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Romance Auctoritas In Le Livre Du Cuer D’amours Espris And Jehan De Saintré
Get PDFThis dissertation asks whether, by the end of the Middle Ages in France, the romance genre had gained literary authority, or auctoritas, and, if so, how it had gained it and what the social impact of this auctoritas was. This line of questioning is executed through a study of two mid-fifteenth-century romances: René d’Anjou’s Livre du Cuer d’Amours espris and Antoine de la Sale’s Jehan de Saintré. These two works, written near the end of the Middle Ages when romance was at the height of its popularity and influence, heavily imitate and cite earlier romances, and in so doing, offer an insightful response to the genre and its position in French courtly society. They confirm that while the genre may not have had a traditional scholarly auctoritas, it certainly had a level of courtly auctoritas, exemplified by the literary traditions of the Roman de la Rose and Prose Lancelot. These literary traditions exerted cultural auctoritas as they came to functional as behavioral and moral guides in the courtly disciplines of love and chivalry. Furthermore, this study argues that two principle writing strategies served to establish romance auctoritas despite the fictionality of the genre. The first, exemplified by the Roman de la Rose and imitated by the Livre du Cuer, was to present the romance’s fictions as allegory, with the argument that they covered hidden moral truths. The second, exemplified by the Prose Lancelot and imitated by Jehan de Saintré, was to deny the fictionality of the romance, and to instead present it was a work of historia. The two late-medieval works at the center of this study each employ one of these two romance strategies in an attempt to build their own auctoritas, even while criticizing the socially harmful influence of romance ideology. In so doing, they confirm the genre’s courtly auctoritas and reveal the strategies employed to achieve it
Rapid, Site-Specific Labeling Of \u27off-The-Shelf\u27 And Native Serum Autoantibodies With T Cell-Redirecting Domains
Get PDFGenerating new bispecific antibodies typically requires extensive engineering and cloning. New technologies such as made-to-order genes, advanced expression systems, and high efficiency cloning have simplified and accelerated this process. However, the timeline to create new bispecific antibodies is in the order of months, the resulting yield can be low, and adequate functionality is not guaranteed.Here, we developed a simple method to produce bispecific antibodies by site-specifically and covalently attaching a T cell redirecting domain to any off-the-shelf, human Immunoglobulin G (IgG). Our method excludes antibody engineering, cloning or prior knowledge of the antibody sequence, and the bispecifics are created in two hours. We demonstrated the applicability by assessing in vitro cytolysis of bispecific antibodies made using three FDA-approved monoclonal antibodies. We also show the ability to create personalized T cell redirecting autoantibodies (TRAAbs) by labeling native antibodies isolated from tumor-bearing mice, including two syngeneic murine models. TRAAbs were found to induce anti-tumor effects in vitro and in vivo. TRAAbs were also found to preferentially bind tumor over healthy tissue, highlighting a window for safe therapy. The use of autoantibodies to direct the tumor targeting of bispecific antibodies represents a new paradigm in personalized medicine that eliminates the need to identify tumor biomarkers and can potentially overcome tumor antigen loss, which commonly results from mono-targeted immunotherapies
Integration Of Single Cell Transcriptomics And Epigenomics To Identify New Regulators Of T Cell Development And Function
No full textab lineage T cells, most of which are CD4+ or CD8+ and recognize MHC I or MHC II-presented antigens, are essential for immune responses and develop from CD4+CD8+ thymocytes. The absence of in vitro models and the heterogeneity of ab thymocytes have hampered analyses of their intrathymic differentiation. Here, combining single-cell RNA- and ATAC- (chromatin accessibility) sequencing, we identified conserved developmental trajectories for both mouse and human ab thymocytes. Integrated analyses of MHC I- and MHC II-signaled cells demonstrated asymmetric emergence of CD4+ and CD8+ lineages. Through computational analysis of single cell data and binding sites for the CD4+-lineage transcription factor Thpok, we inferred transcriptional networks associated with CD4+- or CD8+-lineage differentiation, and with expression of Thpok or of the CD8+-lineage factor Runx3. Finally, we identified Zfp148 and Zfp281 as novel transcription factors that regulate CD4+ T cell development and function via cooperation with the transcription factor Gata3. Our findings provide new insights into the mechanisms of CD4+ and CD8+ T cell differentiation and CD4+ T cell function
Essays On Heterogeneity In Macroeconomics
