increased consumer price shopping or improved insurer bargaining position but could instead raise health care prices via improved provider bargaining or either tacit or explicit provider collusion. We conduct a randomized-controlled trial to examine the impact of a state-wide medical charge transparency tool in outpatient provider markets in the state of New York. In the experiment, individual providers’ billed charges (list prices) were released randomly at the procedure X geozip level. We use a comprehensive commercial claims database to assess the impact of this intervention and find that the intervention causes a small increase in overall billed charges (+1%) but a relatively lower increase in the charges for procedures with many out-of-network claims (-2%). We find no evidence for quantity effects. We find larger charge increases for specific categories that are almost always insured and less elective in nature, e.g. MRI (+6%) and radiology (+3%) and charge decreases for categories that are less often insured and more elective in nature, e.g. psychology (-2%) and chiropractor (-3%) services. Taken together, these results are consistent with our intervention having a minimal effect on consumer price shopping but a meaningful effect driving increases in providers’ charges, especially for less elective services that are almost always covered by insurance, potentially reflecting perverse price effects resulting from tacit collusion or reduced information asymmetries.

Advisor: Handel, Benjamin
Recent Advances in Urban Mobility: Analyzing Efficiency, Equity and Safety

Transportation systems are the backbone of our modern economy. The ease of urban mobility is crucial for the success of cities. The automobile, which revolutionized urban mobility in the 20th century, is now struggling to keep up with demands for safety, efficiency, and equity. With more than 36,000 lives lost annually to traffic crashes in the US, and the average American spending 97 hours every year stuck in traffic, there is an imminent need for innovative solutions./nTwo recent technologies show promise in delivering the next leap in urban mobility: (a) transportation network services, and (b) automated vehicles. Transportation network services (TNS) are businesses that connect people spread across the transportation network for efficient provision of goods and services. Examples include ride-hailing services such as Uber, and delivery services such as Instacart. Automated vehicles (AVs), popularly known as self-driving cars, obviate the need for a human to be in the driver’s seat. The combination of AVs and TNS is expected to significantly reduce traffic fatalities, alleviate congestion, and improve accessibility./nDespite their transformative potential, the path to a bright AV-TNS future of urban mobility seems unclear. Companies have realized after years of effort that designing safe AVs is much more difficult than originally anticipated. Recent studies have found that TNS companies have increased congestion in major US cities. Moreover, a significant proportion of TNS workers are unable to earn the prevailing minimum wage in their jurisdictions. This thesis is an attempt to understand why the promised AV-TNS future has remained elusive./nWe explore two broad themes along this path: (a) economics of transportation network services, and (b) automated vehicle safety. Our work on these themes constitute the two halves of this thesis. In the first half, we introduce a unified framework to analyze the economics of transportation network services. Using this framework, we analyze the impact of recent labor regulations on the ride-hailing ecosystem and suggest alternatives that can achieve better outcomes. Adapting this framework to the case of delivery services, we demonstrate how the trade-off between delivery times and the cost of delivery, mediated by the extent of order pooling, dictates their economic viability. In the second half, we use a combination of theoretical models and empirical data to argue why connectivity is indispensable for safe AV deployment. Recognizing that some crashes are inevitable without connectivity, we propose a risk assessment framework that leverages human driving data along with on-road AV testing data to develop insights into their safety capabilities. We discuss several applications of this framework that inform safe AV deployment.

Advisor: Poolla, Kameshwar
Recent Developments in Robust Statistics

The design of statistical estimators robust to outliers has been a mainstay of statistical research through the past six decades. These techniques are even more prescient in the contemporary landscape where large-scale machine learning systems are deployed in increasingly noisy and adaptive environments. In this thesis, we consider the task of building such an estimator for arguably the simplest possible statistical estimation problem -- that of mean estimation. There is surprisingly little understanding of the computational and statistical limits of estimation and the trade-offs incurred even for this relatively simple setting. We make progress on this problem along three complementary axes./nOur first contribution is a simple algorithmic framework for constructing robust estimators. Our framework allows for a significant speed-up over prior approaches for mean estimation while also allowing for easy extensibility to other statistical estimation tasks where it achieves state-of-the-art performance./nSecondly, we investigate the statistical boundaries of mean estimation where we demonstrate the necessary statistical degradation incurred in extremely heavy-tailed scenarios. While prior work showed that estimation could be performed as well as if one had access to Guassian data, we establish that this is no longer true when the data possesses heavier tails. We provide lower bounds which exhibit this degradation and an (efficient) algorithm matching them./nLastly, we consider the stability of these estimators to natural transformations of the data. Inspired by the empirical mean, classical work constructed estimators equivariant to affine transformations. These works, however, lacked the strong quantitative performance of more recent approaches. We demonstrate that such trade-offs are in fact necessary by constructing novel lower bounds for affine-equivariant estimators. We then show that classical estimators are quantitatively deficient even in this restricted class and devise an estimator based on a novel notion of a high-dimensional median which matches the lower bound.

