Alliance One Tobacco (Malawi)
Academic Research Repository at the Institute of Developing EconomiesNot a member yet
52305 research outputs found
Sort by
BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells
No full textTh17 cells are heterogenous, consisting of non-pathogenic Th17 cells (npTh17) that contribute to tissue homeostasis and pathogenic Th17 cells (pTh17) that mediate tissue inflammation. Here, we characterized regulatory pathways underlying Th17 heterogeneity and discovered substantial differences in the chromatin landscape of npTh17 and pTh17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTh17 cells share accessible chromatin programs with Tregs, whereas pTh17 cells exhibit features of both npTh17 cells and Th1 cells. Integrating single-cell ATAC-seq and single-cell RNA-seq, we inferred self-reinforcing and mutually exclusive regulatory networks controlling the different cell states and predicted transcription factors (TFs) regulating Th17 cell pathogenicity. We validated that BACH2 promotes immunomodulatory npTh17 programs and restrains pro-inflammatory Th1-like programs in Th17 cells in vitro and in vivo, Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identified regulators of Th17 heterogeneity as potential targets to mitigate autoimmunity.Accepted Manuscrip
Exploring Protein and Circuit Design Spaces Using Massively Parallel Microscopy-Based Screening
No full textWe have developed a platform to characterize transcriptional circuit dynamics and protein bio-
physics for hundreds of thousands or millions of variants in a single experiment using time-lapse
microscopy. The platform comprises “mother machine” microfluidic devices that allow a million
or more bacterial lineages to grow under uniform conditions, automated liquid handling to read
out RNA-FISH barcodes for every cell in the device, long-read sequencing to link the RNA-FISH
barcode to the variant sequence, a sequencing pipeline to accurately map each of the hundreds of
thousands or millions of RNA-FISH barcodes to an error-free variant consensus sequence, and an
image analysis pipeline to handle the terabytes of data and billions of imaged cells per experiment
Meaning, Reference, and Verbal Knowledge in Indian Philosophy: An Introduction, Translation, and Commentary on the Chapter on Word Meaning in Gaṅgeśa’s Jewel of Reflection on the Nature of Things (Tattvacintāmaṇī)
No full textThis dissertation focuses on a pivotal debate in classical Indian philosophy of language as presented by the influential 14th-century thinker Gaṅgeśa over the meaning of common nouns. The debate centers on reconciling two intuitive assumptions: first, words are about objects (i.e., in any given context C where an utterance is true, every expression E in the utterance stands for some individual object(s) in C); and second, common nouns (focusing on their indefinite use) have a constant meaning that is grasped by any competent language user across contexts. Gaṅgeśa and his opponents strive to resolve the tension between the two assumptions, which arises from the fact that common nouns can refer to different objects in different contexts while still having a constant meaning across those contexts.
In my introductory chapter, I reconstruct and evaluate Gaṅgeśa’s theory of meaning of common nouns, which I call “Context-Sensitive Direct-Referential Descriptivism.” To resolve the tension between the two intuitions that are in tension, Gaṅgeśa proposes a hybrid theory in which the meaning of a common noun includes both a universal (e.g., cowness) and a particular (e.g., a particular cow). I also explore challenges to Gaṅgeśa’s theory, particularly regarding cases where speakers use common nouns without specific referents in mind. I argue that Gaṅgeśa will have to give up a direct-realist position when it comes to verbal utterances involving general terms like common nouns.
