VictorJuiz/thesis huggingface dataset:
Global mapping of herpesvirus-host protein complexes reveals a novel transcription strategy for late genes

Mapping host-pathogen interactions has proven instrumental for understanding how viruses manipulate host machinery and how numerous cellular processes are regulated. DNA viruses such as herpesviruses have relatively large coding capacity and thus can target an extensive network of cellular proteins. To identify the host proteins hijacked by this pathogen, we systematically affinity tagged and purified all 89 proteins of Kaposi’s sarcoma-associated herpesvirus (KSHV) from human cells. Mass spectrometry of this material identified over 500 high-confidence virus-host interactions. KSHV causes AIDS-associated cancers and its interaction network is enriched for proteins linked to cancer and overlaps with proteins that are also targeted by HIV-1. This work revealed many new interactions between viral and host proteins. I have focused on one interaction in particular, that of a previously uncharacterized KSHV protein, ORF24, with cellular RNA polymerase II (RNAP II)./nAll DNA viruses encode a class of genes that are expressed only late in the infectious cycle, following replication of the viral genome. These ‘late’ genes are subject to tight regulation and must be robustly induced during a period of significant cell stress, yet in many cases have strikingly minimal promoters. For most viruses, the mechanism underlying the activation of these genes has remained largely unknown. I have shown that late gene expression in KSHV requires ORF24, which nucleates a non-canonical transcription complex. I have found that ORF24 is a modular protein that binds directly and specifically to viral late gene TATA-like boxes through its central domain, which was previously predicted to structurally mimic TATA-box-binding protein (TBP). Chromatin immunoprecipitation analyses show that ORF24 functionally replaces human TBP at these promoters. This is highly unusual, as cellular TBP canonically serves as a critical nucleation factor for the assembly of transcription pre-initiation complexes (PICs) at promoters. Through residues in its N-terminus, ORF24 then binds RNAP II to activate late gene expression. This strategy appears to be conserved in multiple related herpesviruses, and represents a novel, streamlined mechanism for transcriptional activation./nAs the late gene PIC appears deviates from the canonical complex, I have worked to define the viral and cellular proteins assembled at these promoters. Foundational work in related herpesviruses has revealed a complex of six viral proteins (including ORF24) to be essential for late gene expression. We have mapped the pairwise interactions between these viral proteins and found that the four other late gene viral transactivators (vTFs) interact with ORF24 through the viral protein ORF34. The interaction between ORF24 and ORF34 is essential for the expression of late genes. Aside from ORF24 and ORF34, the precise roles of the other vTFs in late gene expression remain unknown and are an ongoing area of research.

Advisor: Glaunsinger, Britt
Relationship between perceptual accuracy and information measures: A cross-linguistic study

The current dissertation studies how the information conveyed by different speech elements of English, Japanese and Korean correlates with perceptual accuracy. Two well-established information measures are used: weighted negative contextual predictability (informativity) of a speech element; and the contribution of a speech element to syllable differentiation, or functional load. This dissertation finds that the correlation between information and perceptual accuracy differs depending on both the type of information measure and the language of the listener./n/nTo compute the information measures, Chapter 2 introduces a new corpus consisting of all the possible syllables for each of the three languages. The chapter shows that the two information measures are inversely correlated./n/nIn Chapters 3 and 4, two perception experiments in audio-only and audiovisual modalities, respectively, are described. The experiments adopt a forced-choice-identification paradigm. In both experiments, subjects listened to VC.CV stimuli composed of spliced VC and CV chunks, and they were asked to identify the CC sequence. Multiple statistical models are constructed to predict the perceptual accuracy of a CC stop cluster from the associated information measures of relevant speech elements in the listeners' languages./n/nThe estimated models show that high informativity has a generally negative effect on the perceptual accuracy of stops. Functional load shows less consistent correlations with perceptual accuracy across different model specifications, but generally has a positive effect on the perceptual accuracy./n/nIn addition, Japanese listeners show highly consistent results across the two experiments and different model specifications. This contrasts with less consistent results for English and Korean listeners./n/nThe current dissertation provides the first empirical evidence for a significant relationship between informativity and functional load, and between the information measures of speech elements and their perceptual accuracy. Furthermore, it reveals how listeners' native languages affect that relationship, and how the cross-linguistic variation of that relationship may be related to the characteristics of individual languages such as their syllable structures.

