1,011 research outputs found
Cancer cells exhibit clonal diversity in phenotypic plasticity
No full textPhenotypic heterogeneity in cancers is associated with invasive progression and drug resistance. This heterogeneity arises in part from the ability of cancer cells to switch between phenotypic states, but the dynamics of this cellular plasticity remain poorly understood. Here we apply DNA barcodes to quantify and track phenotypic plasticity across hundreds of clones in a population of cancer cells exhibiting epithelial or mesenchymal differentiation phenotypes. We find that the epithelial-to-mesenchymal cell ratio is highly variable across the different clones in cancer cell populations, but remains stable for many generations within the progeny of any single clone - with a heritability of 0.89. To estimate the effects of combination therapies on phenotypically heterogeneous tumours, we generated quantitative simulations incorporating empirical data from our barcoding experiments. These analyses indicated that combination therapies which alternate between epithelial- and mesenchymal-specific treatments eventually select for clones with increased phenotypic plasticity. However, this selection could be minimized by increasing the frequency of alternation between treatments, identifying designs that may minimize selection for increased phenotypic plasticity. These findings establish new insights into phenotypic plasticity in cancer, and suggest design principles for optimizing the effectiveness of combination therapies for phenotypically heterogeneous tumours.National Science Foundation (U.S.) (Grant 1122374)National Institutes of Health (U.S.) (Grant 2T32GM007287-36
Intra-tumor heterogeneity and evolution
No full textThesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2017.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references.Although the treatment of cancer is a major focus of biomedical research, many cancers are extremely hard to treat. Tumors likely resist treatment because each tumor is heterogeneous, and can evolve. Although tumor evolution has long been appreciated, it remains incompletely understood. In this thesis, I will explore two questions related to cancer heterogeneity and evolution: how evolution can affect plastic phenotypes, and the role of purifying selection in cancer evolution. Different cell states or phenotypes have been observed within tumors, and they are associated with treatment resistance and metastasis. The observation that these phenotypes are plastic leads to a conundrum: how can selection act on such an unstable phenotype? We determined that plasticity, in the form of cell state bias, varies widely across clones in a tumor. These different biases are heritable, with each cell faithfully passing its differentiation bias to its daughters. Simulations revealed that this makes plasticity an evolvable phenotype--- in a changing environment, an optimal state bias will be selected. The second question explored in this thesis is the role of purifying selection in cancer evolution. It is widely thought that tumor evolution is dominated by positive selection. We posited that, as in the evolution of species, purifying selection would prevent the fixation of deleterious mutations in tumors. Through computational analysis of tumor genomes, we determined that purifying selection acts to remove deleterious mutations. Genes under purifying selection must be important to tumors in vivo, as only mutations in these genes would be problematic. Consistent with this prediction, most genes under purifying selection in tumors were essential in cancer cell lines. To find genes essential to tumors but not generally cell-essential, we developed a method to find genes under increased purifying selection in one tumor type over others. This revealed a number of pathways under selection in melanomas, but not other tumor types, such as DNA damage pathways. By seeking genes important to tumors, but not generally essential, our analysis revealed potential therapeutic targets. Purifying selection offers an unprecedented view into which genes are essential to tumors in vivo, a finding predominantly inaccessible through experimentation.by Robert Austin Mathis.Ph. D
'Magnetars', Soft Gamma Repeaters and Very Strong Magnetic Fields
No full textThis site describes soft gamma repeaters. The author, Robert C. Duncan of the University of Texas at Austin, explains how these strange, physically-extreme stars form, and why they emit steadily pulsating X-rays with sporadic, bright outbursts. The author also tells the story of their discovery and of the theoretical efforts which helped to reveal their bizarre nature. A version of the site is also available in Spanish
Spatial associations of dockless shared e-scooter usage
