UCLA

Estrogen deficiency at menopause is associated with a plethora of symptoms with long-lasting effects on quality of life and health span. These symptoms include decreased energy expenditure that is often accompanied by unpredictable and uncomfortable changes in body temperature known as hot flashes. Hormone therapy can improve metabolic profiles after menopause but can also increase the risk for certain cancers. The overarching goal of my dissertation is to uncover the neuronal and molecular targets of estrogen in the hypothalamus that modulate various aspects of thermoregulation and understand the physiologically relevant contexts in which they function. Ultimately, my research may identify therapeutics that mimic the thermal effects of estrogen while circumventing the negative effects of hormone therapy.The ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl) modulates aspects of energy expenditure and comprises heterogenous estrogen-sensitive neuronal populations. However, whether its role in energy expenditure arise from the activity of specific neuronal subpopulations or the genes defining them, remains unknown. We previously found that the p53-regulated and estrogen-responsive gene Reprimo (Rprm) is expressed within the VMHvl, shows higher expression in females than males, and increases body temperature when transiently silenced. While this initial work identified a molecular candidate that may regulate body temperature in a sex-specific manner, outstanding questions remained due to the lack of a mouse model allowing us to probe further into the function of this specific cell type. My dissertation research has aimed to rigorously define the function of the Rprm+ neuronal population in the VMHvl by discriminating the role of the Rprm gene from the actions of Rprm+ neurons. This is an important distinction to make since the function of a gene does not necessarily equate to the function of the cells that express it. For instance, genes can function in cell non-autonomous ways and neurons express many different genes that coordinate function. To address this, we generated a RprmCre-FRT knock-in mouse model that has enabled me to use state-of-the-art viral tools to understand the molecular, cellular, and circuit-level characteristics of this neuronal population. Altogether, this dissertation makes three key contributions to our understanding of the Rprm+ population in the VMHvl. First, I thoroughly characterized the novel RprmCre-FRT mouse line, verifying construct integrity, Cre recombinase activity and function, and gene expression fidelity (Chapter 2). With this model validated, I then took advantage of the Cre-lox system to define the function of Rprm+ neurons, both by manipulating their activity to determine whether this was sufficient to alter thermoregulation, and by using circuit-mapping viral tools to characterize the anatomical circuitry in which these neurons operate (Chapter 3). Finally, I leveraged the RprmCre-FRT mouse model and the Flp-FRT system to permanently ablate Rprm expression via two approaches differing in temporal and spatial scale, assessing its necessity for thermoregulation across different physiological contexts (Chapter 4).

In everyday social interactions, humans rely on visual cues to form impressions, evaluate, and recognize others. Both bodies and faces serve as uniquely rich sources of information for these processes. While face perception has been extensively researched, the study of other visual stimuli, including bodies, has been comparatively limited. Therefore, face perception research serves as a foundation for studying other visual stimuli. Due to recent technological advances, studying bodies is more plausible than ever before. Moreover, while decades of research have centered on assessing individual targets, the prevalence of group settings in our natural social encounters underscores the importance of extending social cognitive research to encompass group perception. Recognizing these dual needs, my dissertation (1) provides a comprehensive review of the body perception literature to identify key areas necessitating further exploration and (2) addresses some of the identified gaps by establishing a publicly accessible database of biological motion (point light display) stimuli for scientific researchers and experimentally testing the impact of body motion on individual and group target perception. Through these efforts, my dissertation advances our understanding of both individual and group social cognition by bridging crucial gaps in existing research.

