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E7, PTPN14, and YAP1: How Papillomaviruses Retain Cells in the Basal Epithelial Layer with Implications for Persistence and Carcinogenesis
No full textPersistent human papillomavirus (HPV) infections cause about 4.5% of the human cancer burden. The HPV E7 oncoprotein is one of the primary drivers of HPV-mediated carcinogenesis and facilitates HPV replication. The most well-studied HPV E7 activity is inactivation of the retinoblastoma tumor suppressor (RB1), which dysregulates the cell cycle. However, there is substantial evidence to suggest that HPV E7 must have other activities in addition to RB1 inactivation. HPV E7 proteins from diverse HPV genotypes interact with the host cell tumor suppressor protein tyrosine phosphatase non-receptor 14 (PTPN14). Many HPV E7 proteins also direct PTPN14 for proteosome-mediated degradation. Through my dissertation work, I sought to identify the role of PTPN14 degradation by HPV E7 in the HPV replicative cycle and carcinogenesis. To initially characterize PTPN14 function in keratinocytes, we used mutant HPV E7 proteins that cannot degrade PTPN14, CRISPR knockout of PTPN14, and high throughput RNA sequencing to assess differential gene expression. We found that PTPN14 degradation by HPV E7 broadly represses genes related to keratinocyte differentiation. In a subsequent study, we used three-dimensional organotypic epithelial cultures to study the mechanism downstream of PTPN14 degradation. We found that PTPN14 loss in keratinocytes promotes basal cell-specific activation of the HIPPO pathway transcriptional regulator YAP1. PTPN14 degradation and YAP1 activation by HPV E7 did not prevent terminal differentiation in these cultures. Instead, the repression of differentiation observed in monolayer culture translated to delayed commitment to differentiation and promotion of basal cell identity in the three-dimensional system. This indicated that PTPN14 degradation by HPV E7 may help HPV resist epithelial turnover and facilitate persistent infection. YAP1 and its paralogue TAZ are oncogenes when dysregulated. Accordingly, through these studies we also found that PTPN14 degradation and YAP1/TAZ transcriptional activity contribute to the ability of HPV E7 proteins from oncogenic genotypes to extend the lifespans of primary keratinocytes, a metric of E7 carcinogenic activity. Overall, the experiments described in this dissertation outline the effects of PTPN14 degradation by HPV E7 in keratinocytes and stratified squamous epithelia which have implications for HPV persistence and HPV-mediated carcinogenesis
Time\u27s Deep Rhythms: Models, Mechanisms, and Narratives in Historical Explanation
No full textMy dissertation is focused on the question of how it is that explanation works in the “historical sciences” (i.e. scientific disciplines dealing with questions of the deep past). I survey the extant literature in order to develop a loose taxonomy of approaches as developed up to this point. While there are some deep differences in these approaches, at least one common theme emerges: the overwhelming majority of philosophical (and scientific) work on historical narrative explanation understands such explanations to be focused on highly particularized explanatory targets. That is, narrative explanations are understood to involve the reconstruction of highly particular causal histories that are supposed to explain the generation of a highly particular explananda of interest. The majority of the literature, then, has (wittingly or unwittingly) upheld the distinction between the so-called nomothetic sciences (e.g. physics) and the idiographic sciences (e.g. paleontology). The nomothetic sciences, it is supposed, offer explanations in terms of laws and regularities, whereas the idiographic sciences explain by “depicting” narrative structures. Further, the idiographic sciences, insofar as they explain, supposedly do so in a way that is impoverished relative to the nomothetic sciences. I thinkthis distinction rests on several mistakes, which I attempt to remedy in my dissertation
Learning Environmental Models with Multi-Robot Teams Using a Dynamical Systems Approach
No full textRobots monitoring complex, spatiotemporal phenomena require rich, meaningful representations of the environment. This thesis presents methods for representing the environment as a dynamical system with machine learning techniques. Specifically, we formulate machine learning methods that lend to data-driven modeling of the phenomena. The data-driven modeling explicitly leverages theoretical foundations of dynamical systems theory. Dynamical systems theory offers mathematical and physically interpretable intuitions about the environmental representation. The contributions presented include distributed algorithms, online adaptation, uncertainty quantification, and feature extraction to allow for the actualization of these techniques on-board robots. The environmental representations guide robot behavior in developing strategies such as optimal sensing and energy-efficient navigation. The methods and procedures provided in this thesis were verified across complex, spatiotemporal environments and on experimental robots