In addition to my reconstruction and analysis of Gaṅgeśa’s theory, a significant portion of my dissertation is devoted to translating and commenting on the original Sanskrit text. My translation of Gaṅgeśa’s text aims to be clear and philosophically precise, suitable for use in a philosophy classroom or by scholars engaging with Indian philosophical texts. The accompanying commentary elucidates the background knowledge, technical terminology, and unstated assumptions that Gaṅgeśa expects his readers to bring to the text
AAV-associated toxicity caused by transgene expression in the retinal pigment epithelium
No full textThe field of AAV gene therapy has recently experienced multiple clinical successes, and AAV continues to be a relatively safe viral vector. Nevertheless, there is a long history of toxic side effects at higher doses, culminating in the first cases of AAV-associated fatalities in 2020. As gene therapy moves forward, it is critical to understand and account for potential factors driving AAV-associated toxicity. Here we use the murine eye as a model system to study AAV-associated toxicity from transgene expression. In our model, high expression of EGFP induces degeneration of the retinal pigment epithelium (RPE), which leads to deterioration of photoreceptors. By evaluating the impact of various AAV vectors on the eye, we show that expression-based toxicity can occur independently from the dose of AAV capsid or DNA. As expected, AAV-associated toxicity due to EGFP increases with increasing expression. More surprisingly, toxicity can remain unaffected across multiple immune knockout lines, including knockouts of the Toll-like receptors (TLRs), cytotoxic T cells, and the viral RNA sensor MAVS. We show that EGFP RNA is not sufficient for inducing toxicity, suggesting that it is being caused by off-target activity of the expressed protein. Along that line, as different proteins have different activities, we observed that the severity of toxicity varied by transgene. In addition, we do not see a clear correlation between toxicity and self vs. non-self transgenes. Taken as a whole, our results illustrate the risks of aiming to maximize transgene expression. Although optimizing for increased expression has been attractive in the effort to lower the doses for AAV gene therapy, it is worthwhile to distinguish the effective level of expression per organism from the effective level per cell. Identifying the maximum level of beneficial transgene expression at the cellular level may be an important factor in mitigating AAV-associated toxicity.Medical SciencesMedical Science
Motional Control of Polyatomic Molecules for Precision Measurement
No full textExtending AMO techniques of motional control to heavy polyatomic molecules opens new possibilities for precision measurements of fundamental physics. Though various laser-cooling and deceleration techniques have been applied to diatomic molecules throughout the last decade, their application to more complex molecules has heretofore been focused on light species, leaving generalizability to heavy species an open question. To investigate the high-mass frontier, we here study how to extend motional control to heavy-atom-containing polyatomic molecules. First, we discuss Zeeman-Sisyphus deceleration of YbOH, which can be used to decelerate species capable of scattering only ~10s of photons. Then, we discuss radiative slowing and magneto-optical trapping of SrOH, techniques only extendable to species capable of scattering photons. The last work focuses on spectroscopy of nonlinear molecules to assess the viability of extending techniques of motional control to more complex species. We find a dependence of both rotational and vibrational control on symmetry group, and identify a next-generation candidate for laser cooling. We end with a overview tying these projects together, and assessing the future of motional control along mass and complexity axes, including brief suggestions of how complementary methods to those studied here can further expand into the frontiers of molecular control
Genetic studies of malaria parasite invasion into red blood cells
No full textMalaria is a global health burden, particularly affecting African countries. The invasion of red blood cells (RBCs) by Plasmodium falciparum is an essential stage in the parasite's life cycle and is crucial for establishing virulence. The parasite employs various invasion ligands to interact with host surface receptors to invade RBCs through various pathways. While many of these ligand-receptor interactions are well understood, the impact of polymorphisms in parasite ligands and host receptors, resulting from selection pressures, on these interactions remains unclear. This study uses genetic methodologies to scrutinize novel host and parasite determinants involvement in P. falciparum invasion.
In our investigation of the functional roles of host determinants in P. falciparum invasion, we generated and characterized a novel immortalized erythroid cell line, BF cells. We characterized the maturation profiles, morphology, and biophysical parameters, and invasion efficiency of enucleated differentiated BF-RBCs. Our findings indicated that enucleated BF-RBCs exhibit that enucleated BF-RBCs are comparable to reticulocytes generated from primary HSCs. Finally, we demonstrated the genetic adaptability of BF cells by deleting several host determinant genes and characterized the effects of ADP-Ribosyltransferase 4 (ART4) RBC gene deletion in BF-RBCs to elucidate the role of host receptor ART4 in P. falciparum invasion.
On the parasite front, we identified parasite determinants mediating invasion pathway utilization through bulk segregant analysis. Our study revealed that the known invasion ligand, RH2b, and novel candidate MSP1 mediate alternative invasion pathways. The parental strains used for bulk segregant analysis inherited different alleles of MSP1 dimorphism - the MAD20-like and the K1-like MSP1. We showed that the MAD20-like and the K1-like MSP1 parasites have comparable merozoite counts per schizont and MSP1 expression level. Lastly, we pinpointed an epistatic relationship between MSP1 and Rh2b in mediating parasite utilization of the alternative invasion pathway
Dynamic Electrochemical Processes at Solid-solid Interfaces in Alkaline Ion Batteries
No full textThis dissertation presents the theoretical, experimental and computational results of studies on the dynamic electrochemical processes at solid-solid interfaces in lithium solid state batteries and in layered sodium transition-metal oxide (NaTMO2) cathodes. More specifically, the term “dynamic” refers to the phenomenon that the kinetics interrupts the thermodynamic reaction pathway herein. For lithium solid state batteries, the study is on the dynamic evolution of the inter-material solid-solid interfaces from a thermodynamically unstable state to a kinetically stable state. For the sodium ion cathodes, the thermodynamic phases and redox evolutions are affected by the intra-particle solid-solid phase boundary kinetics.