No full textThis thesis focuses on the formation of micro-level heterogeneity and its implications for macroeconomics and macroeconomic policies. The first chapter studies how the heterogeneity of job types (occupation-industry) in terms of worker turnover shapes the employment fluctuations of the United States. I first document two novel facts: 1) separation and hiring of low turnover job types in cross-section co-move more with the aggregate business cycle and 2) the matches with high-quality workers formed in recession dissolve more quickly than comparable ones formed in the boom. Moreover, for matches with low-quality workers, this pattern is reversed. I then build a model that, when disciplined by the average worker flows in cross-section, can 1) replicate the business cycle facts documented above and 2) naturally lead to amplification of the employment to productivity shocks. The mechanism relies on two key elements: 1) there exist multiple job creation technologies such that stable jobs are more costly, which makes low turnover jobs more cyclical. 2) There exists sorting between worker and job types, such that endogenous changes in the composition of applicants affect firms’ job duration expectation at business cycle frequency, and thus the job creation motive. In the second chapter, we develop a novel model to study the role of venture capital (VC) in shaping US wealth inequality and mobility. In our model, households choose entrepreneurship entry and the source of external funds (bank or VC) based on project quality and household wealth. The model has three distinct features: 1) VC offers synergy with entrepreneurs through unobservable effort, while entrepreneurs incentivize VC through a profit-sharing contract. The non-contractible nature of VC effort implies expertise and funding must be combined if VC is involved. 2) VC is chosen endogenously only when project quality is high, making entrepreneurship depend more on project quality compared to wealth. 3) Internal capital of a business is more mobile for entrepreneurs compared to external funding, leading to a lower internal capital cost than external cost. This difference creates a strong saving motive for households, which is particularly relevant for wealthy entrepreneurs. The model can quantitatively match the income distribution and wealth distribution in the United States. When calibrated to occupational transitions and entrepreneurs’ equity shares, the model generates that the VC sector: 1) increases the wealth share of the top 0.1% households by 1 percent points and the wealth share of the top 1% households by 2.1 percent points, 2) increases the probability that the households at the bottom 99% move to the top 1% after a generation by 1.4 percent points. The third chapter assesses the power of forward guidance--promises about future interest rates--as a monetary tool in a liquidity trap using a quantitative incomplete-markets model. Our results suggest the effects of forward guidance are negligible. A commitment to keep future nominal interest rates low for a few quarters--although macro indicators suggest otherwise--has only trivial effects on current output and employment. We explain theoretically why in complete markets models forward guidance is powerful--generating a ``forward guidance puzzle --and why this puzzle disappears in our model. We also clarify theoretically ambiguous conclusions from previous research about the effectiveness of forward guidance in incomplete and complete markets models
Emergence Of A Deterritorialized Nation: How Tibetan Political Practices Confront The Precarity Of Statelessness
No full textThis research is based on eighteen months of fieldwork in the Tibetan communities and settlements of Dharamsala, Bengaluru, and Bylakuppe, in India, and in New York and Washington, D.C. Through interviews and archival research, I develop a multilayered understanding of an alternate political configuration—what I have called the deterritorialized Tibetan nation—that emerges through protest practices, political participation, and alternate claims of national belonging by Tibetans across a transregional space of exile. Through these practices, Tibetans transform settlements from sites of displacement and exclusion into spaces of national belonging. Thus, this political entity, by the very nature of its existence, challenges the limits imposed by a global order of nation-states that “secretes” statelessness. My research is broadly concerned with four interrelated questions: (1) How do stateless communities continue to articulate alternate models of nationhood despite the hegemony of the global order of nation-states? (2) How are stateless communities engaging with and challenging discriminatory and exclusionary citizenship regimes in host nations? (3) What are the intracommunity conflicts and compromises that arise due to geopolitical conditions of statelessness? (4) How do conditions of stateless precarity compromise and motivate communal intimacy? To answer this, I study practices ranging from invocations of national fervor across a transnational “citizenry” following self-immolations and hunger strikes, to voting, paying taxes to an exile state, and forging and celebrating their affective ties as a national community. In surveying a shifting geopolitical landscape from the Cold War to the Global War on Terror, I show that far from being mere victims of their circumstances, the Tibetans are active political actors capable of protecting the interests of their fragile polity. But this is no triumphant story: I also show how these global shifts exact costs on the community, fomenting schisms, paranoia, and intracommunity conflict
Removing Strong Data Assumptions In Causal Inference Via Large-Scale Optimization
Get PDFMany traditional and newly-developed causal inference approaches require imposing strong data assumptions, and if those assumptions were violated in practice, these approaches may be inapplicable, suffer from low statistical power, or lead to misleading causal conclusions. In this dissertation, we present three papers to show how large-scale optimization can sometimes aid in removing strong assumptions about the data generating process or the data collection procedure that are required by some existing causal inference approaches.