Neural Synchrony in Successful Communication
No full textCommunicating our experiences to others relies on complex shared social, cultural, and psychological mechanisms. Research increasingly shows that shared neural mechanisms also play a role in the success of interpersonal communication. Synchronous activity in shared or complementary regions of the brain promotes emotional connections, cooperation, and memory between communicators. Regions of the brain involved in social and self-relevant information processes – (1) mentalizing, or thinking about the thoughts of others, and (2) self-relevance, or prospecting about the importance of information to the self – show synchrony in ways that correlate with communication outcomes. Synchrony can occur between two individuals, like speakers and their listeners, but it can also occur among a group of listeners, the audience. We use a form of neuroimaging called functional near-infrared spectroscopy to study neural activity as people tell and hear stories. First, we measure synchrony between storytellers and listeners. Chapter 2 shows that synchrony in mentalizing brain regions between a storyteller and her listeners predicts effective communication of emotional states. Next, we consider how synchrony across larger groups of audience members relates to successful communication. Chapter 3 demonstrates that an individual listener\u27s similarity to the average brain response in other audience members, in self-relevance processing regions, predicts the listener\u27s ability to authentically re-tell a story. Finally, extending this work, we also examine whether shared preferences predict neural synchrony in audience members. Chapter 4 integrates information about audience members’ individual preferences for content with audience-level neural synchrony. Within audiences of sports fans and theater lovers, self-reported content preferences predict behavioral liking for entertainment, but neural synchrony does not predict similar preferences in this case. Together these studies explore how synchrony between individuals predicts understanding and ability to transmit stories
Un/making The City: Politics Of Urban Infrastructural Construction In Pakistan
No full textUn/Making the City follows the lives of people in a neighborhood partially demolished during the construction of the Orange Line Metro Train (OLMT) in Lahore, Pakistan to understand the ways in which infrastructural development constitutes the city and its citizens. By attending to relevant bureaucratic and legal practices, micro politics of engagement between citizens and the state, everyday negotiations between people and their sociomaterial environment I show how cities and citizens are mediated and made through the discursive and material practices of infrastructural development. If infrastructures exist as unsteady assemblages of social and material relations, their development and construction are critical sites for unmaking and remaking a multiplicity of historical, technical, political, and temporal forms. Across five substantive chapters I show how an analytic focus on the ‘meantime’ of infrastructures visibilizes the normally invisible relationship between destruction and development and challenges linear narratives of progress. This undoing of the city and citizens is a contested process that occurs at the conjuncture of colonial legal and bureaucratic structures, postcolonial development priorities, and the post 9/11 securitization of Pakistan’s infrastructural policy. The dissertation is also informed by the understanding that infrastructures are nested in a range of material and social relations and flows. Understanding the impact of their construction then necessitates attention to the ways in which socio-material boundaries around their development are constructed and contested. At stake here are questions of legibility, and attribution of cause and responsibility for rectification regarding the varied spatial and temporal effects of infrastructural construction. The chapters in this dissertation focus on the ways in which construction of the metro train engages with land ownership practices, informs people’s access to the city and participation in decision making processes, inflicts debilitating physical ruination, and impacts people’s relations and expectations with the state. Although infrastructures seek to build the liberal (and neoliberal) city, citizens, and a circulating public, this dissertations argues that their very construction and existence, as revealed through a focus on the development process, is predicated on the active production of illiberal citizen-subjects whose rights to housing, work, and the city are undermined. This ethnography is based on fieldwork conducted in the Old Anarkali area of Lahore over a period of sixteen months from 2016-2018