My contribution to the solid state battery theory follows the mechanically induced metastability and kinetic stability formulated previously in the Li group, which added an energy penalty to the electrochemical decomposition, thus broadening the operating voltage window. Importantly, atomic diffusion is suppressed by the local strain field in the decomposition front and the decomposition is kinetically prevented by the diffusion limiting process. Within this framework, a dynamic voltage stability picture for lithium metal-solid electrolyte interface is depicted by a two-parameter space consisting of reaction energy and critical effective modulus to classify different electrolytes for lithium metal dendrite constriction for long cycling without battery short. The electrolyte needs to have sufficient initial thermodynamic reaction energy with lithium metal, and a low critical modulus to stop the decomposition without cracking the electrolyte. A high throughput calculation-machine learning prediction-experimental synthesis and characterization methodology is used to successfully obtain new materials in the two-parameters space, which is a proof of concept of the dynamic voltage stability.
Next, silicon anode with much smaller lithiation capacity in solid electrolyte than in liquid electrolyte is used as a model system for dynamic voltage stability study. Silicon lattice shrinkage and shear during lithiation due to inhomogeneous strain field in solid state battery can shut down lithium diffusion pathway. The constriction sensitivity of lithium capacity and the anodic voltage together guided the search for anode materials to suppress lithium dendrite.
Alongside these new understandings, it was realized that the sulfide solid electrolyte we’ve been working on is compliant yet brittle, so that it would have cracked before reaching the GPa level local stress, therefore to keep the local stress small, the kinetic stability should contribute a significant portion to the dynamic voltage stability. The meaning of effective modulus is then broadened to include the kinetic stability. The constrained ensemble computational approach is applied across most types of solid-state electrolytes to systematically evaluate and compare their dynamic stability voltage windows in response to the mechanical constriction effect. High-throughput calculations are used to search for coating materials for different interfaces between sulfide, halide, and oxide electrolytes and typical cathode materials with enhanced dynamic voltage stability. A comparison with experiment is given to highlight the value of these computational predictions. This work sums up the solid state battery part in the thesis.
Lastly, the hysteresis of charge-discharge in P2-Na2/3Mg0.205Ni0.1Fe0.05Mn0.645O2 is studied. It is found that the thermodynamic two-phase reaction during charge (sodium de-intercalation) forms a P2-O2 solid-solid two-phase boundary with Schottky barrier to impede electron and Na diffusions in discharge only, thus making the kinetically preferred P2 solid solution phase abnormally coexist with the thermodynamic two-phase region during discharge, which increased the discharge voltage comparing to P2-Na2/3Mg0.28Mn0.72O2. A more general description of comparison between working voltage of thermodynamically or kinetically preferred electrochemical process is given as a criterion for whether the hysteresis will happen. Other two kinetics related cathode studies follow as the end of this thesis. In P2-Na0.75Mn0.6Fe0.2(CuxNi0.2-x)O2, better electron conductivity at high voltage phase and better Na ion conductivity at low voltage phase benefits the cycling stability. In LixNa2-y¬TMF7, room temperature Li/Na ion-exchange enables new intercalation Li metal fluoride that is hard to achieve by high temperature sintered thermodynamic phases
Opening the Democratic Heart: Interest, Charity, and Well-Being in the Political Thought of Alexis de Tocqueville
No full textAlexis de Tocqueville’s concept of intérêt bien entendu, as developed in Democracy in America, is among his most notable concepts. However, it is also among his most ambiguous, with interpretations of its meaning ranging from civic republican to utilitarian to Christian, among others. It is ironic that a concept that roughly translates to interest rightly understood remains so varyingly understood. However, that may explain why his theory of civil society also remains poorly understood, despite Tocqueville’s renown as a theorist of civil society.
This dissertation examines Tocqueville’s often neglected notes on intérêt bien entendu to highlight his theorization of it in light of what he understood as forms of Christian virtue and love. In the process, it reconstructs his account of human nature; interrogates his understandings of utility and virtue, and honor and virtue; and draws attention to his style and goals as “democracy’s spiritual director.” It then considers what this reading of intérêt bien entendu clarifies about soft despotism and its effects on democratic institutions and democratic character. The often-unremarked fact that intérêt bien entendu disappears under soft despotism corresponds to the characterization of soft despotism as atomizing, atomistic, and personally individualistic. It also reflects soft despotism’s structural weakening of the spaces and practices of a free, participatory democratic politics and of the civic and social spaces where moral virtues are practiced, habituated, and elevated through the “reciprocal action of men upon one another.” “There is no vice of the human heart that pleases [despotism] as much as egoism: a despot easily pardons the governed for not loving him, provided that they do not love each other.”
