Matching Items (14)
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- All Subjects: Evolution
- All Subjects: Diabetes
- Creators: School of Molecular Sciences
Description
Brown adipose tissue (BAT) is thought to be important in combating obesity as it can expend energy in the form of heat, e.g. thermogenesis. The goal of this study was to study the effect of injected norepinephrine (NE) on the activation of BAT in rats that were fed a high fat diet (HFD). A dose of 0.25 mg/kg NE was used to elicit a temperature response that was measured using transponders inserted subcutaneously over the BAT and lower back and intraperitoneally to measure the core temperature. The results found that the thermic effect of the BAT increased after the transition from low fat diet to a high fat diet (LFD) yet, after prolonged exposure to the HFD, the effects resembled levels found with the LFD. This suggests that while a HFD may stimulate the effect of BAT, long term exposure may have adverse effects on BAT activity. This may be due to internal factors that will need to be examined further.
ContributorsSion, Paul William (Author) / Herman, Richard (Thesis director) / Borges, Chad (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Cancer is a disease that occurs in many and perhaps all multicellular organisms. Current research is looking at how different life history characteristics among species could influence cancer rates. Because somatic maintenance is an important component of a species' life history, we hypothesize the same ecological forces shaping the life history of a species should also determine its cancer susceptibility. By looking at varying life histories, potential evolutionary trends could be used to explain differing cancer rates. Life history theory could be an important framework for understanding cancer vulnerabilities with different trade-offs between life history traits and cancer defenses. Birds have diverse life history strategies that could explain differences in cancer suppression. Peto's paradox is the observation that cancer rates do not typically increase with body size and longevity despite an increased number of cell divisions over the animal's lifetime that ought to be carcinogenic. Here we show how Peto’s paradox is negatively correlated for cancer within the clade, Aves. That is, larger, long-lived birds get more cancer than smaller, short-lived birds (p=0.0001; r2= 0.024). Sexual dimorphism in both plumage color and size differ among Aves species. We hypothesized that this could lead to a difference in cancer rates due to the amount of time and energy sexual dimorphism takes away from somatic maintenance. We tested for an association between a variety of life history traits and cancer, including reproductive potential, growth rate, incubation, mating systems, and sexual dimorphism in both color and size. We found male birds get less cancer than female birds (9.8% vs. 11.1%, p=0.0058).
ContributorsDolan, Jordyn Nicole (Author) / Maley, Carlo (Thesis director) / Harris, Valerie (Committee member) / Boddy, Amy (Committee member) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
For the past couple decades, there has been a continuous rise in obesity and Type II Diabetes which has been attributed to the rise in calorically dense diets, especially those heavy in fats. Because of its rising prevalence, accompanied health concerns, and high healthcare costs, detection and therapies for these metabolic diseases are in high demand. Insulin resistance is a typical hallmark of Type II Diabetes and the metabolic deficiencies in obesity and is the main focus of this project. The primary purpose of this study is (1) detect the presence of two types of insulin resistance (peripheral and hepatic) as a function of age, (2) distinguish if diet impacted the presence of insulin resistance, and (3) determine both the short-term and long-term effects of caloric restriction on metabolic health. The following study longitudinally observed the changes in insulin resistance in high-fat fed and low-fat fed rodents under ad libitum and caloric restriction conditions over the course of 23 weeks. Fasting blood glucose, fasting insulin, body weight, and sensitivity of insulin on tissue were monitored in order to determine peripheral and hepatic insulin resistance. A high fat diet resulted in higher body weights and higher hepatic insulin resistance with no notable effect on peripheral insulin resistance. Caloric restriction was found to alleviate insulin resistance both during caloric restriction and four weeks after caloric restriction ended. Due to sample size, the generalizability of the findings in this study are limited. However, the current study did provide considerable results and can be viewed as a pilot study for a larger-scale study.