The amyloid protein fold refers to a multimeric, fibrillar structural motif in which polypeptides of the same sequence fold into relatively planar vertebrae that stack to form fibers. Each layer contributes β-strands to β-sheets that run the length of the fiber, so that the fibers are stabilized longitudinally by backbone hydrogen bonds and laterally by stretches of intercalating, usually hydrophobic sidechains that form "steric zippers." The aggregation of proteins into such fibers is a hallmark of hundreds of protein misfolding disorders, including neurodegenerative diseases such as Alzheimer’s disease (AD), making studies of both disease-associated fiber structures and their protein folding pathways valuable targets in drug discovery. Current computational methods for both protein folding modeling and structure prediction are not suitable for either of these tasks, however. Most proteins are monomorphic, with a single protein sequence producing a single protein structure, usually assumed to be a thermodynamic minimum; amyloid fibers are polymorphic, however, meaning that a single protein sequence will produce many different amyloid fiber structures, currently thought to be kinetically metastable. Subsequently, current computational methods have thus far focused on monomorphic proteins, predicting a relatively limited number of highly similar structures rather than full folding landscapes because of major recent breakthroughs in protein structure prediction methods that make no attempts at protein folding. This dissertation attempts to fill this gap for amyloid fibers by proposing a method for amyloid structure enumeration rather than merely prediction of a singular or limited set of structures that also enables various energetics experiments to explain fiber folding pathways. This is done by modeling amyloid polymorphs as discrete, combinatorial objects, and creating a “steric zipper” representational schema that mimics that of RNA base-pairing. Despite noting some mismatch between observed and recapitulated structures and its causes, our method recapitulates the overall architecture of multiple tau polymorphs while also finding a much broader landscape. Given our structure enumeration is initially energy agnostic and generates a finite but large search space that must be parsed to identify disease-associated polymorphs and their folding pathways, we also assess a knowledge-based energy function used in the field for predicting steric zippers for this purpose and evaluate several explanations for amyloid folding. Our method only generates single layers of amyloid structures, however, leading us to explore determinants of twist between layers, an important global amyloid parameter necessary to reconstruct full fibers. We find that twist is well-predicted by calculating the twist at which inter-layer amino acid sidechain steric clashes are minimal. This work offers an approach that can be further developed and refined to create full, polymorphic folding landscapes of amyloid fibers convertible to atomic models.

This dissertation examines how music and listening became instruments of American psychological warfare. Centering the Office of Strategic Services’ MUSAC Project during the Second World War, it traces the institutional organization of covert musical persuasion and the postwar persistence of personnel and cultural expertise. MUSAC connected American intelligence, British clandestine broadcasting, commercial recording networks, and émigré artists to produce music for German soldiers and civilians under concealed Allied sponsorship. Drawing on archival correspondence, production records, lyrics, scores, recordings, and reports of listening, I reconstruct the relationships among institutional directives, musical decisions, broadcast circulation, and evaluations of efficacy. I develop strategic listening as a method connecting musical analysis, institutional history, semiotics, and acoustemology. Paradigmatic and syntagmatic analysis illuminate how institutional priorities shaped the selection, transformation, and sequencing of musical materials.I argue that MUSAC made entertainment itself a medium of psychological warfare. Familiar repertories, rewritten texts, vocal personae, and gendered address were coordinated to redirect attachments to home, intimacy, and cultural memory toward disaffection with Nazi leadership and continued fighting. Jewish émigré participation is situated within particular careers, antifascist commitments, and artistic claims to American belonging. Mobilizing artists and cultural practices repudiated by Nazi institutions enacted an anti-entartete reversal. Women’s administrative and creative labor likewise expands the account of musical authorship to include operational decisions and institutional coordination.Distinguishing persuasive design from demonstrated effects, I examine how reports of listening became institutional knowledge and claims of operational success. Postwar personnel histories and comparisons with later clandestine broadcasting examine how cultural expertise and practices of listening operated across changing intelligence institutions. I propose an acoustemology of strategic warfare to explain the recursive relationship among cultural knowledge, sonic intervention, and institutional listening: institutions drew on cultural experience to construct musical operations, then interpreted accounts of listening to assess those operations and consider further uses. The supplementary research spreadsheet documents 304 recording entries and their personnel, repertory, and classifications.