Advisor: Johnson, Keith
Host-Factor Enhancement of Therapy for Tuberculosis

Host-Factor Enhancement of Therapy for Tuberculosis/nby/nMichael David Schump/nDoctor of Philosophy in Infectious Diseases and Immunity/nUniversity of California, Berkeley/nProfessor Lee W. Riley, Chair/nTuberculosis (TB) is a disease of major public health importance and improvements to its treatment could greatly benefit efforts aimed at eliminating the disease. Current treatment options for TB are limited in effectiveness and have numerous fundamental failings due to the necessarily lengthy duration of therapy and toxicity of the antimicrobial drugs deployed, among other issues. The studies described herein where undertaken with the goal of developing adjunctive treatments or modifications of existing treatments which could improve the treatment course, outcome, or both for standard TB antimicrobial chemotherapy./nThree areas of research are discussed beginning with adaptive immune augmentation through therapeutic vaccination, proceeding to investigations of innate immune adjuvant therapy and concluding with host environment mediated improvement of selectivity index of TB antimicrobial compounds./nA post-treatment, therapeutic vaccine was studied with the goal of developing a tool which could prevent relapse or reactivation disease. Though the project was a follow up to a study which demonstrated exceptional protection, the vaccine candidate did not demonstrate any detectable efficacy in three parallel murine infection experiments. Possible reasons and implications of this failure are discussed./nBecause correlates of protection for adaptive immunity to TB are poorly understood and have not proven to be tractable for intervention, innate immune enhancement was investigated. Autophagy, a cell-intrinsic process with antimicrobial capabilities, was selected due to its well described tuberculocidal activity and pharmacologic manipulability. However, despite the apparent capacity of some test compounds to increase autophagic flux, none demonstrated robust restriction of mycobacterial growth in murine or human macrophages. That study did, however, lead to the serendipitous discovery that pH based drug partitioning can increase the selectivity index of antimicrobial drugs against M. tuberculosis inside cultured macrophages.

Advisor: Riley, Lee W
Action selection and coordination: Perspectives from movement speed learning

In his 1945 book The Phenomenology of Perception, French philosopher Maurice Merleau-Ponty wrote, “The body is our general medium for having a world.” When learning to move, our bodies implicitly know what to do, letting experiences tweak our neural circuits to etch in precise models of the world. These experiences wire up complex capabilities in bodies that were born ready to move, but did not yet know what a pen, a cartwheel, or a hug was./nWhat is arguably more difficult is using our minds to gain explicit understanding of the processes governing learning and movement. For this, we have science. Merleau-Ponty later wrote, “Science manipulates things and gives up living in them. It makes its own limited models of things; operating upon these indices or variables to effect whatever transformations are permitted by their definition, it comes face to face with the real world only at rare intervals.” In this dissertation, I present the outcomes of my own manipulations, my own limited models which, at rare intervals, come face to face with the ways in which our bodies construct our world./nIn Chapter 2, I investigated a potential problem for the use of functional magnetic resonance imaging (fMRI) to study human motor behavior. Task-related changes in heart rate can cause changes in the blood oxygen level dependent (BOLD) signal, potentially masking effects of interest. Correcting for heart rate fluctuations did not fundamentally change the brain's responses to arm movements. However, because these corrections did improve the explanatory power of fMRI analyses, my work stands as an illustration of the efficacy of this correction./nIn Chapter 3, I had people learn to produce movements of certain speeds in a virtual shuffleboard game. When learning movement directions, delayed feedback impairs performance due to processing limitations in a brain structure called the cerebellum. Because feedback is naturally delayed in shuffleboard, I asked whether delays affect learning of speeds, as well. They did not, suggesting that the cerebellum is not involved in learning movement speeds from errors./nIn Chapter 4, I sought to confirm this speculation using fMRI. I scanned the brains of people as they played shuffleboard. I found no evidence that the cerebellum was involved in the processing of errors of movement speed. However, successful task performance robustly activated the dorsal striatum, a structure involved in learning from rewards and forming habits. These results suggest that, when people learn to move at certain speeds, they depend more on memories of times they got it right than on feedback telling them to speed up or slow down.

Advisor: Ivry, Richard B
Keyboard Playing and the Mechanization of Polyphony in Italian Music, Circa 1600