Splendors of the Serenissima in a Digital Age: The Master of the Murano Gradual Reconsidered
Get PDFThe Master of the Murano Gradual is one of the most enigmatic illuminators working in early fifteenth-century Venice. The eponymous choir books were commissioned by the Camaldolese monastery of San Mattia a Murano and today comprise a single intact volume in the Kupferstichkabinett in Berlin (MS 78 F.1) and about fifty historiated initials dispersed in twenty-five public and private collections in Europe and the United States. The fragmentary nature of the overall corpus is a central challenge to studying the artist and to understanding the contours of the workshop. This article provides a reassessment of the corpus of work attributed to the Murano Master—including an appendix with provenances of the whereabouts of the series—and makes a case for future collaborations that can build upon digitization efforts that make the fragments available online and upon recent technical analysis into the pigments used by the illuminators. The methodological approach of the authors has been twofold. Firstly, to study each of the fragments and manuscripts in person, and to locate digital assets for as many works as possible with the aim of creating an eventual website or online repository for scholars to consult. Secondly, to investigate codicological features of the individual fragments that have been hitherto overlooked, including the measurement of musical stave heights or blind-ruled lines for song, and the possible relationship between decorated and filigree letters to over one-hundred cuttings with decorated letters that have also been associated with the San Mattia series. Finally, the study also clarifies the dating of the Murano choir books, which were most likely produced in the 1420s
The Mother Of All Decisions: How Women Make Career Decisions Around Motherhood
Get PDFThis capstone seeks to discover how women make career decisions around motherhood. Specifically, what types of factors are involved when a woman chooses to become a mother and how workplaces can support their workforce around motherhood. With no government mandated paid maternity leave, organizations are required to meet the call of supporting the female workforce around motherhood, which inevitably can cause some friction and opportunities for bias. Through interviews of eight women who recently became mothers or are looking to start a family in three years, this research provides findings on how women are influenced in their decision making. The research dives into the history of women’s rights in the United States and the current state of government involvement, with trends and experiences in the workplace. The interviews determine how external and internal factors impact how women make decisions and provides suggestions to mothers, coworkers, and organizations on how to make the transition easier for women
Demystifying The Role Of Culture In Coaching Relationships
Get PDFThis capstone examines the role of culture and cross-cultural competence in coaching relationships. The business world is becoming increasingly globalized, with workers interacting across geographic and linguistic and cultural differences. In addition, many American companies are actively diversifying their leadership teams, which increases cultural differences in C-suites and beyond. These individuals need to develop significant cross-cultural competence in order to effectively engage with one another. Coaches working with these diverse and globalized companies need to both develop their own cultural competency and grow their expertise in coaching others to develop cultural competency. In this study I engaged in intensive coaching with two Asian–American women, reflected on each of the coaching sessions, and analyzed the content of the sessions as well as my reflections. My findings include the following: Aspects of a coach\u27s culture influence how they perceive and engage with a client; aspects of a client\u27s culture influence how they perceive and engage with a coach; clients and coaches make assumptions about each other based on a number of factors, including race; and the identities of coaches and clients are expressed and negotiated through stories. This capstone raises many interesting questions for future examination, including what strategies can be deployed beyond awareness of cultural differences and building more inclusive coaching models
Penn Library\u27s LJS 434 - [Jadāvil-i ikhtiyārāt]. = [جداول اختيارات]. (Video Orientation)
No full texthttps://repository.upenn.edu/sims_video/1179/thumbnail.jp
Penn Library\u27s LJS 436 - Ḍawʼ al-sirāj. = ضوء السراج. (Video Orientation)
No full texthttps://repository.upenn.edu/sims_video/1181/thumbnail.jp