Finally, it turns to Tocqueville’s writings on charity, social reform, and public policy in the Memoirs on Pauperism and other texts to underline the relationship between intérêt bien entendu and charity and to nuance his account of soft despotism with the help of his writings on the democratic welfare state. Informed by the Christian political economy of his day, Tocqueville’s wrestling with the challenges posed by pauperism and industrialization demonstrates sensitivity to the distinction between ideal theory and what is prudent or possible. It likewise reflects a desire to balance the just demands of solidarity with the vulnerable against the variable political, social, and moral consequences of different forms of public charity. Tocqueville readily admits the necessity of a limited welfare state, or “Christian charity applied to politics.” However, a flourishing democratic social state requires association, the activities of which include pursuing goals associations set themselves and the distinctive moral formation that occurs in the space between the State and the family through fellowship, mutual dependence, and roles and relationships both chosen and given.
Following this thread through Tocqueville’s thought helps us situate him in a specific French moral tradition and in discussions of his day about religion’s bearing on liberal political economy and democratic politics. It also suggests Tocqueville may be a resource for contemporary discussions of the anthropological, theological, and religious underpinnings of welfare policy, liberalism, theories of social justice and solidarity, and accounts of human flourishing
Algorithmic Hollywood: Data, Production, and the Cinematic Imagination 2008- Today
No full textThis dissertation investigates the centrality of algorithms in contemporary Hollywood cinema, exploring issues of industry, production, spectatorship, and narrative. Understanding the algorithm as an essential mathematical element of computation, as both a pragmatic process for problem-solving and as the central emblem of a broader episteme and ideology, the dissertation is structured according to case studies of different films and techniques in Hollywood that explore the wider significance of this technology and logic for cinema. The bourgeoning of algorithmic technologies since the turn of the 21st century has resulted in a cultural milieu shaped by tendencies towards prophecy and prediction, avoidance of risk, numeric rationality, personalization of consumption, enumeration of data, and a general sense of opacity in the way all these things operate. All these characteristics are found in Hollywood production today; furthermore, Hollywood has been instrumental to the emergence and shape of this milieu.
In the first chapter, I explore the Netflix Recommendation Engine, an algorithmic method for personalizing and categorizing films to individual viewers, an apparatus which has engendered distinctive modes of exhibition and spectatorship. The second chapter chronicles the prehistory of the Recommendation Engine in 1940s experiments in data-centric audience research, arguing as to a genealogy of contemporary Algorithmic Hollywood in the Studio System. The final chapter further investigates the links between these two periods, arguing that the advent of algorithmic technologies has not caused a revolutionary disruption to the American film industry as was previously predicted, but has further consolidated historically persisting monopolies, practices, and styles
Applications of Coalescent Theory to Introgression Inference and Analysis of Genomic Studies of Sex and Sexuality
No full textCoalescent theory uses a backwards-in-time approach to model the genetic ancestry of a sample. The individuals in the sample can be imagined as residing in the same totally mixed population, as in the standard coalescent model, or in different, potentially isolated populations, as in the multispecies coalescent. It is becoming increasingly evident, however, that species are not entirely isolated, with gene flow, or introgression, occurring across species boundaries. Characterizing the effects and signal of this permeability is vital for understanding how species evolve in nature.
In chapter one, I develop a statistical technique that uses the internal branch lengths of gene trees to infer what portions of the genome may be introgressed. Using simulations, I show that the developed method infers the presence of introgression even under models of population size change and recombination, and, with collaborators, apply it to look for introgressed regions in data from Heliconius butterflies. In chapter two, I present a theoretical study of the joint distribution of gene trees at linked loci in the presence of introgression. Coupled with simulations, I use this model to show that the outcomes of incomplete lineage sorting at linked loci are informative to the true evolutionary history. In chapter three, I explore a connection between recombination rate and a technique from applied topology called persistent homology. With collaborators, I show that various features of the barcode, an encoding of the shape of the data at different scales, of sequences sampled from a population are correlated with recombination rate. Finally, in chapter four, I present interdisciplinary work with the GenderSci lab that places genetic studies of human sex and sexuality under a critical lens and explores possible sites for intervention and critique by gender and sexuality scholars