Keyboard instruments are ubiquitous in the history of European music. Despite the centrality of keyboards to everyday music making, their influence over the ways in which musicians have conceptualized music and, consequently, the music that they have created has received little attention. This dissertation explores how keyboard playing fits into revolutionary developments in music around 1600 – a period which roughly coincided with the emergence of the keyboard as the multipurpose instrument that has served musicians ever since. During the sixteenth century, keyboard playing became an increasingly common mode of experiencing polyphonic music, challenging the longstanding status of ensemble singing as the paradigmatic vehicle for the art of counterpoint – and ultimately replacing it in the eighteenth century. The competing paradigms differed radically: whereas ensemble singing comprised a group of musicians using their bodies as instruments, keyboard playing involved a lone musician operating a machine with her hands. By replacing musicians with a machine, keyboard playing amounted to a mechanization of polyphony./nChapter 1 outlines the mechanization of ars perfecta polyphony through keyboard playing. To illustrate its effects, I analyze several keyboard intabulations in relation to their vocal models, including Marcantonio Cavazzoni's adaptation of the chanson Plusieurs regretz by Josquin, and the intabulation preserved in the Turin Tablature of Rore's Calami sonum ferentes. I show how formal differences relate to changes in agency, script, and sensorimotor experience. Drawing on research in cognition and motor control, I discuss how experiencing polyphonic vocal music through keyboard playing affected how musicians parsed the art form. The remainder of the dissertation examines the relationship between keyboard playing and the ecclesiastical concerto, as exemplified in Lodovico Viadana's Cento concerti ecclesiastici (1602). Chapter 2 investigates the complex material relationship between the vocal partbooks and organ continuo part in printed books of sacred music from the 1590s and early decades of the seventeenth century. I argue that the concerto print served as a virtual site for the convergence of the art of counterpoint and keyboard playing. Chapter 3 proposes that the redesign of the Italian organ in the fifteenth and sixteenth centuries was a crucial precedent for the "concertato style." The concertato style itself represents a stylization of the model of distributed cognition inherent in the sacred concerto.

Advisor: van Orden, Kate
Davies, James Q.
Ecology in the laboratory: the molecules that shape the ecological relationship between D. melanogaster and S. cerevisiae

Drosophila melanogaster and Saccharomyces cerevisiae, two model systems of molecular biology, interact in the wild, but the chemical basis of this interaction is largely unknown. This thesis details an effort to understand the molecular basis of this ecological co-localization./nResults:/nWhile screening a collection of wild and laboratory yeast strains for their ability to attract adult D. melanogaster (Raleigh 437), I noticed a large difference in fly preference for two nearly isogenic strains of S. cerevisiae, BY4741 and BY4742. Using standard genetic analyses, I tracked the difference in preference to lack of mitochondria in BY4742. I used gas chromatography coupled with mass spectrometry (GC-MS) to examine the volatile compounds produced by BY4741 and the mitochondria-deficient BY4742, and found that they differed in their production of many known fly attractants, including ethyl hexanoate and ethyl octanoate, which were produced at much higher levels in yeast strains with mitochondria during aerobic fermentation, a metabolic strategy that distinguishes S. cerevisiae from most other microbes./nThrough a detailed investigation of the volatile profiles and RNA expression patterns produced by yeast under multiple nutritional scenarios, I determined that the production of ethyl hexanoate and ethyl octanoate during aerobic fermentation depends on the level and type of nitrogen present in the substrate. Fermentative growth on nitrogen-limited substrates requires mitochondrial engagement and the metabolic configuration employed by S. cerevisiae to contend with this nutritional scenario results in the production of these ester attractants. This nutritional scenario – high sugar but limited nitrogen – matches the composition of fruit, the natural co-localization environment for flies and yeast, suggesting that these volatiles are ecologically relevant cues for D. melanogaster./nD. melanogaster sense ethyl hexanoate and ethyl octanoate via the odorant receptor genes Or22a and Or22b. A single gene version of this locus, which is a chimera of the two ancestral copies, is segregating in natural D. melanogaster populations. I found that D. melanogaster lines harboring the chimeric locus (including Raleigh 437) show more robust preference for ethyl hexanoate and ethyl octanoate-producing S. cerevisiae cultures. This provides an ecological basis, and possibly selective advantage, for the maintenance of this allele in D. melanogaster.

Advisor: Eisen, Michael B
Optofluidic Devices for Droplet and Cell Manipulation

The field of lab-on-a-chip offers exciting new capabilities for chemical and biological assays, including increased automation, higher throughput, heightened sensitivity of detection, and reduced sample and reagent usage. This area of study has seen remarkable progress in the last decade, with applications ranging from drug development to point-of-care diagnostics. The research presented herein focuses on the development of semiconductor-based optoelectrowetting (OEW) and optoelectronic tweezers (OET) platforms, which can respectively perform operations on droplets and cells/particles. This thesis discusses progress achieved on both OEW and OET platforms. For OEW, a novel optimization model has been developed to accurately predict the interaction of droplets, semiconductor layers, and a programmable DLP-based optical source. Consequently, parallel and arrayed droplet manipulation is now possible over a large operational area (cm × cm). In addition, critical droplet operations such as mixing, splitting, and dispensing have been demonstrated. As a biological application of OEW, this work will discuss the parallel, real-time, isothermal polymerase chain reaction detection of Herpes Simplex Virus Type 1 in droplet arrays. For OET, the effort in long-term culture of adherent mammalian single cells into clonal colonies will be discussed; OET surface functionalization enables large (0.5-mm-diameter) growth patches in which positioned single cells can adhere and proliferate. Lastly, the link between the OEW and OET devices and how both droplet and particle manipulation can be enabled on a unified platform will be presented.

