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This collection contains scholarship produced by the faculty and students at Georgetown University.
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DEVELOPMENT OF NOVEL COMPUTATIONAL METHODS FOR DRUG DISCOVERY AND REPURPOSING IN ONCOLOGIC DISEASES AND OTHER ILLNESSES
DEVELOPMENT OF NOVEL COMPUTATIONAL METHODS FOR DRUG DISCOVERY AND REPURPOSING IN ONCOLOGIC DISEASES AND OTHER ILLNESSES Targeting disease-related proteins is important for drug discovery, yet target-based method have not been fruitful. Bottlenecks involve: (1) establishing biologically valid drug- protein target associations, and (2) assessing the physiologic effects of those interactions at the systems level. Here we develop novel computational methods for overcoming these challenges. For the accurate prediction of drug-target interactions, we investigate the ability of two independent proteochemometric methods entitled R-TMFS and ES-Screen to prioritize known drug binders over decoys for diverse sets of protein targets. R-TMFS is a docking-based method that incorporates molecule shape and physicochemical properties, whereas ES-Screen is an electrostatics-driven method that accentuates the role of electrostatics in biomolecular recognition and binding kinetics. R-TMFS and ES-Screen are also used to predict previously un-reported kinase targets for the anti-hookworm medication mebendazole. Follow-up in vitro binding assays confirm mebendazole inhibition of multiple kinases such as ABL1, JAK2, JNK3, and RAF1, attesting to the repurposing potential of mebendazole for various cancers. For higher-order physiologic contextualization of drug-target signatures, we devised a computational platform named NET-TMFS that annotates drugs with biological endpoint effects including protein-protein interactions, signaling pathways, molecular functions, and disease effects. NET-TMFS recapitulated over 50 drug-disease, 100 drug-pathway, and drug-PPI associations established in the literature. NET-TMFS also predicted potential carcinogenic effects of the cholesterol-lowering drug ezetimibe, a phenomenon documented in clinical trials. In summary, we have developed novel computational methods for addressing major bottlenecks in the drug discovery process. We hope our methods will aid in finding effective therapeutics for many diseases with greater efficiency and lower costs. Ph.D.
HEMATOPOIETIC CELL POPULATION SEGREGATION THROUGH FULL-LENGTH TRANSCRIPTOME SEQUENCING “Progress in science results from new technologies, new discoveries and new ideas, probably in that order.” Nobel Laureate Sydney Brenner (1927 - ); Sequencing the human genome was a critical first step in setting the groundwork to understanding the molecular programming that is involved in transforming a cell from a healthy to a cancerous state. Cellular transcriptome complexity has become increasingly more apparent as technological advances have exposed us to its diversity. Full-length RNA sequencing is crucial for an unbiased analysis of transcriptome complexity. This complexity is due to posttranscriptional processing of primary transcripts that results in a variety of isoforms generated from the same genomic loci. Distinct cell lineages are defined by their transcript isoform expression profiles, and the annotation of cells can be derived from the expression of transcript isoforms that can result in functionally different proteins. Alternate splice site utilization provides cells with a powerful regulatory mechanism of gene expression that can impact the composition of the protein product, and influence the rate of translation of transcripts from multi-exon genes. The overall goal of this project was to delineate the hematopoietic transcriptome revealed by full-length sequencing and assess the shortcomings of transcriptome reconstruction using fragmented-read sequencing. The aims were to (a) evaluate the complexity of the hematopoietic transcriptome using full-length RNA sequencing, to (b) compare the full-length RNA-sequencing transcriptome with the reconstructed transcriptome from fragmented-read sequencing and to (c) evaluate whether hematopoietic cell subpopulations show distinct transcriptome patterns. Sequencing and reconstructing transcripts through transcriptome reconstruction from fragmented read sequencing have advanced our understanding of the transcriptome. Here we show that full-length transcriptome sequencing is necessary to faithfully expose the transcriptome and understand its complexities. Abundance information and pathway analysis support this. Also, full-length sequencing illustrates open reading frames that code for contiguous canonical or fusion proteins that can be validated with peptides. This transcriptome diversity is consistent with distinct phenotypes of cell subpopulations present in tissues. Accurate transcriptome measurement builds a foundation that can be relied upon to ensure higher success rates for therapeutics and lower false discovery rates for biomarkers of disease.; The analysis of transcripts of a set of selected genes as well as the potential for posttranscriptional processing predicts for a highly complex transcriptome and an abundance of hitherto unknown protein isoforms. Classic approaches have not allowed full testing of this hypothesis due to limitations in sequencing lengths. Taking advantage of full-length sequencing technology provides us with an opportunity to uncover transcripts that cannot be obtained through traditional transcript reconstruction techniques. Ph.D.
