222 research outputs found
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Phil Magness: COVID-19 Interview
No full textPhil Magness is a Senior Research Fellow at the American Institute for Economic Research. He is the author of numerous works on economic history, taxation, economic inequality, the history of slavery, and education policy in the United States. Listen to the Policy@McCombs podcast to learn more about the data shaping public policy and the data that should be. Subscribe to our YouTube Channel to watch video versions of the podcasts.Salem Cente
Genetic Engineering to Investigate Driver Mutations of Gastrointestinal Neuroendocrine Tumors
No full textIn the intestine, rare neuroendocrine epithelial cells secrete hormones that aid the digestive process and modulate the immune response. Gastrointestinal neuroendocrine tumors (GI-NETs) are slow growing and comprised of cells that look similar to neuroendocrine cells. The Magness Lab has found that a subset of transit-amplifying (TA) cells found in the crypts of the small intestine have a gene expression signature with features of both stem and neuroendocrine cells. We hypothesize that oncogenic mutation(s) occurring in intestinal stem cells (ISCs) and/or TA cells keep endocrine progenitor cells derived from ISCs from exiting the cell cycle and fully differentiating. There is currently limited experimental evidence on the specific combination of mutations needed to induce GI-NET formation. However, human GI-NETs have been found to express a loss of function in the tumor suppressor MEN1 (Multiple Endocrine Neoplasia Type I) and high levels of SOX4 (Sry-Box 4), a transcription factor that promotes endocrine differentiation. This thesis investigated whether a MEN1 loss of function mutation alone drove NET phenotypes in human ISCs and progenitor cells. CRISPR-Cas9 gene editing was utilized to introduce the loss of function mutation in the MEN1 gene. MEN1+/- cells were characterized for GI-NET phenotypes, including an increase in endocrine marker ChgA and persistent proliferation despite the progression to a more differentiated enteroendocrine cell phenotype. The results showed that a MEN1+/- mutation is insufficient for increased proliferation or increased incidence of enteroendocrine differentiation. Future studies will involve testing cells with homozygous MEN1 mutations, SOX4 overexpression, and the combination of MEN1 and SOX4 mutations for signs of GI-NET formation. If successful, these studies will provide the first functional evidence for GI-NET driver mutations.Bachelor of Scienc
The costs and benefits of adjunct justice: a critique of Brennan and Magness
No full textPost-print version of forthcoming article in the Journal of Business Ethics.In their controversial 2016 paper, Brennan and Magness argue that fair pay for part-time, adjunct faculty would be unaffordable for most colleges and universities and would harm students as well as many adjunct faculty members. In this critique, I show that their cost estimates fail to take account of the potential benefits of fair pay for adjunct faculty and are based on implausible assumptions. I propose that pay per course for new adjunct faculty members should be tied to pay per course for new full-time non-tenure track instructors or to pay per course for new assistant professors. That framework for adjunct faculty justice yields an aggregate cost range of 27.9 billion, one-third to one-half lower than the range computed by Brennan and Magness. Its opportunity cost would not be borne by students since students and faculty are complements, not substitutes, in the educational process. Instead it could be financed by reducing spending on non-educational purposes. Current adjunct faculty members would be protected from job displacement in this justice framework. The real obstacle to achieving justice for adjunct faculty is the priorities of university administrators, not budget constraints or opportunity costs
The role of Sox4 in normal intestine and colorectal cancer
No full textThe intestinal epithelium is one of the most rapidly dividing tissues in the
mammalian organism, with near complete replacement of the epithelial monolayer every 7-10
days (Wright et al., 1984). The start site of this impressive cellular renewal and division begins
with a pool of intestinal epithelial stem cells (IESCs) that reside at the base of the crypts. The
crypts are small depressions in the intestine that extend to the lamina propria and house both the
IESCs and supporting niche cells at its base (Cheng et al., 1974). As the IESCs divide, their
