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Role Of Pre-Mrna Alternative Splicing In Protein Diversity And Epigenetics
No full textPre-mRNA alternative splicing (AS) has long been proposed to contribute greatly to proteome complexity. However, the extent to which mature mRNA isoforms are successfully translated into protein remains controversial. In this thesis, I describe the use of high-throughput RNA sequencing and mass spectrometry (MS)-based proteomics to provide evidence for the translation of AS mRNAs. To increase proteome coverage and improve protein quantitation, I optimized cell fractionation and sample processing steps at both the protein and peptide level. Furthermore, I generated a custom peptide database trained on analysis of RNA-seq data with MAJIQ, an algorithm optimized to detect and quantify differential and unannotated splice junction usage. With my analyses, we improved identification of splicing-derived proteoforms by 28% and provided peptide evidence for 554 alternate proteoforms arising from 274 genes. Our increased detection of proteins also allowed us to track changes in the transcriptome and proteome induced by T cell stimulation, as well as fluctuations in sub-cellular localization of proteins.
In this thesis, I also identify 18 histone modifying enzyme (HME) genes whose transcripts are AS upon T cell PMA stimulation. Additionally, I report that RNA binding proteins CELF2 and PSF regulate the splicing of 14/18 HME genes. For several reasons, I focus on the class IIa histone deacetylase HDAC7 as a model system to understand the connections between T cell stimulation, AS and epigenetics. Specifically, I find that in response to T cell activation, HDAC7 is alternatively spliced to favor an isoform that includes exon 9. This isoform, termed iE9, is more highly expressed and stable than shorter isoform lacking E9, termed deltaE9. Expression of the iE9 isoform alone resulted in altered gene and protein expression of key T cell surface receptors that receive and propagate T cell activation signals, such as CD3, CD28 and CD69. Thus, we have uncovered a positive feedback loop that helps sustain T cell activation signals. Moreover, I observed that expression of either HDAC7 protein isoform leads to dysregulated histone PTMs. Overall, the work presented in this thesis underscores the contribution of alternative splicing to the diversity and regulation of the proteome, as well as the regulation of chromatin marks
Lifelong Machine Learning Of Functionally Compositional Structures
Get PDFA hallmark of human intelligence is the ability to construct self-contained chunks of knowledge and reuse them in novel combinations for solving different yet structurally related problems. Learning such compositional structures has been a significant challenge for artificial systems, due to the underlying combinatorial search. To date, research into compositional learning has largely proceeded separately from work on lifelong or continual learning. This dissertation integrated these two lines of work to present a general-purpose framework for lifelong learning of functionally compositional structures. The framework separates the learning into two stages: learning how to best combine existing components to assimilate a novel problem, and learning how to adapt the set of existing components to accommodate the new problem. This separation explicitly handles the trade-off between the stability required to remember how to solve earlier tasks and the flexibility required to solve new tasks. This dissertation instantiated the framework into various supervised and reinforcement learning (RL) algorithms. Empirical evaluations on a range of supervised learning benchmarks compared the proposed algorithms against well-established techniques, and found that 1)~compositional models enable improved lifelong learning when the tasks are highly diverse by balancing the incorporation of new knowledge and the retention of past knowledge, 2)~the separation of the learning into stages permits lifelong learning of compositional knowledge, and 3)~the components learned by the proposed methods represent self-contained and reusable functions. Similar evaluations on existing and new RL benchmarks demonstrated that 1)~algorithms under the framework accelerate the discovery of high-performing policies in a variety of domains, including robotic manipulation, and 2)~these algorithms retain, and often improve, knowledge that enables them to solve tasks learned in the past. The dissertation extended one lifelong compositional RL algorithm to the nonstationary setting, where the distribution over tasks varies over time, and found that modularity permits individually tracking changes to different elements in the environment. The final contribution of this dissertation was a new benchmark for evaluating approaches to compositional RL, which exposed that existing methods struggle to discover the compositional properties of the environment
From Meditation To Information: Reading After Unigenitus
Get PDFIn 1713, the Papal Bull Unigenitus condemned 101 propositions extracted from the Jansenist Pasquier Quesnel\u27s popular, seventeenth-century, French-language Bible commentary, the Réflexions morales. This dissertation argues that Unigenitus and the controversies that followed it transformed the ways in which readers of the controversies read and conceived of what they were doing when they did so. Confronted by all legitimate authorities in the Church and French monarchy, Jansenist polemicists appealed to the public to judge if Unigenitus\u27 condemnation of Jansenism was just. To judge, though, this public needed to be informed. To this end, Jansenist polemicists prescribed new models of reading and provided members of this public with both theological and historical arguments to justify the condemned doctrine. These arguments took a wide variety of forms, including cutting-edge genres, such as periodicals; more traditional ones, such as catechisms and almanacs; and non-textual forms, such as engravings and songs. These messages traveled through both formal and informal