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Bile acid metabolism by gut bacteria
No full textThe human gut microbiome significantly affects host biology. In particular, gut bacteria modify important pools of molecules that impact host physiology. Therefore, further studies of gut bacterial metabolism will provide insights into the significance of gut bacteria and their impact on host health and disease.
Here, I describe my projects that aimed to contribute to our understanding on the gut bacterial modifications of bile acids. Chapter 2 describes our use of a chemical tool to modulate gut bacterial metabolism in vivo. AAA-10 inhibits bile salt hydrolase (BSHs), enzymes that catalyze the gateway step for all gut bacterial metabolism of bile acids. We showed successful modulation of bile acid pools using AAA-10 in both monocolonized and conventional mice, which led to significant changes in metabolic phenotypes and host gene expression, respectively. AAA-10 treatment improved glucose tolerance and reduced liver steatosis in monocolonized mice, while AAA-10 treatment led to preliminary gene expression changes in genes related to the circadian rhythm and immune response in conventional mice. These studies will serve as a guide for future in vivo experiments modulating gut bacterial metabolism of bile acids.
However, AAA-10’s effectiveness as a BSH inhibitor in vivo has room for improvement, and my efforts to understand mechanisms of insensitivity to AAA-10 are presented in Chapter 3. Here, we describe our discovery of a bacteria strain, Lactobacillus intestinalis ASF 360, that has a strong BSH activity that is insensitive to AAA-10 inhibition. Using heterologous expression and bacterial assays, we showed evidence for a transport mechanism that may be involved in removing the inhibitor from the cell during normal growing conditions. We also discovered a new lead inhibitor, DCA-FMK, that inhibited BSH activity in L. intestinalis. Our new lead inhibitor together with our understanding of the resistance mechanism will guide us towards developing a next-generation BSH inhibitor.
Finally, Chapter 4 describes our efforts to elucidate the biosynthesis of the bile acid metabolite isoallolithocholic acid (isoalloLCA), a compound that enhances the differentiation of naïve T cells into Treg cells both in vitro and in vivo. Using a combination of microbial genetics, protein expression, analytical chemistry, and synthetic organic chemistry, we identified a gene cluster that is responsible for isoalloLCA production in the abundant gut bacterial phylum Bacteroidetes. We showed that the gene cluster is necessary and sufficient for both in vitro and in vivo production of isoalloLCA, and both isoalloLCA and the isoalloLCA-producing genes are associated with inflammatory bowel disease (IBD) in human patients. These results highlight a new mechanism by which gut bacterial metabolism mediate host immune tolerance.
Overall, my projects cover a range of topics about gut bacterial metabolism of bile acids. Together, these studies contribute to our understanding of how gut bacteria impact on host health and disease by chemically modifying compounds found in the gut
Multispecies Diplomacy: Ottoman Horses, Mantuan Buyers, and Renaissance Equestrianism (1489-1600)
No full textThis dissertation examines how politics, knowledge production, and material culture linked the Ottoman Empire to Renaissance Italy in the fifteenth and sixteenth centuries through the lens of horsemanship. Because horses acted as ennobled but subordinate partners to humans in military conquest, political image-making, and aristocratic leisure, their movements offer rich opportunities to weave together regionally siloed histories of commerce, diplomacy, culture, and science.
It centers upon the 1490s with the brief but consequential imprisonment of the Ottoman prince Cem in Rome from 1489-1495 as a captive in the papal curia. Cem, as a rival claimant to the throne of his elder brother Sultan Bayezid II (r. 1481-1512) offered first Pope Innocent VIII and later Alexander VI a compelling figurehead for a long-awaited anti-Ottoman crusade. To prevent Cem’s release, the sultan mobilized a dense network of spies, diplomats, and allies from Naples to Venice. Among his friends was the condottiere, cultural patron, and avid horse-breeder Marquis Francesco II Gonzaga of Mantua (r. 1484-1519). During repeated diplomatic embassies to Istanbul, Gonzaga offered luxuries like dogs, mules, and Italian-made armor to Bayezid II and his officials to secure permission to export Ottoman horses. Through his efforts, the stables of small and landlocked Mantua became a premier supplier of coveted Turkish horses (It: turco, pl: turchi) in Italy.
