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The Mll4-Lsd1 Epigenetic Axis Regulates Epidermal Differentiation And Ferroptosis: Implications For Skin Cancer And Disease
Get PDFEpigenetic mechanisms regulate chromatin structure and gene expression to direct organismal development and tissue homeostasis, disruption of which is pervasive in cancer. Epigenetic disruption can lead to the acquisition of each hallmark of cancer and almost half of all human cancers bear mutations in epigenetic regulators. The histone methyltransferase MLL4 (KMT2D) has been described as an essential gene in both humans and mice. In addition, it is one of the most commonly mutated genes in all of cancer biology with the highest frequency of mutation occurring in cutaneous squamous cell carcinomas (cSCC). The opposing demethylase LSD1 acts in a genetic and epigenetic axis with MLL4 and is highly overexpressed in various human cancers, which has resulted in the development of highly specific and potent LSD1 inhibitors. Despite this, how the MLL4-LSD1 epigenetic axis regulates normal epidermal homeostasis or becomes dysregulated to drive cSCC tumorigenesis is not well understood. Here, using transgenic mouse models, next-generation sequencing, and human skin models, we address this gap in knowledge. First, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression. Mice lacking Mll4, but not Mll3 (Kmt2c), display features of impaired differentiation and human precancerous neoplasms, all of which progress with age. Mll4 deficiency profoundly alters epidermal gene expression and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Gpx4, Slc7a11). Beyond revealing a new mechanistic basis for Mll4-mediated tumor suppression, our data uncover a potentially much broader and general role for ferroptosis in the process of differentiation and skin homeostasis. In addition to these findings, we also show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of features squamous cell carcinoma. Together, this work reveals critical functions for the MLL4-LSD1 epigenetic axis during epidermal differentiation, ferroptosis, and tumorigenesis and offer new therapeutic strategies to be tested for the treatment of cSCC
breve Y Eficaz: Exemplum And Pedagogy In Iberian Didactic Literature (1169-1611)
Get PDFThe idea of literature as a set of ethical examples for readers to imitate is a familiar justification for the arts in the classical and medieval eras. Nothing better encapsulates this application of storytelling than the “exemplum,” brief narratives with a moral lesson. Through these short historical or fictitious tales, various preachers, tutors, and counselors sought to shape the religious, political, and ethical decisions of audiences. Some of the most iconic works of medieval and renaissance Iberian literature are cast as collections of exemplary tales, such as Juan Manuel’s El Conde Lucanor, Juan Ruiz’s Libro de buen amor, and Cervantes’ Novelas ejemplares. However, the exemplary function of texts has not been explored for the full range of its pedagogical possibility. I argue that in premodern contexts, there is an epistemological “way of example” that coexists in subordination to a “way of reason” or “way of logic” that philosophy, theology, and science have consistently favored. The Iberian didactic texts that appear here all demonstrate an epistemology of exemplum that enables readers to encounter the world through imitation. The Islamic philosopher Averroes predicates poetry itself on the movement of the soul towards and away from models of virtue and vice. Juan Ruiz mocks this ethical poetic, but uses his Libro de buen amor as an aesthetic example that invites participation and emulation of his verse technique. The Mallorcan philosopher and preacher Ramon Llull uses exempla as a way to understand the universe as one great analogy. The Castilian nobleman Juan Manuel resorts to his own life experience as a source of archetypal value and encourages us to do the same, while the seventeenth-century lexicographer Covarrubias encourages us to look toward the natural world for a source of ethical models
Música Y Crisis En Una Isla En Cambio: Cultura Punk En Cuba
No full textEl punk en Cuba surgió a principios de la década de 1990 como respuesta al colapso del bloque soviético. Considerado por el gobierno una influencia del imperialismo estadounidense que iba en contra de los ideales revolucionarios de masculinidad, valores culturales y ética laboral, el punk nacional ha sido censurado y relegado a canales de distribución y consumo extremadamente marginales. Mi disertación, en cambio, ve en esta cultura un microcosmos sociocultural rico que permite un acercamiento innovador y no institucional a la historia del país de los últimos treinta años. Concretamente, esta disertación argumenta que el surgimiento del punk es sintomático del fracaso del proyecto socialista de la Revolución Cubana y que, como cultura de disenso, el punk anticipa el descontento popular generalizado que, en los últimos años, ha ido creciendo en la isla. Mi análisis compara las culturas underground de Cuba con las de Europa y EE. UU., lo que ayuda a situar el punk nacional en un contexto global y expone la realidad de la vida postsoviética en la isla (definida por una economía precaria, una cultura global americanizada y una colonialidad afectada por desigualdades de raza, género y clase). A través del análisis de un corpus original de música y testimonios orales, complementado con colecciones de historias cortas y películas sobre el punk y otros subgéneros del rock, este manuscrito (re)construye una historia crítica del punk y otras manifestaciones underground en la Cuba contemporánea