No full textIn this study, we explore the usage of e-scooter sharing services in Austin, Texas over about a six-month period. The study is based on trip records of all the shared e-scooter operators in Austin and includes trip start and end locations. We use both analysis of trip patterns and spatial regression techniques to examine how the built environment, land use, and demographics affect e-scooter trip generation. Our findings show that people use e-scooters almost exclusively in central Austin. Commuting does not seem to be the main trip purpose, and usage of e-scooters is associated with areas with high employment rates, and in areas with bicycle infrastructure. People use e-scooter sharing regardless of the affluence of the neighborhood, although less affluent areas with high usage rates have large student populations, suggesting that students use this mode of travel. Implications for planners suggest that better bicycle infrastructure will facilitate e-scooter usage, college towns are a ready market for e-scooter sharing services, and e-scooters may be a substitute for some short non-work trips, reducing car usage, and benefiting the environment.Peer reviewe
AMPK promotes tolerance to Ras pathway inhibition by activating autophagy
No full textTargeted inhibitors of oncogenic Ras (rat sarcoma viral oncogene)-Raf signaling have shown great promise in the clinic, but resistance remains a major challenge: 30% of tumors with pathway mutations do not respond to targeted inhibitors, and of the 70% that do respond, all eventually develop resistance. Before cancer cells acquire resistance, they respond to initial drug treatment either by undergoing apoptosis ('addiction') or by surviving treatment albeit with reduced growth ('tolerance'). As these drug-tolerant cells serve as a reservoir from which resistant cells eventually emerge, inhibiting the pathways that confer tolerance could potentially delay or even prevent recurrence. Here, we show that melanomas and other cancers acquire tolerance to Ras-Raf pathway inhibitors by activating autophagy, which is mediated by the cellular energy sensor AMP-activated protein kinase (AMPK). Blocking this AMPK-mediated autophagy sensitizes drug-tolerant melanomas to Ras-Raf pathway inhibitors. Conversely, activating AMPK signaling and autophagy enables melanomas that would otherwise be addicted to the Ras-Raf pathway to instead tolerate pathway inhibition. These findings identify a key mechanism of tolerance to Ras-Raf pathway inhibitors and suggest that blocking either AMPK or autophagy in combination with these targeted inhibitors could increase tumor regression and decrease the likelihood of eventual recurrence.Melanoma Research Alliance (Grant 311800
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Implications of urban design strategies for urban heat islands : an investigation of the UHI effect in downtown Austin, Texas
No full textGiven growing concerns about Urban Heat Islands (UHI), this master’s thesis aims to document the principal factors contributing to the formation of UHIs and assess how urban design parameters can be modified to prevent or mitigate UHIs. Drawing on literature from three different areas of research (UHI causes and impacts, UHI measurement and simulation tools and techniques, and urban design strategies’ influence on urban climate), the author conducted a case study of Downtown Austin, Texas, which has been rapidly growing and densifying during the past decade. To characterize the impact of the future development proposed for the downtown area in the Downtown Austin Plan (DAP), the UHI measurement tool Urban Weather Generator (UWG) was used to simulate the UHI over Downtown in 2020 and 2039 (at the end of the implementation of Downtown Austin Plan). Finally, this study proposes an urban design solution to mitigate Austin’s intensifying UHI.Community and Regional PlanningSustainable Desig
Experimental study of thin film sensor networks for wind turbine blade damage detection
No full textDamage detection of wind turbine blades is difficult due to their complex geometry and large size, for which large deployment of sensing systems is typically not economical. A solution is to develop and deploy dedicated sensor networks fabricated from inexpensive materials and electronics. The authors have recently developed a novel skin-type strain gauge for measuring strain over very large surfaces. The skin, a type of large-area electronics, is constituted from a network of soft elastomeric capacitors. The sensing system is analogous to a biological skin, where local strain can be monitored over a global area. In this paper, we propose the utilization of a dense network of soft elastomeric capacitors to detect, localize, and quantify damage on wind turbine blades. We also leverage mature off the shelf technologies, in particular resistive strain gauges, to augment such dense sensor network with high accuracy data at key locations, therefore constituting a hybrid dense sensor network. The proposed hybrid dense sensor network is installed inside a wind turbine blade 1:25 scale model, and tested in a wind tunnel to simulate an operational environment. Results demonstrate the ability of the hybrid dense sensor network to detect, localize, and quantify damage.</p