Advisor: Bartlett, Peter
Metamorphic Medium: Materializing Silver in Modern China, 1682-1839

“Metamorphic Medium” offers a new approach to the question of how objects can elucidate connections between local and global contexts, by centering the very material of early modern globalization. The dissertation is a social art history of silverwares that moved through the southeastern Chinese port city of Guangzhou. During the late Ming (1368-1644) and Qing (1644-1911) periods, silver exploited from mines in Latin America flowed into China through southern coastal ports, transforming the empire culturally and economically. Silverworking was a handicraft trade which relied on material, technical, and artistic knowledge to produce wares for both Chinese and foreign markets with connections to the region. Art historians have overlooked this topic due to the limited survival of Qing-period silverwares in China outside of court collections, and art-historical investments in literati and court art over vernacular, “export,” and ephemeral forms of art and material culture. Further, while silver is often evoked as the archetype for global commodity exchange, there has never been an object-based study of how silver circulated across incommensurable systems of value./nThis dissertation asks how the production and transaction of silver objects illuminate connections between craft and mercantile knowledge, consumer tastes, and the power differentials of value negotiated across oceanic distances. It converses with art histories of global exchange, commodity histories, and histories of globalization. It views silver objects not as permanent works of art, or rationalized units of uniform value, but rather as contingent crystallizations of a mutable and heterogenous medium. At a historiographic level, the study traces how local and global forces have shaped art history. It argues that silver during this period was interpreted and claimed as something other than Chinese, due to the separate agendas of, as well as interactions, between Ming-Qing literati canons of taste, and the foreign and primarily European appropriation of global commodities and their histories. At a historical level, the study positions regional Chinese silversmiths as powerful agents that impacted silverware production, consumption, and history in regions often viewed as the global centers of metalworking innovation. Finally, it argues for approaches to art history that regard the ongoing material transformation of objects and their points of social transaction as primary methodological concerns, in order to expand the subjects studied and histories produced by the field.

Advisor: Lovell, Margaretta
How a Whale Becomes a Molecule: A Geography of Modern Olfaction

This dissertation, How a Whale Becomes a Molecule: A Geography of Modern Olfaction, argues that the sense of smell is a material relation and that it evolves through a set of geographic processes in distinct places and times. I follow the transformation of ambergris, a whale metabolic aberrance, into its chemical articulation, Ambroxan, to show how an evolving political economy mobilizes epistemic practice, iteratively conditioning the nature of olfaction. I explore the modern sense of smell as an ensemble of human industrial affective processes: first in the context of American imperial whaling through which marine life becomes entangled within several scales of commodity rendering, then through the embodiment of ambergris in practices of social-spatial hierarchy relative to both hygiene and class in 18th and 19th century France. I then focus on the translation of these imperial and industrial values into a consolidated olfactory paradigm wherein ‘the nose’ in the perfume industry deciphers and authorizes material identity, creating the possibility for chemical fungibility./nIn showing how the processes of rendering ambergris are coterminous with knowledge systems that rationalize, commodify and reproduce it, I posit that 1. objects are assembled through the distinct practices and are inseparable from the political life in which they’re embedded, and 2. that ‘the nose,’ in its geographic instantiations, is produced as a stable arbiter and means of knowing the world, and is conscripted to connect objects in the world in a certain way. I show that there is no essential object or character to things and that material affects are objects in flux, whether squid spawn or fossil fuel and their reverberation depends on the durability of bodily affects alongside the material, semiotic codes into which they are trained.

Advisor: Kosek, Jake
Watts, Michael
Detection of waves in the Earth’s outer core using geomagnetic data-driven techniques

Short-period fluctuations in the Earth’s geomagnetic field have been observed through satel- lite observations over the past 20 years. In this work, we explore the use of two data driven-techniques to quantify and interpret the short-period fluctuations. Complex empirical orthogonal functions (CEOFs) are applied to observations of the second time derivative of the geomagnetic field (secular acceleration) from several localized regions of the CHAOS6 model (Finlay et al., 2016). We found evidence of eastward and westward traveling waves with periods of 7.08 ± 0.58 and 15.73 ± 4.44 years, respectively, in the Atlantic and South Asia regions. Furthermore, we have applied dynamic mode decomposition (DMD) to investigate the temporal evolution of the radial magnetic field (Br) and secular variation (SV) at high latitudes using CHAOS7 (Finlay et al., 2020). Our results exhibit waves with periods of 19.1 and 58.4 years. A 60-year wave is compatible with prior predictions for zonal waves in a stratified fluid. The 20-year wave is consistent with previous findings at high latitudes, although the wave characteristics do not permit a simple interpretation. Finally, we study positive and negative geomagnetic acceleration patches moving westward at high latitudes. Magnetic Rossby waves offer one possible interpretation of the observations. This type of waves can account for the propagation direction and phase velocity. However, the predicted spatial pattern of the magnetic field variation is more complex than the observations. Zonal MAC waves, however, can explain the observed field with a stratified layer at the core’s top. In conclusion, these results are significant for comprehending the dynamics of the geomagnetic field and its impact on the Earth’s outer core structure.