Novel Mechanisms Of Braf-V600e Regulation Of Inflammation In Dendritic Cells Of Langerhans Cell Histiocytosis
No full textLangerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by abnormal cells, called “LCH cells,” closely related to conventional dendritic cells (DCs). LCH cells universally exhibit hyperactive-ERK signaling due to gain-of-function mutations in the Ras-ERK pathway, commonly BRAFV600E. The pathologic features of LCH cells and the mechanisms by which hyperactive-ERK drives them remains largely unknown, and the need for more effective, safer, and curative therapies are needed. We aimed to better understand the DC-specific consequences of harboring BRAFV600E. Since DCs rely on ERK signaling to produce inflammatory molecules in response to environmental cues, we hypothesized that BRAFV600E-DCs have enhanced inflammatory response to pathogenic stimuli. To address this, we used a transgenic mouse model of LCH which expresses BRAF-V600E in DCs (BRAF-V600Efl/+:CD11c-Cre) and used them to generate mixed-bone marrow chimeras to titrate the number of mutated DCs present. We observed increased LPS-induced circulating cytokines in the transgenic mice, and an inflammatory phenotype that was dependent on the number of LCH cells reconstituted in the chimeras. Additionally, we generated bone-marrow derived DCs (BMDCs) and specifically investigated TLR4-induced TNFα production with or without pharmacologic BRAFV600E inhibition. We observed a reversible increase in secreted TNFα and a partially reversible increase in TNFα protein per-cell, despite a decrease in TLR4 signaling and Tnfa transcripts compared to controls. This prompted us to examine ERK-driven, post-transcriptional mechanisms that contribute to TNFα production and secretion using biochemical and cellular assays. We identified a reversible increase in TACE activation, the enzyme required for TNFα secretion, and most strikingly, a largely irreversible increase in translation efficiency of transcripts, including TNFα, and a reversible increase in the rate of ribosomal elongation. A high throughput exploration of the translatome revealed an enrichment of LPS-response transcripts. These data suggest that LCH cells are hyper-responsive to pathogenic cues which may contribute to LCH pathogenesis. Specifically, these data demonstrate that BRAFV600E exploits multiple post-transcriptional mechanisms in DCs to amplify inflammatory responses. Together, this research advances our understanding of DC biology and LCH pathobiology, lays the groundwork for future studies to further investigate the mechanisms and consequences of both the hyper-responsiveness and altered translatome of LCH cells, and offers novel molecular targets for potential therapeutics
Reconstructing 3d Humans From Images
Get PDFThe past decade we have seen remarkable progress in Computer Vision, fueled by the recent advances in Deep Learning. Unsurprisingly, human perception has been the center of attention. We now have access to systems that can work remarkably well for traditional 2D tasks like segmentation or pose estimation. However, scaling this to 3D remains particularly challenging because of the inherent ambiguities and the scarcity of annotations. The goal of this dissertation is to describe our contributions towards automating 3D human reconstruction from images. First, we will explore the use of different representations for human mesh recovery, discuss their advantages and show how they can be useful for learning deformations beyond standard parametric body models. Next, motivated by the limited availability of annotated data, we will present a method that leverages a collaboration between regression and optimization methods to successfully address this. Subsequently, we will describe our work on modeling the ambiguities in 3D human reconstruction and demonstrate its usefulness for solving a variety of downstream tasks, such as human body model fitting. Last, we will move beyond single-person 3D pose estimation and show how we can scale our methods to work on challenging real-world scenes with multiple humans
Coordination And Conflict In The Global Apparel Value Chain