ContributorsZuo, Dana (Author) / Trumble, Benjamin (Thesis director) / Herman, Richard (Committee member) / Department of Psychology (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The understanding of normal human physiology and disease pathogenesis shows great promise for progress with increasing ability to profile genomic loci and transcripts in single cells in situ. Using biorthogonal cleavable fluorescent oligonucleotides, a highly multiplexed single-cell in situ RNA and DNA analysis is reported. In this report, azide-based cleavable linker connects oligonucleotides to fluorophores to show nucleic acids through in situ hybridization. Post-imaging, the fluorophores are effectively cleaved off in half an hour without loss of RNA or DNA integrity. Through multiple cycles of hybridization, imaging, and cleavage this approach proves to quantify thousands of different RNA species or genomic loci because of single-molecule sensitivity in single cells in situ. Different nucleic acids can be imaged by shown by multi-color staining in each hybridization cycle, and that multiple hybridization cycles can be run on the same specimen. It is shown that in situ analysis of DNA, RNA and protein can be accomplished using both cleavable fluorescent antibodies and oligonucleotides. The highly multiplexed imaging platforms will have the potential for wide applications in both systems biology and biomedical research. Thus, proving to be cost effective and time effective.
ContributorsSamuel, Adam David (Author) / Guo, Jia (Thesis director) / Liu, Wei (Committee member) / Wang, Xu (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
While specific resistance mechanisms to targeted inhibitors in BRAF-mutant cutaneous melanoma have been identified, surprisingly little is known about the rate at which resistance develops under different treatment options. There is increasing evidence that resistance arises from pre-existing clones rather than from de novo mutations, but there remains the need for a better understanding of how different drugs affect the fitness of clones within a tumor population and promote or delay the emergence of resistance. To this end, we have developed an assay that defines the in vitro rate of adaptation by analyzing the progressive change in sensitivity of a melanoma cell line to different treatments. We performed a proof-of-theory experiment based on the hypothesis that drugs that cause cell death (cytotoxic) impose a higher selection pressure for drug-resistant clones than drugs that cause cell-cycle arrest (cytostatic drugs), thereby resulting in a faster rate of adaptation. We tested this hypothesis by continuously treating the BRAFV600E melanoma cell line A375 with the cytotoxic MEK inhibitor E6201 and the cytostatic MEK inhibitor trametinib, both of which are known to be effective in the setting of constitutive oncogenic signaling driven by the BRAF mutation. While the identification of confounding factors prevented the direct comparison between E6201-treated and trametinib-treated cells, we observed that E6201-treated cells demonstrate decreased drug sensitivity compared to vehicle-treated cells as early as 18 days after treatment begins. We were able to quantify this rate of divergence at 2.6% per passage by measuring the increase over time in average viability difference between drug-treated and vehicle-treated cells within a DDR analysis. We argue that this value correlates to the rate of adaptation. Furthermore, this study includes efforts to establish a barcoded cell line to allow for individual clonal tracking and efforts to identify synergistic and antagonist drug combinations for use in future experiments. Ultimately, we describe here a novel system capable of quantifying adaptation rate in cancer cells undergoing treatment, and we anticipate that this assay will prove helpful in identifying treatment options that circumvent or delay resistance through future hypothesis-driven experiments.
ContributorsDe Luca, Valerie Jean (Author) / Wilson Sayres, Melissa (Thesis director) / Trent, Jeff (Committee member) / Hendricks, William (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Tremendous phenotypic variation exists across people with Turner syndrome (45,X). This variation likely stems from differential dosage of genes on the X chromosome. X-inactivation is the process whereby all X chromosomes in excess of one are silenced. However, about 15% of the genes on the silenced X chromosome escape this inactivation and are candidates for affecting phenotype in people with Turner syndrome. In this study we take an evolutionary approach to rank candidate genes that may contribute to phenotypic variation among people with Turner Syndrome. We incorporate analysis of patterns of DNA methylation from 46,XX and 45,X individuals, and estimates of variable X-inactivation status across 46,XX individuals, with patterns of gene expression conservation on the X chromosomes across five tissues and ten species. We find that genes that escape XCI are possible candidate genes for Turner syndrome phenotype, indicated by the constant levels of expression in escape genes and inactivated genes. Variation in these genes is expected to affect phenotype when dosage is altered from typical levels.