Undertaking the first comprehensive study of Gonzaga’s Ottoman diplomacy since 1965, this dissertation uses correspondence from the Archivio Gonzaga and the Topkapı Palace Archives to establish a definitive narrative of the envoys and embassies exchanged between the two rulers. It traces how Bayezid II’s envoys in Italy cultivated relationships with Mantuan agents and how Gonzaga in turn learned about the Ottoman court and deepened ties with the empire’s provincial and central office-holders. On this basis, it argues that Francesco II’s horse trade was thoroughly politicized and identifies how Venetian tutelage and papal policies enabled (and eventually foreclosed) opportunities for equine exchange. As a result, it grants the Ottoman Empire a significant place in Francesco II’s dynastic strategies. Furthermore, it begins the important task of re-assessing Bayezid II’s diplomacy with the papacy during his brother’s captivity and demonstrates that these contacts were more substantive than has previously been recognized.
Additionally, it examines the broader role of Ottoman horses in Renaissance equestrian culture. As military changes reconfigured the relationship between nobility and horsemanship, Italians increasingly imported and bred diverse horse types suitable for new functions and pioneered a new riding style, maneggio/manège, in the academies of Naples. Historian Donna Landry has hypothesized that these schools played a further role: popularizing Ottoman horse care first in Italy and later in England, where new horse breeds like the Thoroughbred would be developed by importing stock from the Ottoman Levant in the seventeenth and eighteenth centuries. By contrast, this dissertation places Mantuan grooms, cavalrymen, and diplomatic agents at the forefront of this trend. It argues that the adoption of Ottoman equine husbandry in sixteenth-century Italy was preceded by a positive re-assessment of the Turks as horse-keepers in the fifteenth century when European authors began to regard Ottoman horsemanship not as neglectful but instead as kindly and effective. These discursive shifts redefined turchi horses as desirable commodities: an element of Ottoman military success that could be replicated at home in novel light cavalry units. By the turn of the century, Ottoman horses were arriving with equipment like shoes, saddles, and bridles suited to a style of veterinary care and riding which differed from Italian practices.
Despite this appeal, Ottoman equine pedagogy also challenged Italian notions of good riding: turchi horses suffered injury and illness in their care while their behavior failed to conform to manège standards. In response, equestrian writers developed a heterogeneous repertoire of methods and equipment intended to ‘correct’ their mounts. As a form of both inter-species and cross-cultural translation, this repertoire adopted some Ottoman practices (like shoeing) but rejected others (like bitting). Thus, Italian equestrians’ acknowledgement of Ottoman expertise was tempered by a racialized discourse that stereotyped the Ottoman Turks, their history, and their society in order to categorize (and discipline) their horses in increasingly essentializing ways.
Through an enriched understanding of Mantuan-Ottoman diplomacy, this dissertation intervenes in the growing historiography on Renaissance horsemanship. It demonstrates that beyond Naples, the Adriatic acted as a crucial axis of horse exchange between Ottoman southeast Europe and northern Italy. Through these exchanges, a diverse cast of diplomats, viziers, grooms, merchants, popes, and cavalrymen brought Ottoman equestrian material culture and practices to Italy long before the publication of the first printed manège treatise in 1550. In this way, the Ottoman Empire was a vital participant in the innovative and dynamic field of early modern horsemanship whose influence extends through Mantua, Naples, and England to the breeds dominating competitive horse racing today
Genetic Evaluation of Rare Cancer Syndromes Using a Combined Analysis of the Germline and Tumor Genome Data
No full textResearch in oncology is often conducted by assessing the germline and somatic information separately. The tumor genome can help identify cancer types and therapeutic targets. Conversely, the germline genome can reveal cancer predisposition risk. The separate assessment of germline and somatic genomes can lead to challenges in understanding the full extent of tumor biology and tumor etiology.
This thesis study hypothesizes that investigating a combination of germline and somatic information is more informative than assessing tumor-only or germline-only information. To test this hypothesis, 203 variants were randomly selected and assigned to three different cohorts based on genomic origin: 1) Cohort 1 included 42 somatic variants without any germline data; 2) Cohort 2 included 63 germline variants without any somatic data; and 3) Cohort 3, or Germline Plus, included 98 germline variants with combined somatic data. All variants were annotated using variant type, protein effect, genomic region, and population allele frequency. Allele frequency values were obtained informatically from the publicly available gnomAD database.
Comprehensive variant analysis was performed to assess loss of heterozygosity (LOH), and whether LOH was sporadically or constitutionally driven. For each variant and gene, the associated cancer type was assessed. The annotated and analyzed variants were aggregated into a comprehensive database to enable the assessment of the informative status for each variant. The variant interpretation was performed using a combination of LOH status and cancer-type information. The determination of cancer etiology was performed to distinguish inherited versus non-inherited cancer types.