The first and second papers show how large-scale optimization can sometimes help remove strong assumptions about the data generating process. In the first paper, a new adaptive approach is proposed to combine two test statistics in matched observational studies. The proposed adaptive approach asymptotically uniformly dominates both of the two component test statistics in sensitivity analyses, regardless of the underlying data distribution. In the second paper, a model-free and finite-population-exact framework is proposed to analyze randomized experiments subject to outcome misclassification. This new framework is based on large-scale integer programming and can help researchers analyze a randomized experiment subject to outcome misclassification in a more comprehensive way without imposing any additional assumptions on a randomized experiment.
The third paper illustrates how large-scale optimization can help remove strong assumptions about the data collection procedure. Specifically, to study the effect of reducing malaria burden on the low birth weight rate in sub-Saharan Africa, a pair-of-pairs approach to a difference-in-differences study is proposed, which is built on optimal matching (a large-scale network flow problem) and cardinality matching (a large-scale integer programming problem). Unlike the traditional difference-in-differences studies, this pair-of-pairs approach does not require either panel data or repeated cross-sectional data to be collected before the analysis stage
Single-Component Optogenetic Tools Fo Cytoskeletal Rearrangements
Get PDFThe Rho family of small GTPases coordinate actin cytoskeletal rearrangements underlying crucial cell processes including migration and mechanotransduction. Dysregulation in these signaling pathways has been associated with neurodegenerative disease and cancer. Rho GTPase signaling is tightly controlled in space and time: GTPases are activated by guanine nucleotide exchange factors (GEFs) and inactivated by GTPase accelerating proteins (GAPs) at the plasma membrane. To study Rho GTPase signaling, several optogenetic tools have been developed, most of which use light to induce a protein-protein interaction, recruiting a GTPase-activating GEF to the plasma membrane. Other optogenetic strategies involve the use of single-chain photoswitches sterically occluding a constitutively active GTPase, which can result in undesirable high dark-state activity of the tool. We sought to create single-component optogenetic tools to perturb Rho GTPase signaling at the GTPase, GEF, and GAP level, resulting in lower dark state activity and easier implementation in mammalian systems.In this work, we used BcLOV4, a fungal photoreceptor which directly binds membrane lipids in response to blue light inputs, to recruit Rho signaling proteins to the membrane, resulting in spatiotemporally precise signaling perturbation. We created BcLOV4 activation tools using the GTPase and GEF from the three best studied Rho GTPase pathways: RhoA, which induces cell contraction through stress fiber formation; Rac1, which induces sheet-like lamellipodial protrusions; and Cdc42, which induces spiky filopodial protrusions. Notably, we demonstrated that the BcLOV4 system is compatible with wildtype GTPases, resulting in lower unintended pathway activation in the dark state. We also report progress toward the creation of RhoA termination tools using GAP domains and dominant-negative GTPases, allowing for the induction of signaling activation and termination on the same optogenetic platform. Using structural knowledge we gained from Rho GTPase tool development, we created a plasmid set and cloning workflow to simplify BcLOV4 tool engineering for other signaling targets. Together, the BcLOV4 optogenetic toolbox will further the study of Rho GTPase signaling and enable others to use this technology for single-component optogenetic membrane recruitment
Essays In Environmental Economics
Get PDFIn the first chapter of this dissertation we evaluate potential benefits of drinking water infrastructure investments in the United States. We estimate willingness-to-pay for high-quality drinking water using consumer avoidance behavior in response to health-based drinking water quality violations. To do so we estimate a household-level discrete choice model of drinking water. We find that the average household is willing to pay $162 per year to avoid a one standard deviation decrease in water quality. We additionally find that WTP for bottled water increases in income. We use these estimates to evaluate several counterfactual scenarios. In a scenario in which the United States\u27 water infrastructure deteriorates to the levels of Flint, MI in 2014, we find that US households would be willing to spend 1.4 times the annual US public spending on water infrastructure, suggesting that consumer preferences strongly justify major increases in water infrastructure investments