Interreligious Debates, Rational Theology, and the ʿUlamaʾ in the Public Sphere: Muḥammad Qāsim Nānautvī and the Making of Modern Islam in South Asia
Interreligious Debates, Rational Theology, and the ʿUlamaʾ in the Public Sphere: Muḥammad Qāsim Nānautvī and the Making of Modern Islam in South Asia The nineteenth century was a time of tremendous change for Islamic intellectual traditions in South Asia in an era of colonialism, the decline of traditional authority, and the transformations of modernity. In spite of these challenges, Muslim scholars, theologians, and intellectuals proved to be particularly creative in this period, laying the foundations for the rethinking and reconfiguration of Islamic intellectual traditions in a modern context. The perspectives adopted by modernist and ‘fundamentalist’ Muslims to these modern developments and new contexts have been widely studied. However, the intellectual responses of representatives of the historically continuous classical tradition, the religious scholars (‘ulamā’), theologians, and Sufis, has received far less attention.; Mawlānā Muḥammad Qāsim Nanautvī (1833-1880), among the most important figures of modern Sunni Islam in South Asia, was a prominent religious scholar, philosophical theologian, and Sufi. Although he is best remembered for being the co-founder of the school of Deoband, the most influential South Asian Islamic seminary of the last two centuries, his participation in interreligious debates with Christian missionaries and Hindu reformers, including the first public Hindu-Muslim polemics, and his articulation of a rational theology for the public sphere are equally significant. Nanautvī’s career and writings provide an insightful lens onto the ways Islamic intellectual traditions came to be reconfigured by the rise of the public sphere, the emergence of reified and oppositional religious identities in South Asia, and the increasing popularity of modern rationalism and empiricism. Nanautvī’s work demonstrates how a Muslim scholar ‘translated’ classical Islamic intellectual traditions, in his case, Islamic philosophy (ḥikmah) and theology, into a new discourse for modern public and pluralistic contexts where Muslim scholars not only had to engage other Muslim scholars, as they did in the past, but to present and justify ‘Islam’ to new Muslim publics as well as non-Muslim scholars and publics. Such a discourse represented a ‘public theology’ that situated and justified Islam as a rational religion vis-à-vis both the claims of other religions and those of modern thought and can serve as a critical example of how Islamic traditions have negotiated continuity and change in the modern world. Ph.D.
El(la) Mapping: An Integrated Account of Learning Context, Feedback and Agreement Morphology in the Processing of OclVS Sentences in Advanced L2 Spanish
El(la) Mapping: An Integrated Account of Learning Context, Feedback and Agreement Morphology in the Processing of OclVS Sentences in Advanced L2 Spanish Previous literature has shown that beginning and intermediate English-speaking learners persistently misinterpret O-cliticVS sentences in Spanish, preferring word order over morphology when assigning semantic functions to the NPs of non-canonical sentences. Following the Competition Model (Bates & MacWhinney, 1982, 1989; MacWhinney, 2012), this dissertation investigated from an on-line and off-line account whether English-speaking advanced learners of Spanish are also prone to such misinterpretations, and whether their reconfiguration of L1 processing strategies benefits from: (a) mismatches in number agreement morphology, (b) immersion experience, and (c) computer-delivered feedback.; Three self-paced readings were conducted. In Experiment 1 (N=38), matching/mismatching number agreement between clitic and verb was manipulated to measure the usefulness of contrastive agreement to overcome word order bias. Experiment 2 (N=20) investigated whether a 5-week Study Abroad program promoted learners’ OclVS sentence development. Experiment 3 (N=90) investigated potential interactions between agreement conditions and the provision or absence of computer-delivered feedback.; Results showed that advanced learners continued to rely on word order when interpreting OclVS sentences, but different agreement conditions were not processed alike. In Experiment 1, accuracy significantly improved in the mismatching condition in which the morphological cue was on the verb. Participants also tended to present longer reading times in the verb of ClsgVplSpl structures. In Experiment 2, learners significantly improved at Week 5 and paid more attention to the verb and post-verbal subject, which are highly informative. In Experiment 3, the [+ Feedback] group outperformed the [- Feedback] group, which only received practice decoding manipulated input. Also, the [+ Feedback] group exhibited a speedup across experimental trials in the baseline condition (ClsgVsgSsg) whereas the [- Feedback] group exhibited a significant slowdown in the mismatching ClsgVplSpl condition.; This dissertation has implications for research on intra-subject L2 processing variation and emerging bilingualism. It also contributes to the debate on whether short-term studies overseas influence L2 grammar skills. Finally, the extent to which exposure to manipulated input alone helps learners reconfigure their L2 processing strategies is discussed along with feedback’s potential role in enhancing this process. Ph.D.