progeny migrate upward to the top of the crypt towards the lumen, into what is termed the
transit-amplifying zone. Once in this zone, the transit
amplifying cells mature into one of four well defined postmitotic
cell lineages: absorptive enterocytes, goblet cells,
enteroendocrine cells, and Paneth cells (Figure 1). With the
exception of the Paneth cells, all of these cell types continue
to migrate upward into the large finger-like villi, where they
live for several days before dying and being sloughed off at
the tip of the villus (Cheng et al., 1974). Each cell type in the
villus has a distinct role; absorptive enterocytes are
responsible for absorbing nutrients and transferring them to
the bloodstream, goblet cells secrete a protective mucus layer
over the epithelium, and enteroendocrine cells produce
important signaling hormones (Cheng et al., 1974). Paneth cells are unique in that they migrate
downward from the transit-amplifying zone back to the crypt base where they secrete
antimicrobial peptides and serve as niche cells to the stem cells (Sato et al., 2011). This rapid
cycle of tissue renewal, coupled with well-defined post-mitotic lineages, make the intestinal
epithelium an ideal model for the study of factors that regulate the potency and self renewing
capability of the IESCs, which to date remain poorly understood. Mutations or deficiencies in
these properties of stem cells, collectively considered “stemness,” lie at the heart of many
gastrointestinal disorders. Establishing a better understanding of the processes and transcription
factors that regulate stemness is critical to developing novel cellular and gene-based therapies for
those afflicted with GI disorders and cancers.Bachelor of Scienc
Crypts-on-a-Chip: Developing an ex vivo Model of the Intestinal Crypts
No full textCurrently, stem cell behavior following injury, inflammation, and viral/bacterial challenge is difficult to study in vivo due to the inability to control variables, limited human tissue resources, the prohibitive costs involved with animal studies, and/or the lack of cross-species infection by species-specific microbes. The goal of this thesis is to develop an ex vivo model of the gut epithelium and underlying mesenchyme to facilitate studies that are not possible due to these technical, ethical, and financial constraints. Microfabricated well arrays that mimic intestinal crypt dimensions demonstrated that PDLA, polystyrene, and 1002F promote proliferation of gut myofibroblasts more rapidly than PDMS. Methods were developed to enhance crypt seeding into microwells and standardize the isolation of epithelial tissue. Advanced 3-D imaging techniques using multi-photon excitation (MPE) and Imaris were also developed. These studies are a stepping stone in the development of an organ-on-a-chip for the intestine, and provide proof of concept for intestinal tissue engineering with microfabricated scaffolds
Investigating the Role of FoxA1 and FoxA2 as Candidate Transcriptional Regulators of Sox9 in Intestinal Crypt Stem Cells
No full textTwo stem cell states have been identified within the crypts of the small intestine: ‘quiescent’ and ‘active’. SOX9, a transcription factor encoded from the Sox9 gene has been hypothesized to be the master regulator between these ‘active’ (low expression of SOX9) and ‘reserve’ (high expression of SOX9) intestinal stem cell states. Therefore, putative cis-regulatory sequences upstream of the SOX9 promoter have been analyzed through TRANSFAC© to determine potential candidates for up-regulation of SOX9 in quiescent and active stem cells. Preliminary results indicate that FOXA1and A2 represent potential transcriptional regulators of the SOX9 gene. This hypothesis has been supported by immunohistochemistry, qRT-PCR analysis, and ChIP-sequencing demonstrating that FOXA1/2 co-expresses in cells that express high levels of SOX9 within the intestinal crypt. These studies provide further understanding of how stem cell identity is normally regulated in the cells of the intestinal crypt.Bachelor of Scienc
Intrinsic and extrinsic regulation of potency in the intestinal stem cell niche