in the United States.The second chapter studies the design of renewable energy portfolios standards (RPSs). We focus on solar energy and analyze two common RPS rules: cross-state trading restrictions and state-specific interim annual targets. Using historically observed RPSs, together with our estimated state-level solar supply curves, we find that allowing for cross-state trading reduces cost by 24% and significantly changes the geographic distribution of new solar installations. Removing interim annual targets over the 2015-2019 period reduces cost by 32% by back-loading installations to later years. These cost reductions become much larger when considering more ambitious RPS targets. Our results suggest that more flexible program design such as allowing for cross-state trading, back-loading interim targets, or banking and borrowing renewable energy credits can avoid escalating costs and preserve the political feasibility of renewable energy standard
Unlocking New Odd-Electron Pathways Via Photoactive Catalysis
Get PDFIn the past decade, renewed interest in odd-electron pathways has reaffirmed organic chemistry’s indispensable role in the synthesis of complex molecules and in drug-discovery efforts. Odd-electron intermediates unlock reactivity patterns that are not observed in two-electron processes and offer complementary chemoselectivity. Importantly, these processes are often “blind” to the source of radical and can thus be adapted toward a diverse array of chemical feedstocks. Photoredox catalysis harnesses radicals in a controlled, predicable manner and can be used to orchestrate elaborate radical and polar bond-forming processes, which allowed the development of the radical-polar crossover annulation reaction (RPAR) paradigm. Furthermore, these catalysts, in conjunction with transition metal complexes, enable multiple C-C bond-forming events in so-called dicarbofunctionalization (DCF) reactions, and can even be used to functionalize commodity materials via photochemical C-H abstraction. Visible light can also be used to excite electron donor-acceptor complexes in the absence of a photocatalyst to permit radical generation. This mode of reactivity has provided an avenue to new bioisosteric space via the late-stage introduction of bicyclo[1.1.1]pentyl (BCP) motifs. Finally, photochemically-initiated hydrogen-atom transfer (HAT) catalysis can be harnessed to access strong single-electron reductants that permit the single C-F bond activation of trifluoroacetates and -acetamides. This has allowed facile access to gem-difluoromethylene containing compounds that are challenging to prepare by state-of-the-art methods. Discoveries in each of these arenas will be discussed
Interrogating Ptb-Associated Splicing Factor\u27s Rna Recognition Motif/rna Binding-Mode
Get PDFPTB-associated splicing factor (PSF) is a multifunctional nucleic acid binding protein vital for cell survival. PSF plays several roles throughout the cell, yet many aspects of PSF’s mechanisms of interacting remain elusive. While protein and nucleic acid binding partners of PSF have been identified, binding consensus sequences reported in the literature vary.Previous studies in the Lynch Laboratory have found that PSF’s second RNA recognition motif (RRM2) is necessary and sufficient for binding, but this binding can be occluded by interacting with cofactor protein TRAP150. Additionally, binding is dependent on phosphorylation of PSF in T-cells. Identifying the interaction interfaces of PSF/RNA and PSF/TRAP150 yields insight into the regulatory mechanism governing RNA-binding. First, I utilize biophysical techniques to overcome challenges characterizing PSF/RNA. The smallest RNA to bind with low/modest affinity is 65-nucleotides long, making the protein/RNA pair nonideal for crystallization or NMR experiments. PSF has long N- and C-terminal unstructured regions that aid in PSF’s functional aggregation, creating another challenge for biophysical characterization. Here I use several biophysical techniques to characterize PSF’s dynamics and binding interfaces. Mass spectrometry experiments indicate PSF contacts RNA using 30-60% of the accessible surface area. Interestingly, a charged hydrophobic loop region when mutated from “DDRGR” to “AAAAA” increases affinity for ESS-RNA 10-fold. A neighboring residue Lysine-413 also increases affinity for RNA when mutated to alanine. Arginine-474 and Threoinine-485 within the NOPS domain lose their ability to bind RNA when mutated. It is not clear whether these residues affect local conformation of playing a direct role in binding. Additionally, I identify hundreds of PSF-dependent alternative polyadenylation changes and begin characterization of PSF/TRAP150 and phosphorylated PSF by HDX-MS. Together, these results indicate PSF interacts with RNA using a large portion of the surface accessible area to do so, and PSF uses a loop in RRM2 to aid in RNA-interaction