Marian E. Barnes and Joanie Stewart, March 7, 1998
No full textPortrait of Marian E. Barnes and Joanie Stewart. Written on verso: Marian E. Barnes and daughter Joanie Stewart at induction ceremony for African American Women's Hall of Fame. Austin 3-7-98.The Atlanta University Center Robert W. Woodruff Library acknowledges the generous support of the National Endowment for Humanities - Humanities Collections and Reference Resources Implementation Project Grant in supporting the processing and digitization of a number of its major archival collections as part of the project: Spreading the Word: Expanding Access to African American Religious Archival Collections at the Atlanta University Center Robert W. Woodruff Library.</em
Tagging of Biomedical Articles on CiteULike: A Comparison of User, Author and Professional Indexing
No full textThis paper examines the context of online indexing from the viewpoint of three different groups: users, authors, and professional indexers. User tags, author keywords and descriptors were collected from academic journal articles, which were both indexed in Pubmed and tagged on CiteULike, and analysed. Descriptive statistics, informetric measures, and thesaural term comparison shows that there are important differences in the use of keywords between the three groups in addition to similarities which can be used to enhance support for search and browse. While tags and author keywords were found that matched descriptors exactly, other terms which did not match but provided important expansion to the indexing lexicon were found. These additional terms could be used to enhance support for searching and browsing in article databases as well as to provide invaluable data for entry vocabulary and emergent terminology for regular updates to indexing systems. Additionally, the study suggests that tags support organisation by association to task, projects and subject while making important connections to traditional systems which classify into subject categories
Punk Journalism : searching for authenticity and identity in Robert Juan-Cantavella’s ‘El Dorado’
No full textIn his 2008 work El Dorado, author Robert Juan-Cantavella explores what it means to be ‘Spanish’ through what he claims to be a new genre called Punk Journalism. The protagonist (Juan-Cantavella's alter ego) claims that Punk Journalism is the bastard son of American author Hunter S. Thompson’s Gonzo Journalism. Several articles have been written about this work, but few have done so with academic rigor—most notably are Maria Egea’s De Las Vegas a Marina D’or. O como llegar desde el New Journalism norteamericano de Hunter S. Thompson hasta la nueva narrativa española de Robert Juan-Cantavella (2011) and Tanteos, calas y pesquisas en el dossier genético digital de ‘El Dorado’ de Robert Juan-Cantavella (2014) by Benédicte Vauthier. While these works tackle the events surrounding its publication—neither of them take a holistic study focused on the themes of authenticity and identity (pertaining to both the narrative, and the publication itself). The first part of this study focuses on the authenticity of the novel itself and serves to validate or discredit critic Maria Egea’s claim that Escargot’s literary creation, Punk Journalism, deserves to be considered “algo nuevo” (Egea 122). I accomplish this through comparative analysis, juxtaposing El Dorado with Fear and Loathing in Las Vegas (1971) while also addressing Maria Egea’s claims. The second part of this investigation reveals that identity is intrinsically linked to authority and power and that Escargot’s inability to pinpoint the identity of his nation is due more to a symptom of language than Spain itself. This study also finds that although Juan-Cantavella's work is a derivative of El Dorado, due to its scope, subjects, and style—Escargot does indeed achieve the creation of ‘something new.’ This newness comes to fruition through Escargot’s use of hyper self-awareness, extreme narrative experiments like switching from first person to third person omniscient at will, increased political commentary, and a more obvious desire to ‘trick’ the reader.Arts, Faculty ofFrench, Hispanic, and Italian Studies, Department ofGraduat
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