The wrist and finger joints allow us to position the hand, grasp objects, and perform activities of daily living. Their small size, complex anatomy, and substantial internal loads make reconstruction after disease or injury challenging. Arthrodesis can relieve pain and provide stability, but sacrifices motion at the reconstructed joint. Arthroplasty seeks to relieve pain while preserving motion, but current implants face limitations in load bearing, stability, fixation, and durability. Our objective was to develop novel, long lasting compliant implants that bridge this gap by combining inherent mechanical stability with functional motion and load bearing for daily activities. For active patients with extensive wrist bone loss, we designed and optimized an implant based on two nested cross axis flexural pivots. These provide two degrees of freedom for flexion and deviation, which can combine to allow dart throwing motion. Elastic deformation guides movement and provides inherent mechanical stability without a rubbing or sliding bearing, eliminating a conventional source of implant wear. Finite element analysis, precision manufacturing, mechanical characterization, and cadaveric evaluation established a functional titanium prototype. Mechanical testing demonstrated wrist motion under compressive loads up to 600 N and dart throwing motion at up to 300 N. We then extended this principle to patients affected by finger arthritis who require surgery to relieve pain and restore function. For the proximal interphalangeal joint, we sought to improve stem fixation and lateral stability while preserving the greater flexion needed for functional finger use. We replaced the metal flexures with a cable tensegrity weave embedded in silicone to accommodate one principal degree of freedom within a smaller anatomical envelope. Titanium stems were designed to accommodate porous surfaces for bone ingrowth. Separate acute motion and compression tests demonstrated a 120° unloaded arc and load support above the 200 N development target. Lateral testing of three tensegrity configurations demonstrated stabilizing restraint without collateral tissue. Together, these proof of concept studies show how compliant implant architectures can accommodate the distinct mechanical demands of the wrist and finger joints, offering a promising path toward restoring the function patients rely on in daily life.

As demand for computing power and memory continues to increase, continued scaling requires the integration of Ru as a replacement for Cu in the lowest level of metal wiring, and CoFeB for enabling magnetoresistive memory cells. To etch these materials, a systematic approach was taken. In this work, thermochemical analyses were performed to assess the feasibility of each chemistry and guide the experimental work. A combination of modelling, diagnostics, and sample characterization was used to determine the etch mechanisms, enabling selectivity and anisotropy.A cyclic chemical process with sequential exposure to N2, H2, and O2 plasmas was developed to circumvent the isotropic etch profile formed by O2 plasma without loss of selectivity. RuN was formed in N2 plasma to act as a passivation layer against O2 plasma etching of Ru. A hydrogen plasma was able to reduce RuN to Ru, with low energy hydrogen ions enhancing the reduction. The cyclic process yielded an etch rate of 3.6 nm per cycle with ions present, but did not etch when ions were excluded. The ion-dependent etch was confirmed by etching nano-scale patterned ruthenium samples. Oxygen plasma produced an isotropic etch profile with an etch anisotropy of 4 and a selectivity of 27 with respect to the hard mask, SiO2. The N2/O2 cyclic process increased the anisotropy to 10, but the etch profile was tapered due to passivation by RuN. The N2/H2/O2 cyclic process maintained an anisotropy of 10 while achieving a more vertical etched profile and a selectivity of 16. On nanoscale features, the cyclic process was anisotropic, less dependent on aspect ratio, and maintained a high selectivity versus the hard mask.To remove CoFeB chemically while circumventing redeposition of less volatile reaction products, atomic layer etching (ALE) of CoFeB was performed using a two-step process. Oxygen plasma was used to increase the oxidation state of the metal, enabling reactions with organic acid vapor to form volatile products. The use of O2 plasma was found to cause the formation of Co3O4, a mixed valence oxide that led to lower etch rate of Co by preventing the formation of Co (II) products. Formic acid or hexafluoroacetylacetone (hfac) were both shown to be able to etch the oxidized CoFeB surface in a controlled manner. The process using formic acid a had a lower etch rate, 0.26 nm per cycle, and organic residue remained on the surface, but the selectivity vs. W was effectively infinite. Etching with hfac had a higher etch rate of 0.55 nm per cycle without organic residue on the surface, but the selectivity vs. W was 6 and the surface was enriched with Co.This work utilized a systematic approach involving thermochemical analysis followed by experimental verification to develop cyclic etching processes for Ru and CoFeB. Surface modification steps were used to induce anisotropy in Ru or control the removal of CoFeB, allowing these materials to be integrated into next-generation devices where control of etch results is critical.