The results showed that a combined assessment of the germline and somatic information is more informative. The Germline Plus Cohort produced the most informative results, as 98% of variants were informative. Somatic-only analysis showed that 57% of variants were informative. Germline-only analysis without any tumor information did not provide full details of tumor etiology. The findings of this research project support the hypothesis that the combined assessment of somatic and germline genetics sheds light on the etiology of cancer and tumor biology
Adaptation to Climate Change Among the Rural Poor
No full textThe economic consequences of climate change hinge on adaptation among the poor, and in particular those agricultural households whose livelihoods directly depend on the environment. I examine this topic in Bangladesh, ground-zero for global warming's most devastating impacts. In Chapter One, I dive into the microfoundations of climate adaptation by examining the causes and consequences of environmental beliefs—a key primitive in the decision-making process. Rice farmers' misperceptions of their soil's salinity stem from a fundamental identification problem they face in learning about their local environment, with substantial consequences for technology adoption and profits. In Chapter Two, I study the role of adaptation in mitigating the macroeconomic damage of floods, the world's most common natural disaster. Equipped with a new satellite-derived measure of inundation, I show that floods push labor out of agriculture, spur migration, and increase schooling, and I find evidence of experience-driven adaptation that mitigates a third of floods' economic harm. In Chapter Three, I explore how both households and communities cope with the spatially covarying shocks characteristic of environmental threats. Amid more concentrated agricultural risk, households self-insure through temporary migration—an adaptation margin which ultimately increases participation in village risk sharing networks
Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration
No full textMitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons, and that GSDME plays a critical role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase dependent GSDME cleavage and rapid localization to mitochondria in axonal processes, where GSDME promoted mitochondrial depolarization, trafficking defects along axons, and neurite retraction. Expression of activated N-GSDME in primary neurons was sufficient to drive mitochondrial dysfunction, neurite loss and cell death. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 also induced GSDME activation and mediated damage to mitochondria and neurite loss; knockout of GSDME in primary mouse neurons was protective. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Lastly, knockout of GSDME in the mutant SOD1G93A mouse model of ALS prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammatory markers. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that contributes to neurodegeneration.Medical SciencesMedical Science
From the Periphery to Power: The Impact of Underrepresented Groups in the Indian Governmen
No full textThis paper studies the impact of gender on parliamentary speech in India through the analysis of “Question Hour” between 1999 and 2023. I use transformer-based language models to demonstrate the existence of gender differences in parliamentary behaviour and categorise speech into distinct and meaningful topics. I also use quasi-experimental variation in the gender of legislators to explore its effect on question content and find that women consistently prioritise women and children’s issues in parliament. I show that these priorities are driven by women’s perspectives on general legislative issues. These results suggest that India’s future quotas to increase the number of women in parliament will have significant impacts on public policies designed to benefit women
Characterizing immune crosstalk in the precancerous tissue
No full textExtensive work within the field of cancer immunology has successfully characterized the tumor immune microenvironment and its impact on patient responses to therapy. However, there has been substantially less work dedicated to understanding the early factors that facilitate the formation of the tumor immune microenvironment. In particular, understanding changes in early precancerous cells and the subsequent impact on the precancerous tissue may facilitate our understanding of how the tumor microenvironment forms. In this thesis, we demonstrate that precancerous cells alter their communication with the other cells in their environment well before the formation of a tumor. Leveraging an established model of cutaneous squamous cell carcinoma (cSCC), we find that keratinocytes with carcinogenic mutations change their signaling to both local immune cells and the local neuron population. Mechanistically, precancerous keratinocytes upregulate the expression of cytokines Ccl20 and Thymic Stromal Lymphopoietin (Tslp). These cytokines are known to control the Innate Lymphoid Cell (ILC) population in other skin pathologies. Further, their upregulation by the precancerous keratinocytes coincides with an expansion in the skin ILC population in the precancerous skin. In addition to these cytokines, we also note that the precancerous keratinocytes substantially upregulate Peptide YY (Pyy). We find Pyy receptor expression exclusively within a subset of dermal neurons. We also find that the neuron population within the precancerous skin changes and upregulates expression of genes associated with neuronal regeneration, suggesting the neuron population is becoming poised to engage. Collectively, this work demonstrates that well before the formation of a palpable tumor, precancerous cells alter their communication with their microenvironment. This altered communication demonstrates that the formation of the tumor microenvironment likely starts well before a tumor even exists
Quantum Dynamics of a Particle Interacting with Lattice Vibrations and Disorder Potentials