ContributorsSchaffer, Kara Nina (Author) / Wilson Sayres, Melissa (Thesis director) / Crook, Sharon (Committee member) / Narang, Pooja (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2015-12
Description
Current studies in Multiple Myeloma suggest that patient tumors and cell lines cluster separately based on gene expression profiles. Hyperdiploid patients are also extremely underrepresented in established human myeloma cell lines (HMCLs). This suggests that the average HMCL model system does not accurately represent the average myeloma patient. To investigate this question we performed a combined CNA and SNV evolutionary comparison between four myeloma tumors and their established HMCLs (JMW-1, VP-6, KAS-6/1-KAS-6/2 and KP-6). We identified copy number changes shared between the tumors and their cell lines (mean of 74 events - 59%), those unique to patients (mean of 21.25 events - 17%), and those only in the cell lines (mean of 30.75 events \u2014 24%). A relapse sample from the JMW-1 patient showed 58% similarity to the primary diagnostic tumor. These data suggest that, on the level of copy number abnormalities, HMCLs show equal levels of evolutionary divergence as that observed within patients. By exome sequencing, patient tumors were 71% similar to their representative HMCLs, with ~12.5% and ~16.5% of SNVs unique to the tumors and HMCLs respectively. The HMCLs studied appear highly representative of the patient from which they were derived, with most differences associated with an enrichment of sub-populations present in the primary tumor. Additionally, our analysis of the KP-6 aCGH data showed that the patient's hyperdiploid karyotype was maintained in its respective HMCL. This discovery confirms the establishment and validation of a novel and potentially clinically relevant hyperdiploid HMCL that could provide a major advance in our ability to understand the pathogenesis and progression of this prominent patient population.
ContributorsBenard, Brooks Avery (Author) / Keats, Jonathan (Thesis director) / Anderson, Karen (Committee member) / Jelinek, Diane (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
One of the largest problems facing modern medicine is drug resistance. Many classes of drugs can be rendered ineffective if their target is able to acquire beneficial mutations. While this is an excellent showcase of the power of evolution, it necessitates the development of increasingly stronger drugs to combat resistant pathogens. Not only is this strategy costly and time consuming, it is also unsustainable. To contend with this problem, many multi-drug treatment strategies are being explored. Previous studies have shown that resistance to some drug combinations is not possible, for example, resistance to a common antifungal drug, fluconazole, seems impossible in the presence of radicicol. We believe that in order to understand the viability of multi-drug strategies in combating drug resistance, we must understand the full spectrum of resistance mutations that an organism can develop, not just the most common ones. It is possible that rare mutations exist that are resistant to both drugs. Knowing the frequency of such mutations is important for making predictions about how problematic they will be when multi-drug strategies are used to treat human disease. This experiment aims to expand on previous research on the evolution of drug resistance in S. cerevisiae by using molecular barcodes to track ~100,000 evolving lineages simultaneously. The barcoded cells were evolved with serial transfers for seven weeks (200 generations) in three concentrations of the antifungal Fluconazole, three concentrations of the Hsp90 inhibitor Radicicol, and in four combinations of Fluconazole and Radicicol. Sequencing data was used to track barcode frequencies over the course of the evolution, allowing us to observe resistant lineages as they rise and quantify differences in resistance evolution across the different conditions. We were able to successfully observe over 100,000 replicates simultaneously, revealing many adaptive lineages in all conditions. Our results also show clear differences across drug concentrations and combinations, with the highest drug concentrations exhibiting distinct behaviors.
ContributorsApodaca, Samuel (Author) / Geiler-Samerotte, Kerry (Thesis director) / Schmidlin, Kara (Committee member) / Huijben, Silvie (Committee member) / School of Life Sciences (Contributor) / School of Molecular Sciences (Contributor) / School of Politics and Global Studies (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Cancer rates vary between people, between cultures, and between tissue types, driven by clinically relevant distinctions in the risk factors that lead to different cancer types. Despite the importance of cancer location in human health, little is known about tissue-specific cancers in non-human animals. We can gain significant insight into how evolutionary history has shaped mechanisms of cancer suppression by examining how life history traits impact cancer susceptibility across species. Here, we perform multi-level analysis to test how species-level life history strategies are associated with differences in neoplasia prevalence, and apply this to mammary neoplasia within mammals. We propose that the same patterns of cancer prevalence that have been reported across species will be maintained at the tissue-specific level. We used a combination of factor analysis and phylogenetic regression on 13 life history traits across 90 mammalian species to determine the correlation between a life history trait and how it relates to mammary neoplasia prevalence. The factor analysis presented ways to calculate quantifiable underlying factors that contribute to covariance of entangled life history variables. A greater risk of mammary neoplasia was found to be correlated most significantly with shorter gestation length. With this analysis, a framework is provided for how different life history modalities can influence cancer vulnerability. Additionally, statistical methods developed for this project present a framework for future comparative oncology studies and have the potential for many diverse applications.