channels of the licit and clandestine French book trades. The contents of these texts, their forms, and the modes of production and distribution used to bring them to readers conditioned reading in significant ways, notably, by positioning readers on the side of truth against the arbitrary power of the Church and the French monarchy. The ultimate effect of this campaign was a transformation in reading practices from a reading practice that was primarily meditative, focused on a small corpus of mostly books of piety and aimed at elevating one\u27s thoughts to God through self-reflection, to one that was primarily informative, centered on a wider corpus of texts, especially newspapers and contemporary histories, and aimed at gathering knowledge for judgment and argument in the here and now. In helping to bring about this shift, the Unigenitus controversies contributed, in ways both intended and unintended, to a more general reading revolution in eighteenth-century Europe and to the making of the critical spirit of the Age of Enlightenment among readers up and down the social hierarchy
Learning Their Station: Socialization And Discrimination In Two Elementary Schools
No full textScholars have devoted considerable attention to how inequalities are reproduced across generations. We know much about the impact of family and school resources, of cultural skills and dispositions, and of racial/ethnic and gender discrimination. But cutting across these lines of inquiry is how socialization and discrimination – built on structural and cultural inequities – shape the lessons children receive about their social station. That is, how do schools teach children their position and direction in the world? How are children equipped to fulfil these lessons? And what differences and discrimination are visible in this process, making inequality and social reproduction more likely? I address these questions through a comparative ethnography of two racially diverse elementary schools: one private and upper-middle-class, the other public and working-class. I intensively observed 60 students aged 9-11 during my three years of observations, with dozens of other students from different classrooms and grades repeatedly observed in various school settings. My observations are supplemented by in-depth interviews with students, parents, and teachers. These observations and interviews allow me to examine inter-school class differences and intra-school race and gender differences in socialization and discrimination. The three chapters of this dissertation explore different dimensions of the lessons children receive in perception and practice, or in other words, the ways children are taught to see themselves and the skills they learn to make these visions reality. I highlight discrepancies between the differently classed schools in how children are taught to comport their bodies, with students adopting behaviors likely to be unequally rewarded in situations such as job interviews. I detail differences in what children are taught about their relative identity, moral worth, and situated prospects. And I describe the processes by which dyadic teacher-student relationships of different qualities develop at the public school. I discuss the implications of these findings for our understanding of the processes by which inequalities are reproduced, for recognizing the importance of schools as venues of unequal socialization, for foregrounding the body as a site of socialization and discrimination, and for questioning how structural and cultural inequalities shape children’s sense of their social station
receiving, Sorting And Disposing Of Children : Institutions, Education, And Feeblemindedness In Progressive America
No full textDrawing on the recently opened archive of the Pennsylvania Training School for Feebleminded Children at Elwyn, this dissertation traces the varied ways that psycho-medical experts, educators, and families with kin deemed feebleminded understood feeblemindedness and the purpose of institutional care. From the 1880s through the 1920s, developments in medicine, education, and psychology turned educability and curability into moving targets, fueling debates about whether a feebleminded child could grow into an adult citizen. Rooted in Greater Philadelphia, this dissertation traces these debates and their implications in institutions for the feebleminded, psychological diagnostic clinics, and special classes in public schools. It combines intellectual and social history methods to demonstrate how mundane needs and desires of both experts and non-experts operated at times in tandem and at times in conflict with eugenic ideologies. Everyday people contested and contained expert power to coerce and, by invoking a state obligation to provide care, bent expert priorities toward their own
How Do Digital Intermediaries Shape News Consumption? An Observational Study Based On A Large Web Panel In The Us (2016 To 2019)
No full textThis dissertation investigates how digital intermediaries shape news consumption. In particular, the study is designed to address how social media, search engines, news aggregators, and email are associated with information concentration, audience fragmentation, and news inequality. The analyses leverage a large panel tracking the web browsing behavior and demographic attributes (each month N ~ 100,000 panelists). This panel data is processed and analyzed to uncover temporal trends in news consumption and changes in co-exposure networks (on the aggregate), and to identify mechanisms of exposure to news (at the individual level). Methodologically, the analyses rely on data mining, large-scale text processing, network analysis tools, and fixed- and random-effects regression models
I find that digital intermediaries are associated with a lower level of information concentration; in other words, they help diversify the sources people consume. Direct traffic benefits a narrower set of outlets, compared to mediated traffic. This pattern suggests that mediating platforms are expanding, on average, the range of information sources people access online.
