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To Cross or Not to Cross: Uncovering Novel Regulators of Axon Guidance at the Midline
No full textProper patterning of the nervous system requires accurate targeting of axons. The dynamic process of axon guidance relies on the interaction between conserved axon guidance receptors and their ligands, which triggers downstream signaling cascades to either attract or repel axons. Disruptions of axon guidance are implicated in several neurological disorders, highlighting its essential role during neurodevelopment. The secreted guidance molecule netrin and its Frazzled (Fra)/Deleted in Colorectal Cancer (Dcc) receptor provide a major attractive force to promote axon growth and guidance during the establishment of multiple neural circuits. Canonically, binding of netrin to Fra/Dcc induces cytoskeletal remodeling locally at the growth cone to drive axon turning and growth. Additionally in Drosophila, Fra functions in a non-canonical Netrin-independent manner by generating intracellular domain fragments (ICDs) through γ-secretase cleavage, which can translocate into the nucleus to regulate gene transcription. However, the upstream regulatory signals that modulate these two distinct Fra/Dcc signaling pathways remain unknown. In Chapter one, we discuss recent advances in the field, focusing on new mechanisms that regulate axon guidance receptor function or their downstream signaling pathways. In Chapter two, we describe the identification of the conserved ADAM metalloprotease Tace/ADAM17 as a bi-directional regulator of Fra/Dcc signaling. We provide evidence that Tace-dependent cleavage of Fra is required to induce the non-canonical pathway, yet the cleavage can also suppress netrin responses in commissural axons to inhibit the canonical pathway. Thus Tace/ADAM17 functions by coordinating and establishing a fine balance between the two distinct signaling outputs of Fra/Dcc, which allows the receptors to signal efficiently. In Chapter three, we defined the Fra interactome with an unbiased proteomic approach and established 85 candidate proteins that potentially interact with Fra in vivo and regulate its signaling properties. Promising candidates include Lar, the CSNs and Rho-5, which are highly enriched in the Drosophila ventral nerve cord and function to regulate axon guidance at the midline. In Chapter four, we discuss the remaining knowledge gaps in our understanding of Fra signaling and propose several directions of future investigations that address these questions and expand upon our findings
Qualitative case study evaluation of hospital-led implementation of mobile reproductive & child health clinics in The Gambia: barriers, facilitators, and actionable improvements
Get PDFRapid-cycle evaluation and implementation improvement of community health interventions in low- and middle-income countries (LMICs) are systemically constrained by methodological and resource limitations. In this paper, we present and pilot an adapted approach using a modified version of the Consolidated Framework for Implementation Research (CFIR) to identify barriers, facilitators, and actionable areas of implementation improvement of mobile rural reproductive and child health (RCH) clinics conducted by a major public hospital in The Gambia. We conducted site observations of RCH clinics (n=7), surveys of community health workers (n=5), and semi-structured interviews with relevant hospital staff (n=5) to obtain thick qualitative data for our analysis. In turn, we identified 28 facilitators and 47 barriers across 29 CFIR constructs, each informing an actionable finding for rural RCH delivery implementation improvement. We believe that with further testing and refinement, this approach can have widespread application for timely assessment and improvement of community health intervention implementation in LMICs
A Quantitative Study of Voiced Velar Nasalization in Japanese
Get PDFThis paper presents a corpus-based analysis of voiced velar nasalization (VVN) in the standard (Yamanote) dialect of Japanese, in which a voiced velar plosive /g/ becomes nasalized in prosodic-word-medial position. To the best of our knowledge, this is the first quantitative study of the phenomenon, and confirms the impressionistic observation reported in the previous literature; at the same time, our study finds that these generalizations are stochastic. Looking more closely at the determinants of this variation reveals intriguing ways in which phonological grammar and lexicon interact, as well as the role of frequency in shaping phonological variation. Outside of frequency, we also examine factors such as prosodic length, and the effects of the segmental context on VVN
Against the Argument/Adjunct Distinction
Get PDFThis paper suggests that much of the empirical basis for the argument/adjunct distinction (A/AD) is weaker than traditionally believed. First, I argue that successful argumenthood diagnostics should both (i) identify a distinction among dependents which resembles the conventional A/AD, and (ii) draw a distinction which is not already predicted independently of the A/AD. Focusing on PPs within the VP in English, I argue that purported diagnostics for argumenthood, including omission, \u27do so\u27-substitution, and iteration, do not meet these criteria, therefore do not provide empirical support for the A/AD. After briefly discussing the prospects for several further diagnostics, I conclude that it is plausible that the A/AD might be eliminable. Though this would raise technical questions in various areas, it would be desirable from a Minimalist perspective
Statistical Methods for the Analysis and Development of Quantitative Imaging Biomarkers
No full textThe field of neuroimaging statistics is concerned with elucidating meaningful conclusions from high-dimensional imaging objects, often in the form of single-dimensioned summary statistics. Ideally, these summaries should provide interpretable biomarker measurements that can guide patient diagnoses or treatment decisions while minimizing information loss associated with dimension reduction. This dissertation is focused on (1) exploring methods for analyzing previously developed imaging biomarkers and (2) developing new imaging biomarkers using both well-established and novel imaging analysis techniques. We approach this problem in three ways: in our first project, we assess how previously developed imaging biomarkers can best be incorporated into downstream analyses in the context of a clinical trial. This work conceptualizes imaging biomarkers as measurements which intrinsically contain historical information on a patient and examines the effect of incorporating these predictors on the statistical power in a clinical trial analysis. For our second project, we develop a radiomic predictor that automatically identifies an important prognostic biomarker in multiple sclerosis, relying on quantification of imaging patterns potentially associated with brain atrophy and more severe disease courses. In our third project, we construct a coordinate system and framework for multiple sclerosis lesions analyses for more sensitive and specific biomarker development. We use dimension reduction and flexible nonparametric modelling to assess the diagnostic value of this method. These methods lay the groundwork for improving future work developing and utilizing imaging biomarkers with imaging statistics