No full textThe intestinal epithelium is one of the most proliferative tissues in the adult body, undergoing near total renewal every 5-7 days. This remarkable turnover is driven by a small population of intestinal stem cells (ISCs), which maintain the physiological function and epithelial barrier integrity of the small intestine, and initiate repair following damage. While the anatomical location of ISCs has been appreciated for decades, the complex genetics and cellular behavior of these cells is still the subject of intense research and debate. Emerging research shows that patterns of ISC proliferation and differentiation are governed by highly complex interactions between the extrinsic signaling of the ISC niche and intrinsic genetic programs that regulate ISC behavior on the cell-autonomous level. In this dissertation, we aim to address the regulation of ISC potency at the intrinsic and extrinsic levels. We describe technologic approaches for the isolation and in vitro culture of two distinct human ISC populations, as well as advanced, high-throughput culture conditions for the study of ISC-niche interactions. To address ISC potency from the perspective of intrinsic genetic programming, we examine the role of Sry-box containing 4 (Sox4), which we demonstrate plays a role in ISC differentiation and proliferation, possibly through epigenetic mechanisms. Together, these studies provide valuable tools for examining the effects of extrinsic signaling on ISC potency in vitro, as well as describe a novel mechanistic regulator of ISC differentiation.Doctor of Philosoph
Engineering a platform for increased BEST4+ cell differentiation and potential function
No full textBEST4+ cells (BPCs) are a newly identified human-specific intestinal epithelial cell type with largely unknown functions. This study aims to optimize BPC differentiation in vitro and investigate their role in ion transport, particularly zinc handling. Using human intestinal epithelial stem cells (hIESCs), we found that traditional transwell cultures contain low BPC numbers, but BPC differentiation can be enriched for through air-liquid interface (ALI) culture and a more acidic medium indicating pH sensitive differentiation. NOTCH and TGFB signaling and the overexpression of transcription factor BARX2, previously suspected to influence BPC differentiation, had no effect. To explore BPC function, we assessed their potential role in metal handling. BPCs highly express CNGA1, a nonspecific divalent cation channel, and metallothioneins, which are involved in metal homeostasis. Functional assays using a CNGA1- overexpressing HEK293 model showed increased intracellular zinc accumulation, demonstrating a role for CNGA1 in zinc transport. Furthermore, BPC-enriched ALI cultures exhibited elevated apical to basal zinc transport, supporting their involvement in epithelial metal handling. Finally, to facilitate real-time tracking of BPC differentiation, we generated a BEST4-iRFP reporter cell line, enabling live-cell visualization and fluorescence-based sorting. Collectively, our findings establish a robust method for BPC enrichment, demonstrate their pH sensitivity, and provide support for a potential function in metal ion transport. This work lays the foundation for future studies into BPC function and their potential contributions to gut homeostasis and disease.Bachelor of Scienc
[Photograph 2012.201.B1304.0599]
No full textPhotograph used for a story in the Daily Oklahoman newspaper. Caption: "Rita Magness, left, and Wanda Scott take turns at cooking and dishwashing.
The reintegration of Scott Fitzgerald: The "Basil" stories and "The Crack-Up" essays
No full textIncludes bibliographical references (pages 44)"Of course all life is a process of breaking down" so begins one of the most unusual documents in American letters, "The Crack-Up" essays, written by F. Scott Fitzgerald this side of his fortieth year. The statement that "ail life- is a process of breaking down" forms the thesis Fitzgerald develops in the three "Crack-Up" essays. Because the statement defines the processes of life; the initial approach to Fitzgerald's thesis would logically be from the point of view of the biological sciences. Our biologist would find Fitzgerald's thesis, wanting not in accuracy, but rather in completeness. For the thesis that ''all life is a process of breaking down" is an accurate enough definition of but one-half of the metabolic processes that combine to keep an organism alive. The thesis is an accurate definition of catabolism, or destructive metabolism, the process in a plant or animal by which living tissue is broken down into waste products of a simpler chemical composition. Fitzgerald's definition of life is wanting in that it fails to include constructive metabolism, or anabolism, the process in a plant or animal by which food is\ud
changed into protoplasm and other living tissue. In a word, then, the thesis of "The Crack-Up" essays, while recognizing that "all life is a process of breaking down,??? fails to realize that all life must be a process of building up as well. See more in text
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