Regarding audience fragmentation, I find that digital intermediaries are associated with less fragmentation: they increase density in co-exposure networks and promote traffic from core to peripheral (or niche) outlets. At the individual level, digital intermediaries are also associated, on average, with more ideologically moderate news diets.
Finally, the analyses of news inequality reveal a paradox: on the one hand, digital intermediaries are associated with a reduction or even the reversion of many news gaps separating various demographic groups; on the other hand, they are also associated with a lower level of news engagement (measured in terms of number of pages visited and time spent consuming news). These opposing trends are likely to hinder the positive impact that news exposure can have on civic outcomes, such as an increase in political knowledge and engagement.
Overall, this dissertation uncovers the different pathways giving access to news on the web, and identifies who is more likely to benefit from that access, both from the supply side (news outlets) and the demand side (audiences). By focusing on digital intermediaries, this dissertation casts light on the relevance of online curation in shaping the information people consume
Social Robot Augmented Telepresence For Remote Assessment And Rehabilitation Of Patients With Upper Extremity Impairment
Get PDFWith the shortage of rehabilitation clinicians in rural areas and elsewhere, remote rehabilitation (telerehab) fills an important gap in access to rehabilitation. We have developed a first of its kind social robot augmented telepresence (SRAT) system --- Flo --- which consists of a humanoid robot mounted onto a mobile telepresence base, with the goal of improving the quality of telerehab. The humanoid has arms, a torso, and a face to play games with and guide patients under the supervision of a remote clinician.
To understand the usability of this system, we conducted a survey of hundreds of rehab clinicians. We found that therapists in the United States believe Flo would improve communication, patient motivation, and patient compliance, compared to traditional telepresence for rehab. Therapists highlighted the importance of high-quality video to enable telerehab with their patients and were positive about the usefulness of features which make up the Flo system for enabling telerehab.
To compare telepresence interactions with vs without the social robot, we conducted controlled studies, the first to rigorously compare SRAT to classical telepresence (CT). We found that for many SRAT is more enjoyable than and preferred over CT. The results varied by age, motor function, and cognitive function, a novel result.
To understand how therapists and patients respond to and use SRAT in the wild over long-term use, we deployed Flo at an elder care facility. Therapists used Flo with their own patients however they deemed best. They developed new ways to use the system and highlighted challenges they faced.
To ease the load of performing assessments via telepresence, I constructed a pipeline to predict the motor function of patients using RGBD video of them doing activities via telepresence. The pipeline extracts poses from the video, calculates kinematic features and reachable workspace, and predicts level of impairment using a random forest of decision trees.