Fluorescence imaging in the shortwave infrared (SWIR) region is a powerful approach for the noninvasive visualization of biology due to favorable light-tissue interactions. Compared to other spectral regions, SWIR light improves depth penetration and reduces tissue scattering, and there are very few endogenous emitters contributing to autofluorescence. Collectively these properties lead to real-time deep tissue imaging with exemplary contrast. The irony is that the best wavelengths for imaging through skin and tissue usually correspond to some of the worst dyes. By nature, organic SWIR-emissive fluorophores have restricted brightness, and immense hydrophobicity, thus creating liabilities in the aqueous biological environment. While the field has rapidly evolved to address these shortcomings over the past few decades, major challenges remain to merge the optical advantages of the SWIR region with fluorophores that are bright, water-soluble, and functional all at once. This dissertation explores diverse approaches to optimize SWIR fluorophore development and advance performance for in vivo imaging studies in small mammals, illuminating design strategies that allow SWIR light to shine the brightest.Chapter One provides a perspective of the history and current landscape of clinical fluorescence imaging using the relatively small set of FDA-approved fluorophores and fluorescence imaging agents. This chapter also examines modern clinical motivations, shedding light on where the field is heading next.Chapter Two is a review of the development of SWIR-emissive chromenylium and flavylium polymethine fluorophores and excitation-based multiplexed imaging technologies, setting the stage for the advancements detailed throughout this dissertation.Chapter Three explores an array of hydrophobic SWIR-emissive fluorophores and in vivo delivery strategies, highlighting how each has enabled fundamental imaging applications in mice, as well as new SWIR imaging technologies, and an increased understanding of the optimal parameters to achieve deep tissue visualization. Ultimately, across many avenues of probe design, each of these hydrophobic dyes faced a similar in vivo fate–nonspecific uptake to the liver and other organs associated with the mononuclear phagocyte system.Chapters Four and Five detail synthetic design strategies to achieve a series of bright, water-soluble, and functional small molecule chromenylium polymethine dyes, thus enabling carrier-free in vivo delivery and cutting-edge preclinical imaging studies. Despite meeting all aforementioned requirements of optimal SWIR emitters, nonspecific in vivo interactions still dominated biodistribution patterns.Chapter Six takes a unique approach to merge SWIR brightness, water solubility, and in vivo “stealth” properties via a bright, SWIR-emissive star polymer dye scaffold (named Chromenylium Star, or CStar), leading to the first demonstration of renal clearance with chromenylium dyes. Building on this framework, Chapter Seven leverages polymer size to generate a series of size-differentiated CStars that provide precision control of in vivo biodistribution pathways.Chapter Eight sees the establishment of a versatile targeted CStar platform. Linking an affinity ligand outside the polymer shielding zone allows it to guide in vivo interactions to specifically visualize solid tumors over healthy tissues using noninvasive SWIR imaging.Finally, Chapter Nine explores a few additional developments of the CStar scaffold from a chemistry perspective. These avenues could be expanded upon for future in vivo use.Taken together, these studies integrate advances in chemistry and biological discovery to ring in a new era of SWIR fluorophore design strategies. With bright, water-soluble, and functional contrast agents that minimize nonspecific localizations in the body, the field moves one step closer to the clinical translation of SWIR imaging.

Endothermy is an adaptation that can be traced back hundreds of millions of years and is critical for nearly every aspect of mammalian biology. Despite the advantages associated with a stable internal temperature, endothermy is energetically expensive. To conserve energy when food is scarce, many species of mammals, including mice, have evolved the ability to reversibly enter a regulated state of hypothermia and hypometabolism, known as torpor. While torpor effectively lowers metabolic demands, it comes with significant reproductive tradeoffs. As a result, organisms have evolved sophisticated strategies to balance torpor and reproduction, thereby maximizing their fitness. In Chapter 1, I review the current knowledge of the signaling networks underlying the bidirectional relationship between torpor and reproduction. In summary, little is known about the cues that influence the reproductive system during torpor and their mechanism of action, although hypothalamic kisspeptin neurons are well-positioned to act as integrators. Conversely, gonadal steroids attenuate torpor in multiple species, yet the signaling mechanisms underlying their effect remain unknown. Promising candidates, including the preoptic area, exist, yet there have been no studies to directly test these hypothesized targets. In Chapter 2, I confirm that circulating estrogens attenuate fasting-induced torpor in female mice and test the hypothesis that the preoptic area acts as a central mediator for their effects. In testing this hypothesis, I find that circulating estrogens alter the response properties of torpor-regulating neurons in the preoptic area yet require a peripheral signaling mechanism to drive torpor attenuation. Together, these works advance our understanding of the bidirectional relationship between torpor and reproduction in mammals and represent an important step towards the ultimate goal of manipulating these pathways to improve metabolic and reproductive health in humans.