Advisor: Wu, Ming C.
(Dis)orienting the Reader: Literary Impressionism and the Case of Herman Bang

This dissertation examines the ethical stakes of Herman Bang’s (1857–1912) literary impressionism using both his critical and fictional writings. Against previous scholarship, which argues that Bang’s impressionism was predominantly a nervous stylistic tendency, I contend that his impressionism variously implements a technique I call disorientation, which is in the service of an evolving ethical concern over character. Bang’s distinct employment of disorientation can be read as bearing in mind the reader in an aesthetic logic that recasts impressionism as an ethically concerned aesthetics of fiction. Understanding that Bang’s goal is to disorient the reader can account for the gaps, fissures, ambiguities, and strangeness in his work. He attempts to disorient by manipulating the narrative (e.g., via unusual narrative closure, violent literary language) such that perception is disrupted and made difficult or strange, jolting readers into a reconsideration of what they have just read. In this way, disorientation creates the possibility for a reader to be reoriented to the impression left behind by a character./nIn four chapters, I trace the ethical inflections within Bang’s writings. Chapter one outlines a historical and conceptual framework for apprehending literary impressionism, detailing how Bang’s emerging critical writings engage with an ethically concerned aesthetic logic. In chapter two, I compare Bang’s strategic use of the partial literary portrait in his unpublished “Manuskript til foredrag om Ivan Turgenjev” (ca. 1885, Manuscript for a lecture on Ivan Turgenev) with Henry James’s references to Turgenev both in “Ivan Turgénieff” (1884, 1888) and in his 1908 preface to The Portrait of a Lady. I argue that this comparison reveals Bang and James’s shared interest in a method of capturing and recording their impressions of characters by employing as a model the “literary portrait.” In chapter three, using “Irene Holm” (1886, 1890) and Ved Vejen (1886, By the wayside) as evidence, I look to Bang’s experimentation with disorientation in both the short story and the novel to demonstrate that he is wrangling with the tension between the need for formal closure and the need to preserve the integrity of the impression left by a character. Chapter four offers a close reading of Bang’s novella “Les quatre Diables” (1890, “The Four Devils”) where formal disorientation is taken to such an extreme that the language itself becomes violent. While the first two chapters are concerned with situating Bang’s impressionism as a method rooted in character, the last two chapters discuss specific instantiations of Bang’s use of disorientation.

Advisor: Sanders, Karin L
If Your World Was Built on Dispossession: Strategies of Conquest by Settlement in America

This dissertation explores the role of the history of conquest in the formation of American legal institutions. The histories it presents begin during the early colonial period, and argue that American legal practices—of property-making, contract, and the creation of federal alliances, for example— grew out of colonial relationships and practices aimed at resource extraction, colonial expansion, and indigenous removal. The dissertation also describes how colonial practices of land dispossession developed to become the basis of basic social, political and legal formations in the United States. It considers the relationship between and the past and the present, and how conquest informs an American social world divided by race, class, ancestry and different relationships to money and speculation./nSpecifically, the chapters examine 1) the history of mortgage foreclosure, 2) the relationship between contracts and social contracts, 3) an early federal tort system, which showcases one aspect of the nation’s civil-military approach to war, and 4) how removal policies that constitute the genealogical antecedents of administrative immigration law first emerged in the context of colonial and then federal laws of Indian Affairs. Each chapter examines these histories through the lens of a well-known narrative about American legal and political institutions: respectively, the ideas that speculation and credit can be a healthy fount of economic growth, without concomitant costs; that by virtue of its democratic social contract, America is a government by, for and of the people, based on their consent; that the U.S. has the duty of benevolent intervention in conflicts abroad to keep the world safe from terror; and the idea that the United States is a nation of immigrants, with a long and proud history of offering asylum to the world’s tired and poor./nThe chapters thus together, by performances and analysis, emphasize knowledge production as a form of agency and of historical event. Each chapter presents a counter-narrative to a “settled” legal story that integrates the story of the conquest of America into it. At the same time, each also offers a meditation on the transmission of narratives and concepts and how these carry historical matter into the present.

Advisor: Constable, Marianne