Perception and Production of Intonation among English-Spanish Bilingual Speakers at Different Proficiency Levels
Perception and Production of Intonation among English-Spanish Bilingual Speakers at Different Proficiency Levels This dissertation examined the perception and production of intonation among 55 English-native speakers of Spanish at three proficiency levels (low, high, and very high). Their performance was compared with monolingual speakers of Spanish (n=17) and English (n=17), and English-Spanish early bilinguals (heritage speakers, n=16). The target form was the intonational contour in neutral declarative utterances in Spanish, examined at two tonal events, namely prenuclear peak alignment and final boundary tone height. The study adhered to the theoretical principles of the Autosegmental-Metrical approach (Beckman & Pierrehumbert, 1986; Pierrehumbert, 1980, 2000). Participants completed an imitation task aimed at locating potential categorical shifts in the perception of both tonal events and two production tasks varying in speaking style (sentence reading and storytelling). Results revealed a marked contrast between Spanish and English in perception and production of both tonal events. Spanish speakers generally preferred later alignment of prenuclear peaks and lower height of final boundary tone. In turn, second language (L2) and early bilingual speakers tended to produce values in the middle range between Spanish and English. Performance of low-proficiency speakers generally approximated English monolingual speakers, while L2 speakers of very high proficiency produced values at the same level of heritage speakers under most measures. As regards the role of speaking style in production, some minor effects were found in prenuclear alignment, while no effects were obtained in final boundary tone. A strong relationship between production and perception was also found for prenuclear alignment but not for final boundary tone. Results also seemed to support some predictions made by the Speech Learning Model (Flege, 1995). Findings are discussed from the point of view of cross-linguistic influence, effects of high proficiency on L2 phonology, tonal representations for Spanish and English, and the link between production and perception in L2 prosody. Ph.D.
Readiness to learn: Characteristics associated with implicit learning aptitude Cognitive frailty is one of the biggest threats to healthy aging, and yet our basic understanding of cognitive aging is limited in at least two ways. First, while group differences in the cognitive performance of younger vs. older adults are well-documented, we understand little about the inter-individual variability occurring within age groups, which implies that some individuals are aging more successfully than others in the cognitive domain. Additionally, most cognitive aging research to date has focused on explicit cognitive functions and has neglected an entire subclass of implicit functions that have implications for maintaining health.; To begin addressing these limitations, this dissertation examined characteristics related to implicit learning aptitude. The first study showed that a neural characteristic--the strength of intrinsic connectivity between two learning-relevant brain regions (caudate and medial temporal lobe; MTL)--predicted how well young adults subsequently learned a complex regularity. This finding suggests that communication between learning-relevant regions prior to learning is important for understanding inter-individual variability in learning outcomes. The second study examined a behavioral characteristic—dispositional mindfulness—and revealed a novel negative relationship between mindfulness and implicit learning in two healthy adult samples, suggesting that mindfulness may not benefit implicit cognitive functioning. We posited that the negative association between these two variables might be due to the fact that the balance of neural systems supporting mindfulness is not optimal for supporting implicit learning. The final study tested this hypothesis by examining how the connectivity of learning-relevant regions during learning related to individual differences in both learning and dispositional mindfulness in a sample of healthy older adults. Results showed that stronger connectivity between the caudate and MTL was positively related to implicit learning, and negatively related to mindfulness. Further, the strength of this connectivity mediated the relationship between mindfulness and learning, suggesting that this might be the neural mechanism by which mindfulness impairs this cognitive process. Taken together, the findings advance our understanding of which behavioral and neural characteristics are related to individuals’ propensity, or “readiness”, to acquire complex regularities implicitly, and suggest that such characteristics might modulate the complex interaction between learning systems. Ph.D.