Get PDFThe interdisciplinary paradigm of global value chains gives us a baseline understanding of how the $1.3 trillion apparel market is organized. Brands are believed to be largely responsible for industry organization. While there are many case studies of industries like apparel or electronics, they are rarely carried out with an ethnographic sensibility that digs into the interactions of conflict, coordination, and execution. My dissertation takes us inside apparel factories, buying agencies, and textile mills in India. I use organizational theory, economic sociology, and social psychology to gain an intimate understanding of how fashionable objects are anticipated, designed, sourced, planned, constructed, and tested. The chief substantive contribution of the work is the integration of multiple levels of analysis, from the transnational coordination of forecasting down to the micro analysis of assembly lines. Additional findings, like the existence of brokerage networks that mediate design from the global semi-periphery, counter 125 years of academic and political skepticism. At the brand level, again in contrast to existing evidence, I find that differences between luxury and discount brands extend throughout dozens of decisions and quality parameters. Different assessments are partially explained by occupational positioning. Our self-presentations are cut from global cloth
Relationships Between Structure, Dynamics, And Flow In Sheared Amorphous Materials
Get PDFAmorphous solids, those composed of haphazardly arranged constituents, are found everywhere from our windows as silicate glass, in the ground and foundations as mud and concrete, and our grocery stores as granular piles of oranges. Even though they can be found over a huge range of length scales, it remains a challenge to systematically design their mechanical properties using knowledge of their microstructure. In this thesis, I investigate the link between the microstructure and the mechanical properties of a-thermal solids. First, I probe the particle trajectories for chaotic signatures that relate to bulk rheology. Particles are confirmed to exhibit chaotic, Brownian like motion during cyclic shear, even though the particles are large enough that thermal motion is negligible. I also find that, the average area traced by returning particles is proportional to the amplitude of strain, which could be useful for in situ measurements in industrial, granular, mixing applications. Next, I examine the interconnection between particle dynamics and the arrangements of the constituents. I calculate the characteristic time for particles to shift past each other, called relaxation time, and the configurational entropy of the system in excess of a reference ideal gas. I show that the relaxation time at any given instant is related to the excess entropy a quarter shear cycle later, which implies that the dynamics of particles shape the eventual structure. This means it is possible to take a snapshot of particle positions and infer its mechanical past. Finally, I focus on the interplay between particle positions and bulk yield by using concepts from kinetics, thermodynamics, statistical mechanics, and shear transformation zone theory. I establish a relationship between excess entropy and energy dissipation and uncover a novel definition for the yield transition based on memory signatures within the microstructure. Using these observations, I derive a phenomenological model that links the microstructure to bulk rheology that is physically informed and whose parameters are all quantitatively measurable. This dissertation elucidates how the statistics of particle configurations and dynamics give rise to the macroscopic transition from elasticity to plasticity during yield of amorphous, a-thermal solids
The Islamic State: Discursive Articulations Of Identity, Subjectivity, Community, And Statehood
No full textThis dissertation is a comprehensive critical inquiry into the discourse of the Islamic State (IS) group. Conducting a multi-perspectival discourse analysis of its constructions of collective identity, subjectivity, political community, and statehood, I propose that IS’s ideology, as manifested through its discourse, is a (counter)hegemonic articulation to what the group considers a multilayered and multidimensional crisis of meaning engulfing Muslim communities and, by extension, the broader world today. The ideology, embodying a metanarrative with its grand theory on the historical progression and telos of Muslim collective life, views the present moment of crisis as the outcome of a millennium-long metaprocess of de-Islamification. De-Islamification is characterized by the fading away of the authentic form of the Islamic creed as putatively practiced by the early idealized salaf generation of the religion and the decline of Islam’s role in shaping political and social life. To remedy this, IS formulates a distinct, exclusionary, and totalizing system of meaning, centered on its interpretation of Islam, whereby it discursively aims to interpellate an ideologically unique Homo Islamicus subject who is tied to a tawhidi-caliphal identity and is tasked with radically reconfiguring, primarily through armed means, the Muslim and global social and political life. To that end, the group also espouses distinct visions of political community and statehood in the form of an ever-expansionist, planetary Muslim umma tethered to a caliphate state. The establishment of this coterminous umma-caliphal entity entails derecognizing the nation, and dismantling the nation state and its human-centered system of meaning and sovereignty. The IS caliphate is chiefly to serve as the vehicle for the otherworldly salvation of Muslims, while ensuring this-worldly supremacy of Islam and the global domination of the Sunni Muslim community. Ultimately, IS’s ideological discourse predicated on such articulations of identity, subjectivity, community, and statehood/sovereignty is designed to institute a narrow interpretation of Islam as a culture, in the sense of a whole way of life, upon which the entirety of the social is to be reimagined and reorganized