No full textUnderstanding the fundamental behavior of matter requires studying the quantum dynamics of a particle interacting with lattice vibrations and disorder potentials. In the first part of this dissertation, lattice vibrations are represented using the coherent state representation, resulting in a quasiclassical field that serves as a dynamic disorder potential for a particle. The dynamics of the particle within this potential are treated nonperturbatively to preserve coherence beyond single collision events. This approach is effective in capturing particle coherence effects and computing the density of states. Specifically, the low-energy tail of the spectral density is calculated and its relationship to static disorder potentials is established in the classical phonon limit. In the second part of the dissertation, it is shown that even in the absence of periodic structure in a static disorder potential, sharp Bragg diffraction of the wave is still observed. This phenomenon resembles a powder diffraction pattern but includes nontrivial partially resonant scattering that violates Fermi’s golden rule
Toward Therapeutic Control of Circadian Rhythms: Optimisation of Pharmaceutical Administration Models for Circadian Entrainment via Nonlinear Model Predictive Control
No full textThe ability to shift circadian phase in vivo has the potential to offer substantial health benefits, and constructing an appropriate model — from therapeutic administration to phase response — will enable this possibility. The blood-brain barrier (BBB), however, prevents the absorption of essentially all large and many small molecules, posing a challenge to neurological pharmaceutical development. Motivated by the presence of the circadian molecule KL001, which is capable of causing phase shifts in a circadian oscillator, this work explores the effect of two passive and three active transport mechanisms on the dynamics of circadian phase. Specifically, this thesis investigates the effect of melatonin, which passively diffuses across the BBB, triiodothyronine (T3), amine, and neutral amino acid carrier mediated transport (CMT), and polymeric nanoparticle adsorptive transcytosis administration mechanics. The pharmacokinetic/pharmacodynamic (PK/PD) modeling approach has been considered to describe the physiological dynamic behavior in response to such delivery mechanisms and provides an accurate estimate of the cerebrospinal fluid (CSF) concentration curves. The introduction of the PK/PD models achieves a physiologically accurate prediction of the phase response curve of the circadian oscillator and informs a constrained, infinitesimal parametric phase response curve (ipPRC)-defined, nonlinear model predictive controller (MPC) to compute appropriate dosing for clock re-entrainment. The phase-resetting capacity of these models is investigated through the real-world scenario of jet lag
China-United States Economic Relations, with Focus on Currency Convertibility
No full textThis thesis provides an alternative view of the United States-China relationship through the lens of trade liberalization and economic co-dependency, with a focus on convertibility of Chinese currency. Does the Renminbi (RMB) threaten the global status of the US Dollar (USD)? I address the question by providing a cost-and-benefit analysis of a RMB liberalization exercise. Based on historical evidence, some scholars argue that the United States and China are entering a period of conflict (see, for example, Allison, 2017). From the trade war that began in 2017, and the dispute over semiconductors, to the tech war, and current financial Cold War between the United States and China (Fok, 2020), American leaders seem willing to confront China on multiple fronts.
However, as a controlled currency, the RMB provides a level of protection for China. At the same time, while some observers view China as an autarky that is aiming to become self-sufficient and economically independent, the average US consumer still depends on complex supply chains that originate in China, providing affordable goods. Nike shoes and iPhones, for example, are considered necessities for many Americans.
Is a fully convertible RMB harmful or beneficial to American consumers and working-class citizens? Could the convertibility of the RMB create more financial benefits to American workers, reshape geopolitics locally, and change the course of history? These questions are the subject of this thesis.
Chinese capitalism is ambidextrous in that it simultaneously operates two conflicting models: government control, and entrepreneurialism. This presents significant challenges to the US government. Keyu Jin’s The New China Playbook—Beyond Socialism and Capitalism (Jin, 2023) highlights how economic decentralization and political centralization occur simultaneously under the CCP. Building on The China Paradox (Clifford, 2021), my research provides fresh perspectives on the complex integration of the Chinese Communist Party’s (CCP) autocracy with entrepreneurial renewal.
This research is based on an extensive review of existing literature on the subject, as well one-on-one interviews with 21 leading executives, academics, senior finance professionals, and cabinet-level government officials. The research integrates microhistory with Harvard Business School-style case studies. I selected a group of individuals to interview, and asked them to share their policy views on capital-market reform and the full convertibility of the RMB in the context of US-China conflicts. In addition, I made use of 34 HBS-style case studies and collected sample data from 32 American companies.
Using the data from the interviews and case studies, I calculated a “Benefit Score” for working-class employees in each company. The Benefit Score for each American company is calculated based on seven factors: 1) revenue, 2) number of employees, 3) pay multiple, 4) employee salary, 5) company tax, 6) US locations and 7) weakening RMB. I conclude that a fully convertible RMB is indeed beneficial to working-class Americans