Finally, I have aggregated our findings over all these studies and provide a path forward to continue the evolution of SRAT
Regulation Of Anterior Gene Expression In The Caenorhabditis Elegans Embryo
Get PDFPatterning of the anterior-posterior axis is fundamental to animal development. The Wnt pathway plays a major role in this process by activating the expression of posterior genes in animals from worms to humans. This observation raises the question of whether the Wnt pathway or other regulators control the expression of the many anterior-expressed genes. Using time-lapse laser confocal imaging of wild type and RNAi-treated C. elegans embryos, we found that the expression of five anterior-specific genes depends on the Wnt pathway effectors pop-1/TCF and sys-1/β-catenin. We focused further on one of these anterior genes, ref-2/ZIC, a conserved transcription factor expressed in multiple anterior lineages. Live imaging of ref-2 mutant embryos identified defects in cell division timing and position in anterior lineages. Cis-regulatory dissection identified three ref-2 transcriptional enhancers, one of which is necessary and sufficient for anterior-specific expression. This enhancer is activated by the T-box transcription factors TBX-37 and TBX-38, and surprisingly, concatemerized TBX-37/38 binding sites are sufficient to drive anterior-biased expression in a pop-1/TCF-dependent manner. Taken together, our results demonstrate that TCF can regulate an early-expressed anterior-biased gene in the C. elegans embryo through the binding site of another transcription factor
Opportunities For Engaging Planning\u27s Core Values And Skills To Improve Maternal And Child Health In Rural U.s. Communities
No full textMothers and children living in rural U.S. communities experience a ‘rural mortality penalty’; maternal mortality is rising and infants born in rural counties are less likely than their peers to celebrate their first birthday. Counteracting this inequity requires broad investment in community-based infrastructure, investments which planners may be well-situated to support. Yet, planners often aren’t familiar with maternal and child health (MCH), and decisions about rural planning often bypass perspectives of those most affected – low-resource mothers. I join literature in rural planning with maternal health, arguing that planners have a role in improving MCH. I use a mixed-method approach to identify areas for planning action, doing so by centering the knowledge of low-resource women in rural Pennsylvania. First, I co-create and pilot an index, the Community Need Index for Maternal and Child Health (CNIMCH) that helps planners visualize how health-related indicators within their professional charge are part of a larger ecosystem that supports mothers and children. Then, I contextualize the CNIMCH by partnering with rural mothers to explore, through photovoice, how they perceive place, environment, and community in shaping health, and what they want to convey about improving health. I arrange photos and narratives around eight themes, each visited through the experience of one mother, then traced through the larger photo archive. I link the photos to the CNIMCH, reflecting on the interplay of social context, environment, and time in driving health. I position participant’s imaginative futures in relation to structural influences, including geopolitical and economic forces, that shape education, social services, employment, retail, and healthcare in rural Pennsylvania. These findings contribute to dialogue on planners’ role in addressing MCH through three interlocked conversations: the importance of narrative and story-building for rural places and those left out of public decision making, the structural influences on MCH in a rural post-industrial resource extractive region, and the role and power of rural planning. I underscore the causal pathways between social and structural determinants and MCH, nudging planners to consider where our core values and skills influence these determinants and how we can reimagine our role in supporting rural communities where families thrive
Aging In Place Or Stuck In Place? Transportation Planning For Older Americans In The Digital Era
No full textThis dissertation examines the interaction of the built environment, travel behavior, and technology usage among older adults. Decades-long transportation policies favoring vehicle owners have made many older adults disadvantaged in daily travel. Studies and policies specifically addressing older adults’ travel needs do not keep pace with the increasing number and diversity of the aging population. To fill the research gaps, I conducted a series of empirical studies to analyze the travel pattern trends of older adults in order to identify their difficulties in travel. I first examine how older adults travel differently since 2000. Descriptive analysis and a quasi-panel design using the National Household Travel Survey show that those aged 55-74, the baby boomer generation, did not have higher vehicle travel, especially non-work travel, per person, than people at the same age decades ago. Results also show the travel difficulties of low-income older adults. Second, I use cross-sectional and longitudinal data to identify older adults who had difficulties owning and maintaining vehicles. I find that households headed by retirees, those who had lost their partner, and those who lived alone had a higher possibility of living in low-density areas without vehicles. These families also tended to have a decline in vehicle ownership and did not relocate. Third, given the potential role of information communication technology (ICT) in mitigating older adults’ travel difficulties, I surveyed 2,510 older adults, examining the relationship between ICT usage and travel before and during the pandemic. Results show that overall, those who used ICT less also traveled less. In particular, older adults with low incomes and less education, older adults who lived alone, and older African Americans had lower daily vehicle travel and more difficulties using most technology applications. However, health and social technology applications could reduce the difficulties in daily travel for people of color and those with medical conditions. The survey also reveals that age added to the transport disadvantage and digital divide during the pandemic. This dissertation sheds light on transport equity theories, as well as transportation, land use, and technology policies, in order to promote sustainability and equity in an aging society