Advisor: Buffett, Bruce
The localization of magnetite biogenesis proteins in Magnetospirillum magneticum AMB-1

Bacteria make a wide variety of organelles to assist in specific cellular functions. How these organelles are assembled is poorly understood. One model for prokaryotic organelle biogenesis is the magnetosome, a lipid-bound compartment that contains a magnetic crystal allowing magnetotactic bacteria (MTB) to navigate along magnetic field lines in their environments. To create magnetosomes, MTB localizes many proteins specifically to the developing magnetosome membrane. How these proteins are sorted is an active area of research. This work explores magnetosome formation and investigates the sorting of a class of magnetosome proteins that are only localized to magnetosomes under magnetite-forming conditions. The first chapter of this dissertation, an unpublished review article, introduces the topic of magnetosome assembly in magnetotactic bacteria. It explores the selection of Magnetospirillum magneticum AMB-1 and Magnetospirillum gryphiswaldense MSR-1 as model species for studying magnetosome formation, including early work that created genetic tools enabling molecular characterization. In addition, studies are described that used these tools to identify proteins critical to magnetosome formation. Chapter 1 also describes a working model of magnetosome biogenesis and identifies areas where more research is needed to fill in our understanding of this complex process. The second chapter of this dissertation, an unpublished primary research article, investigates the localization of magnetite shaping protein Mms6 in AMB-1. Mms6 had previously been shown to localize to magnetosomes after iron is added to iron-starved cells. This change in localization suggested that either new Mms6 was produced and targeted to magnetosomes upon addition of iron, or pre-existing Mms6 was able to relocalize after iron addition. Using pulse-chase analysis combined with microscopy, we determine that pre-synthesized Mms6 in the cytoplasm is relocalized to magnetosomes in response to environmental cues. Our findings identify several magnetosome proteins and Mms6 protein domains critical to this dynamic localization behavior. The third chapter of this dissertation, an unpublished primary research article, identifies another protein, MamD, that is also sorted based on environmental conditions. MamD is a magnetosome protein that has been shown to bind magnetite crystal and inhibit magnetosome membrane growth. We use fluorescence microscopy to show that MamD, like Mms6, only localizes to magnetosomes when biomineralization of magnetite crystal is possible. In addition, we show that MamD magnetosome localization requires several of the same magnetosome proteins required for Mms6 localization. Our results suggest that there may be a step in magnetosome assembly where a specific cohort of proteins is conditionally recruited to assist in the nucleation and development of magnetite crystal.

Advisor: Komeili, Arash
Mortality Crises as Experienced by their Survivors: Computational Approaches to the Study of Bereavement

Although the study of mortality is central to demography, comparatively little is known about its lived experience: how population-level mortality translates to individual experiences of loss within families and communities. Given the significance of bereavement for the health and socioeconomic outcomes of survivors, better understanding the impacts of mortality crises on family networks is crucial for predicting their longer-term consequences. The data required to study kin loss, however, is seldom available, leading many demographers to rely on computational approaches such as microsimulation to estimate the impact of these events./nThis dissertation presents microsimulation-based approaches to examining the impact of a mortality crisis, in this case COVID-19, on kin networks in the short and long term. The first study presents estimates of monthly excess kin loss by age and type of kin relation in 31 countries during the period of March 2020 to June 2021. These estimates demonstrate a generational pattern of kin loss reflecting COVID-19 age-specific excess mortality risk, and highlight the significant effect of excess mortality on family bereavement. The second study extends this estimation approach to 120 countries over the 2020-2021 period, documenting high rates of excess kin loss in many low-and-middle-income countries higher than or comparable to those observed in high-income countries. It also considers the extent to which differences in country estimates were shaped by both excess mortality and pre-existing kinship structure. The third study projects how "kinship memory'', the estimated share of national populations related to victims of COVID-19 excess mortality, may change over the next century in 120 countries around the world, and considers what this may mean for how this crisis is remembered in the future. These three studies combined highlight the significant burden of COVID-19 excess mortality in terms of bereavement experienced by surviving family members, and demonstrate the importance of computational approaches in helping better understand the experiences of populations for which limited data exists.

Advisor: Wachter, Kenneth
Goldstein, Joshua