The Role Of Working Memory In Implementing Computational Elements Of Visuo-Spatial Decision-Making
Get PDFDecision making is a dynamic process by which a person integrates sensory evidence with prior expectations to select an action to achieve a desired outcome. Often, this process requires working memory to hold and manipulate the relevant information. Working memory has several known limitations and models of implementation that have not been widely considered in the context of decision-making. For decisions regarding spatial stimuli, the dorsolateral prefrontal cortex (dlPFC) is likely to be essential. Activity in this area has been shown to relate to both decision making and working memory, and has led to concrete models of how spatial information may be stored by population activity. To investigate how this activity might be leveraged to implement several computational elements of decision making, we performed two related experiments.In the first, we had human participants perform a working memory task that required the reporting of a decision variable (average location) to determine how working memory limitations impacted decision precision. We also used models of working memory to predict and interpret what information was being actively maintained. We report not only the novel finding that decision variables held in working memory lose precision over time but also that the degree of precision loss depends on the strategy used to make the decision, which differed across participants and conditions. In our second study, we trained monkeys to perform an adaptive oculomotor delayed response task in which they had to integrate cue information with context to select the target most likely to be rewarded. The goal of this study was to investigate whether the tuning properties of working-memory related dlPFC neurons adjusted according to the statistics of the task, corresponding to adaptive behavior. We found that not all monkeys display adaptive behavior, but developed method for interrogating the dynamics of neural responses in those that do. This body of work contributes to our understanding of how working memory may implement the representation of a decision variable or prior information used to interpret incoming evidence. Such understanding may ultimately lead to more effective approaches to addressing disorders of maladaptive decisions, such as addiction and PTSD
Metal-Air Power Sources With Hydrogel Electrolytes For Long Endurance Robots
Get PDFTo power electronics for long durations, batteries need to be recharged because they store only a small amount of total energy, which is limited by the mass of energy storage materials in the battery electrodes. Harvesters can provide longer continuous energy, but their limited power and need for precise operating conditions severely restricts their application in off-grid robots, microelectronics, and internet connected devices. In this dissertation, we designed a new strategy for powering robots and electronics by electrochemically scavenging energy from metal surfaces, which breaks energy storage scaling laws by allowing robots and electronics to extract energy from large volumes of energy dense material without having to carry the material on-board. When moving across a metal surface, metal scavenging exceeds the energy densities of lithium ion and metal-air batteries by 13x and 2x. We also showed how the same technology can power a vehicle and make computer-free decisions about how to navigate the vehicle’s environment by responding to chemical features through electro-chemotaxis. To minimize the mass loading and cost of catalysts in the air cathode and improve their stability, we synthesized nanoporous gold catalysts with increased (100) surface facets using electrochemical dealloying in sodium citrate surfactant electrolytes. These modified nanoporous gold catalysts achieved a 7.7% higher operating voltage and 30.2% greater power density in aluminum-air batteries over traditionally prepared nanoporous gold, and their performance was superior to commercial platinum nanoparticle electrodes at a 10 times lower mass loading. We investigated morphology changes and material distribution through the anode using microscale X-ray computed tomography (micro-CT) and Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). In addition, we also synthesized poly (vinyl alcohol (PVA)/SiO2 and PVA/Agarose hydrogel to increase water retention to extend the lifetime of the hydrogel, which can significantly contribute to the long duration application of metal-air batteries