The Decomposing Body: Posthumanist Modernism and the Ecology of Decay
No full textThis project takes its motivation from the need to theorize a subversion or decentering of the human subject that has been widely articulated across the contemporary environmental humanities. The critique of anthropocentrism, I have found, can be enriched by engaging with a strain of modernist writing about bodily breakdown and postmortem decay that mobilizes innovative techniques for confronting nonhuman entities and ecological forces that refuse neat containment within the purview of the human symbolic economy. Bodying forth death and decay in language that performatively disfigures itself and thus articulates its own impotence in the face of what resists or refuses representation, modernist writers generated an aesthetic of enmeshment amid more-than-human assemblages that exceed strictly anthropic determinations. Ultimately, I argue that Charles Baudelaire, Djuna Barnes, and Georges Bataille constitute an acutely undertheorized form of posthumanist modernism. Collectively, this tradition advances the writing of dead and decomposing bodies as a means for reorienting the ontology of the human in relation to the beings and forces that precede, traverse, and exceed the strictly anthropic
Unions and Social Capital in the United States
No full textSocial capital, as measured by social trust, pro-social values, or proxies capturing civic engagement, is a strong determinant of an area’s income, economic growth, and political institutions (Guiso, Sapienza and Zingales 2011). But in the US, it has declined significantly over the latter half of the twentieth century, with researchers and policymakers puzzling over why, and how it might be restored. In this dissertation, I propose and test a novel explanation for the decline in social capital—namely, the decline in unionization. Over much of the same period as the social capital decrease, union density decreased by over half, and workers lost “an important locus of social solidarity, a mechanism for mutual assistance and shared expertise” (Putnam 2000). To test this hypothesis, I estimate the effect of unionization on social capital, in two ways. The first is to combine data on NLRB unionization elections with data on commonly used proxies for social capital, and, in a modified RD-DD design, compare the change in social capital in areas that saw a close unionization victory to the change in areas that saw a close unionization loss. The second method is to use the PSID to estimate the effect of becoming unionized on an individual worker’s propensity for charitable donation. The results of the county-level analysis suggest that in the long term, unionization significantly increases voter turnout. However, the estimated effects on membership organizations are statistically insignificant. In an analysis of heterogeneous effects, I further find that the effect of unionization on total organizations is decreasing in a county’s per-capita income. Finally, the results of the individual-level analysis imply strong positive effects of becoming a union member on one’s family’s probability of donating to charity
The Reconstruction Crusade: Rebuilding France\u27s Catholic Churches after World War I, 1914-1939
Get PDFBetween 1918 and 1939, France rebuilt the nearly 4,000 Catholic churches of the Western Front that had been destroyed during the First World War. This thesis presents a cultural history of that process. While it examines technical and financial aspects of reconstruction, the thesis is primarily interested in how Catholics understood the cultural significance of church reconstruction through the shifting and porous contexts of war and peace during the interwar years. It considers how church reconstruction operated at multiple levels: material, conceptual, rhetorical, and ritual. In tracing the evolution of reconstruction efforts across the period—from wartime discourses about reconstruction to the final church reconstructions of the late 1930s—this thesis argues for a trajectory of radicalization. It finds that church reconstruction was initially part of a program for pragmatic post-war reconstruction and modest religious revival in France, but later became the centerpiece of a Catholic crusade for social conquest of domestic political opponents. The history of the reconstruction crusade reveals the persistence of wartime mentalities in French Catholic culture of the interwar period. This thesis ultimately presents the post-war reconstruction of Catholic heritage sites as a fraught process and suggests that conflict can paradoxically persist through the reconstruction of religious sites previously implicated in conflict
Compositional Generalization in Instruction Following Tasks
No full textUnderstanding instructions expressed in natural language is a fundamental task in artificial intelligence. A key feature of natural language that humans use while giving and following instructions is compositionality: the capacity to understand and produce a potentially infinite number of novel combinations from familiar components. This ability is instrumental in being able to learn from limited data and is crucial for instruction following robots to function in the real-world. This dissertation studies the compositional generalization abilities of machine learning models in various instruction following tasks. We study the various dimensions of compositionality for a diverse set of instruction following tasks of varying complexity: semantic parsing in synthetic languages, natural language instruction following in blocks world and vision-and-language navigation in complex indoor environments. We demonstrate empirically that existing systems for these tasks, while performant on the standard iid test set requiring mere interpolation, do not compositionally generalize, which requires extrapolation. We then present different strategies to induce compositionality, ranging from data augmentation, to auxiliary tasks, to a simple neurosymbolic algorithm. We present a compositional spatial representation language and discuss how using such a rich symbolic representation as auxiliary supervision can help generalization in complex, real-world, multi-modal instruction following tasks. Finally, we aim to develop a more foundational understanding of robust generalization by focusing on the task of learning regular languages, where we study the benefits of compositional models over end-to-end ones, from both theoretical and empirical perspectives