ContributorsFox, Morgan Shane (Author) / Maley, Carlo C. (Thesis director) / Boddy, Amy (Committee member) / Compton, Zachary (Committee member) / School of Mathematical and Statistical Sciences (Contributor) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Background.
Type 2 Diabetes Mellitus (T2DM) is a leading cause of health disparities, among Hispanic populations, which are disproportionately afflicted by T2DM. The growing research strongly argues that diabetes treatment interventions should be culturally sensitive to address the needs of their target populations. Nonetheless, there is little consensus regarding the necessary components of a culturally sensitive intervention. This review will examine the intervention contents and activities, and the strategies that have been implemented into culturally sensitive diabetes treatment interventions. This review will also to observe how interventions handle complex issues such as the heterogeneity of Hispanic populations and communities. The overarching research questions examined in this study were, “What are the core components of the culturally tailored diabetes interventions currently implemented with Hispanic populations in the US, and why are they needed?” and 2) “How are studies evaluating the impact of their interventions, and how can the proposed study designs be improved?”
Method.
A systematic review across 3 databases was used to identify culturally sensitive diabetes treatment interventions (CSDTI) developed for Hispanic populations. Accordingly, we searched for studies designed to treat Hispanic individuals already diagnosed with having T2DM. All identified studies provided information on the core components of these culturally sensitive interventions, while only studies that included a control or comparison group were used to assess how the studies evaluated outcomes.
Results.
First, we examined intervention effects as examined from two study designs. We examined a total of [17] interventions in this section. Our review of one study design (Design #1 Studies) includes 12 studies that developed a culturally sensitive intervention and evaluated it using a one-group pretest posttest design, or did not evaluate their intervention at all. A second study design (Design #2 Studies) includes 5 studies. These consisted of a two-group randomized controlled field study that conducted pre-post analyses of the culturally adapted intervention comparing it against a control or comparison group. The heterogeneity of all studies made a conventional meta-analysis impossible.
Second, another review section focused on examining and describing various culturally sensitive core components, we examined a total of 17 studies to describe the types of culturally sensitive components that were incorporated into the diabetes treatment intervention. This analysis resulted in a list of 11 general types of culturally sensitive components as included within these 17 interventions. Of the articles that used control or comparison groups, the manner in which interventions evaluated different outcome measures and their conclusions regarding success were examined.
Discussion.
The culturally sensitive aspects identified from these articles were used to address diverse issues that included: (a) communication barriers, (b) the inclusion of cultural relevant content, for relevance to Hispanic/Latinx patients’ lives, (c) selecting appropriate channels and settings for interventions, and (d) addressing specific cultural values, traditions, and beliefs that can either help or hinder healthy behaviors. It should be noted that the Hispanic populations are extremely heterogeneous, and so interventions that would be sensitive culturally to some sectors of a Hispanic community may not be sensitive to other Hispanic sectors of that same community. The issue of heterogeneity of Hispanic communities was addressed well by the authors of some articles and ignored by others.
Conclusions.
It was ultimately impossible draw quantitative conclusions regarding the efficacy or effectiveness of these two types of diabetes treatment interventions (CSDTIs) as delivered to their targeted sample of Hispanic participants. An emerging conclusion is that factors including ethics, cost, and lack of community acceptance, may constitute factors contributing to the higher proportion of one-group pre-test post-test designs and lower proportion of rigorous scientific designs. In the latter case, some communities oppose the use of randomized controlled studies within their community, and thus that objection may explain the low numbers of these randomized controlled studies. The use of viable and rigorous alternatives to RCTs have been proposed to address this community concern. In this review, the author sought to conduct comparative studies between culturally adapted interventions and their associated unaltered or minimally altered evidence-based interventions, although there exists various difficulties that are associated with the conduct of these analyses.