The Problem With Social Safety Nets: Policy or Psychology? Correia, Tricia
Library Associates Newsletter: Issue 113 Lauinger Library Booth Family Center for Special Collections Opens; From the University Librarian: Commencement; Your Named Endowment: Ensuring the Future; Crisis in America with Ray LaHood; Roosevelt's Second Act with Richard Moe; Patricia Stonesifer and Martha's Table; Clinch Calkins Papers; Undiscovered Printmakers; Lynd Ward's Cup of Sky
The New Porn Platform: Standards Gaps in ‘Revenge Porn’ Policy and Protection Doom, Jilanne
Street Art Dialogue Werthmann, Laura This paper reviews street art dialogism as understood through parallel architecture, remediation, recursion, and combinatoriality of signs through art’s social setting. It exposes the contrast and comparison of the nodes in visual culture, digital media networks, and most importantly the dialogue throughout contemporary art networks such as Abstract Expressionism, Dada, Pop Art, Postmodernism, and Post- Postmodernism. This remix culture forces an engagement from the art world to comment, reply, use, reject, admire, and debate the new semantics of an ephemeral art form that spans across public visual spaces. The ability for street art to be seen is very important and enabled by the structure and dimensions of the wall, but today, it is also facilitated through the digital world as more art is being transformed for an internet viewership that has opened up a new interface outside museums, galleries, and even the streets; it helps enable art become global.
Otto’s Notebook vs the Memex: Comparing the smartphone and the PC as two paradigms of cognitive enhancement
Otto’s Notebook vs the Memex: Comparing the smartphone and the PC as two paradigms of cognitive enhancement Huber, Linda The history of computing has been characterized by an effort to replicate and augment human intelligence. Today’s personal computers are still substantially similar in their overall goals to the “memex,” a hypothetical computer prototype described by Vannevar Bush in 1945: both are designed to use computation to augment advanced forms of intellectual labor. Yet in the last decade, the rise of the smartphone has disrupted this long-standing paradigm of cognitive enhancement. It introduces a paradigm characterized by less complex but more pervasive kinds of cognitive enhancement. This is a kind of cognitive enhancement perhaps more akin to ever-present notebook that facilitated Otto the hypothetical Alzheimer’s patient in his daily activities (as described by Clark and Chalmers in their seminal paper on extended cognition in 1998). In this paper I compare and contrast some of the basic augmentations and affordances of the smartphone as compared to the PC (either desktop or laptop). Using Heersmink’s “multi-dimensional matrix for exploring cognitive-artifact relations” (Heersmink, 2012), I conducted a preliminary investigation suggesting some of the concrete differences between these two paradigms of computation and cognitive enhancement.
Life in the New Media landscape: Ritual Communication and Distributed Cognition on Reddit Miller, Chris The New Media landscape is diverse and complex. More importantly, as noted by Lev Manovich, it is fundamentally new. This paper will explore one instance of New Media, the social news site reddit, in terms of several theoretical frameworks, situating the site both in terms of its historical precedents and novel contributions to the New Media landscape. The analysis will show that the affordances of New Media embodied in reddit, including expansions on Ritual Communication and Distributed Cognition, along with a Web 2.0 ethos that highly values interactivity and user-control, have made reddit a site of 21st century community building.
Carroll Round Proceedings 2015 Carroll, Round Undergraduate economic research papers presented at the 10th Annual Carroll Round Conference at Georgetown University
Carroll Round Proceedings 2014 Carroll, Round Undergraduate economic research papers presented at the 9th Annual Carroll Round Conference at Georgetown University
CIRS Annual Report 2014-2015 Center for International and Regional Studies]
السياسة الطائفية في منطقة الخليج Potter, Lawrence G.; Gengler, Justin J.; Haddad, Fanar; Louër, Laurence; Diwan, Kristin Smith; Valeri, Marc; Peterson, J.E.; Beck, Lois Certain streams of scholarship have suggested that conflicts around sectarian identity lie at the very crux of Middle Eastern politics. Sectarianism may be broadly defined as the process through which forms of ethnic and/or religious identity are politicized. While certain scholars over-emphasize the enduring ideological divides in the region and their continuing influence on socio-political instability, others downplay their significance entirely. There are those who argue that sectarian issues in the region are not the age-old dilemmas that they are often perceived as, but rather are a modern phenomenon, and that sectarian affiliation was not a particular marker of identification, nor a cause for open conflict a century ago.