This dissertation examines the racialized and gendered labor systems that governed access to technical media work in the American film and television industries from the early twentieth century through the 1970s. Focusing on motion picture projectionists, broadcast technicians, and other technical media workers, it argues that technical ability alone did not determine who could build a career in media. Unions, licensing systems, apprenticeship programs, training institutions, referral practices, seniority rules, and professional networks regulated access to technical expertise, employment, and advancement. I describe this occupational system as media technocaste: a hierarchy that links control over technical knowledge to economic mobility, professional status, and cultural authority while privileging white male workers and restricting African Americans, especially Black women.Beginning with motion picture projection, one of the film industry’s earliest established technical occupations, the dissertation traces how technical labor systems adapted across major technological, economic, and political change. African American projectionists organized segregated unions, pursued licensing and training, and challenged white-controlled labor structures. The military’s adoption of film during World War II temporarily expanded opportunities for Black servicemen and Black women in the Women’s Army Corps, demonstrating their technical competence even as unions and postwar employers restricted access to civilian careers. These exclusions persisted through changing institutional forms, including closed referrals, apprenticeship controls, seniority systems, informal hiring networks, and unequal access to training and experience.Drawing on Black newspapers, union records, projectionist license applications, military records, government and civil rights investigations, trade publications, oral histories, occupational data, and archival photographs, this study reconstructs a history fragmented by labor exclusion and archival neglect. Particular attention to Black women reveals how racial and gender hierarchies shaped both access to technical labor and the preservation of that labor in the historical record. By tracing how media technocaste persisted by reconstituting itself across changing technologies and political conditions, this dissertation repositions technical workers as central to media history and shows that struggles over who could operate, maintain, transmit, and control media technologies were also struggles over economic opportunity, professional authority, and cultural power.

The fungus huitlacoche moves across knotted semiotic, agroecological, and political economic relations through which its meaning, value, and subjectivities—as a being, relative, food, pathogen, commodity, and others—are continually negotiated. Drawing from five years of ethnographic research with diasporic Indigenous organizers of the San Diego-based People of Color Fungi Community, interviews with scientists, farmers, and chefs, and analyses of digital content, regulatory policies, and archival materials, this dissertation follows the fungus (and thus the abovementioned negotiations) throughout discursive, spatiotemporal, and institutional sites in the U.S. and Mexico. Within, between, and across these sites, the dissertation asks how the identities, mobilities, and pasts and futures of huitlacoche, maize, and people are entangled, and what these entanglements reveal about knowledge, authority, and multispecies belonging and survival. More specifically, it asks: how do epistemic practices of naming, classifying, archiving, and storytelling produce different ways of knowing and being with huitlacoche? How do relationships with huitlacoche and maize mediate the formation of individual subjectivities and collective identities? How do histories of land, movement, colonialism, and interspecies survival shape the terms of belonging, and what spatiotemporal possibilities assemble in different ontologies of belonging? Finally, how do political economic regimes, institutions, and infrastructures shape the qualitative evaluations through which huitlacoche comes to be recognized as different things; and how do these evaluations, in turn, reproduce, contest, or transform the systems that organize the fungus’ value, mobility, governance, relations, and survival? These questions weave in and out of chapters as huitlacoche gets drawn into different configurations of bodies, histories, institutions, infrastructures, ideologies, semiotic associations, and forms of expertise, making particular qualities and relations more perceptible and consequential than others. With this, one of the project’s primary contributions to anthropological conversations is developing a methodological framework that attends to how material-discursive qualitative evaluations mediate relations of power between people, species, and institutions.