Core components of CSDTIs for Hispanic adults were identified, and their purposes were explained. Additionally, suggestions for improvement to studies were made, to aid in improving our knowledge of CSDTIs through future studies.
Type 2 Diabetes Mellitus (T2DM) is a leading cause of health disparities, among Hispanic populations, which are disproportionately afflicted by T2DM. The growing research strongly argues that diabetes treatment interventions should be culturally sensitive to address the needs of their target populations. Nonetheless, there is little consensus regarding the necessary components of a culturally sensitive intervention. This review will examine the intervention contents and activities, and the strategies that have been implemented into culturally sensitive diabetes treatment interventions. This review will also to observe how interventions handle complex issues such as the heterogeneity of Hispanic populations and communities. The overarching research questions examined in this study were, “What are the core components of the culturally tailored diabetes interventions currently implemented with Hispanic populations in the US, and why are they needed?” and 2) “How are studies evaluating the impact of their interventions, and how can the proposed study designs be improved?”
Method.
A systematic review across 3 databases was used to identify culturally sensitive diabetes treatment interventions (CSDTI) developed for Hispanic populations. Accordingly, we searched for studies designed to treat Hispanic individuals already diagnosed with having T2DM. All identified studies provided information on the core components of these culturally sensitive interventions, while only studies that included a control or comparison group were used to assess how the studies evaluated outcomes.
Results.
First, we examined intervention effects as examined from two study designs. We examined a total of [17] interventions in this section. Our review of one study design (Design #1 Studies) includes 12 studies that developed a culturally sensitive intervention and evaluated it using a one-group pretest posttest design, or did not evaluate their intervention at all. A second study design (Design #2 Studies) includes 5 studies. These consisted of a two-group randomized controlled field study that conducted pre-post analyses of the culturally adapted intervention comparing it against a control or comparison group. The heterogeneity of all studies made a conventional meta-analysis impossible.
Second, another review section focused on examining and describing various culturally sensitive core components, we examined a total of 17 studies to describe the types of culturally sensitive components that were incorporated into the diabetes treatment intervention. This analysis resulted in a list of 11 general types of culturally sensitive components as included within these 17 interventions. Of the articles that used control or comparison groups, the manner in which interventions evaluated different outcome measures and their conclusions regarding success were examined.
Discussion.
The culturally sensitive aspects identified from these articles were used to address diverse issues that included: (a) communication barriers, (b) the inclusion of cultural relevant content, for relevance to Hispanic/Latinx patients’ lives, (c) selecting appropriate channels and settings for interventions, and (d) addressing specific cultural values, traditions, and beliefs that can either help or hinder healthy behaviors. It should be noted that the Hispanic populations are extremely heterogeneous, and so interventions that would be sensitive culturally to some sectors of a Hispanic community may not be sensitive to other Hispanic sectors of that same community. The issue of heterogeneity of Hispanic communities was addressed well by the authors of some articles and ignored by others.
Conclusions.
It was ultimately impossible draw quantitative conclusions regarding the efficacy or effectiveness of these two types of diabetes treatment interventions (CSDTIs) as delivered to their targeted sample of Hispanic participants. An emerging conclusion is that factors including ethics, cost, and lack of community acceptance, may constitute factors contributing to the higher proportion of one-group pre-test post-test designs and lower proportion of rigorous scientific designs. In the latter case, some communities oppose the use of randomized controlled studies within their community, and thus that objection may explain the low numbers of these randomized controlled studies. The use of viable and rigorous alternatives to RCTs have been proposed to address this community concern. In this review, the author sought to conduct comparative studies between culturally adapted interventions and their associated unaltered or minimally altered evidence-based interventions, although there exists various difficulties that are associated with the conduct of these analyses.
Core components of CSDTIs for Hispanic adults were identified, and their purposes were explained. Additionally, suggestions for improvement to studies were made, to aid in improving our knowledge of CSDTIs through future studies.
ContributorsDilli, Christopher Joe (Author) / Castro, Felipe Gonzalez (Thesis director) / Shaibi, Gabriel (Committee member) / School of Molecular Sciences (Contributor) / School of International Letters and Cultures (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05