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Analysis Of The Therapeutic Mechanism Of Action Induced By Selective Activation Of Trβ In Anaplastic Thyroid Cancer
No full textThyroid cancer is the most common endocrine cancer. Papillary thyroid cancer (PTC) is the most common with generally a very good prognosis although treatment resistance and variants also occur. Follicular thyroid cancer (FTC) is less common yet like PTC, FTC is differentiated and has a good therapeutic response. Anaplastic thyroid cancer (ATC) is the most lethal endocrine cancer with no enduring treatments. ATC, which is undifferentiated, accounts for approximately 14-39% of deaths associated with thyroid cancer. ATC has poor prognosis with a survival of less than 9 months from diagnosis, thus urgently needing more combinations of targeted therapies. Two most abundant thyroid hormone receptor (TR) isoforms, TRα and TRβ, are nuclear receptors that mediate thyroid hormone action, activating different signaling pathways to regulate critical physiological processes. The natural ligand of TRs (3,5,3’-triiodo-L-thyronine, T3), acts on both isoforms. While the role of TRα in cancer development is not well defined, it is now well recognized that the nuclear transcription factor TRβ has tumor suppressing effect in thyroid, breast, and other cancers, with preliminary studies establishing that Sobetirome (or GC-1), a TRβ selective agonist, has the potential to alter tumorigenic phenotypes and inhibit tumor growth. It is hypothesized that modifying TRβ gene regulation will induce specific important physiological changes and reveal GC-1 mechanisms of action on ATC cells. The aim of this project is to conduct an integrated analysis of the therapeutic mechanism of action induced by selective activation of TRβ in both normal thyroid cells and aggressive thyroid cancer cells, through characterization of agonist-induced gene regulatory network and gene differential expression using RNA-seq, and how TRβ agonism affects chromatin accessibility using ATACseq. The results of these studies unveiled previously unknown additional tumor suppressors, upregulated by selective TRβ activation. Certain genes, such as TNFRSF9 and IGFBP4, have been shown to possess anti-tumor and apoptosis-enhancing effect in other cancer types. Transcription factor analysis of publicly available RNA-seq data from thyroid cancer patient tissues, using decoupleR, identified several novel transcription factors, associated with TRβ-mediated chromatin accessibility, including SP1 and the Krüppel-like factor family, which has been potentially linked with more aggressive thyroid cancer phenotypes. All of these bioinformatic analysis provide exploratory groundwork for future experiments that would validate these genes and transcription factors, before investigating their potential as therapeutic targets for anaplastic thyroid cancers.PharmacologyMaster of Science (MS
Valuing Traditional Seed Systems: Farmer seed saving provides critical “evosystem services”
No full textProfessionally-bred crops are dependent upon external inputs of fertilizers, pesticides, and irrigation, but less resistant to drought, pests, and nutrient deficiencies. Although breeders depend upon landraces to introduce the genetic diversity needed to increase stress tolerance in commercial crop varieties, the traditional seed systems that produce landraces urgently need support. Our future food supply depends upon a diversity of crop varieties that can grow under a wide range of environmental conditions with minimal inputs. Farmer-led traditional seed systems provide evosystem services that are essential for the security and diversity of the globe’s current and future seed supply. Agricultural evosystem services are the societal benefits derived from small-scale farmer seed saving. Small-scale farmers who save seeds and engage in farmer-to-farmer exchange provide critical evosystem services necessary to adapt food production to a rapidly changing climate. Currently, seed saving is declining at an alarming rate due to inadequate policy support for traditional seed systems. Effective access, investment, and benefit-sharing mechanisms are essential to ensure that farmers can continue managing crops to adapt to environmental changes as well as provide sources for future formal seed systems
Combinative Strategy To Advance Target-Based Anticryptosporidial Drug Discovery.
No full textCryptosporidiosis is a prevalent diarrheal disease characterized by infection of the small intestine by apicomplexan Cryptosporidium parasites. These intestinal parasites effectuate life-threatening diarrhea in young children and immunocompromised patients such as those on long-term immunosuppressants, or people living with HIV/AIDS. There are presently no vaccines to prevent cryptosporidiosis in humans. Unfortunately, the only FDA-approved treatment, nitazoxanide, lacks efficacy in immunocompromised patients but shows moderate efficacy in children, populations in which cryptosporidiosis is most severe and persistent. To engage the obvious paucity in the availability of novel anti-Cryptosporidium therapeutics, large-scale phenotypic screenings of compounds made available by Merck KGaA, Darmstadt, Germany, led to the identification of pyrazolopyrimidine human phosphodiesterase (PDE)-V (hsPDE-V) and 1,5-naphthyridine phosphatidylinositol-4 kinase (PI4K) inhibitors with potent in vitro anticryptosporidial characteristics and in vivo efficacy following oral administration in C. parvum-infected immunocompromised mouse models of cryptosporidiosis. The lead phosphodiesterase inhibitor (PDEi) and phosphatidylinositol-4-kinase inhibitor (PI4Ki) series showed comparable anti-C. parvum and C. hominis potency, are fast-acting in tissue culture, and have minimal off-target effects in a preliminary safety screening assay panel. Our main objective was to validate the molecular targets of the novel PDEis and PI4Kis lead series in Cryptosporidium. By extension, we sought to uncover the mode-of-action of these novel lead series in C. parvum and highlight important target-based strategies that can be exploited for drug target identification in anticryptosporidial drug discovery. We demonstrated the mode-of-action of the lead series by employing life-cycle phenotypic assays which identified the parasite egress stage as the key life stage blocked by the PDEi and PI4Ki series. Subsequently, we utilized in vitro enzyme assays to confirm on-target engagement of our lead PDEis and PI4Kis against recombinant CpPDE1/CpPDE3 and CpPI4K enzymes, respectively. Guided by in silico analyses, we identified two residues (Val900 and His884) in the CpPDE1 active site predicted to be important for pyrazolopyrimidine PDEi binding. We produced a CRISPR-engineered C. parvum CpPDE1-V900A transgenic strain which exhibited altered susceptibility to our lead PDEi series, providing genetic support for CpPDE1-pyrazolopyrimidine PDEi interaction. Our findings suggest that CpPDE1, a validated pyrazolopyrimidine molecular target, can be exploited for target-based lead optimization in our anticryptosporidial drug development scheme. Furthermore, to genetically validate CpPI4K as a molecular target of the novel naphthyridine PI4Ki lead series, we overexpressed the wild-type CpPI4K gene in wild-type C. parvum to confirm the development of a resistance phenotype in the CpPI4K over-expressing transgenic strain. The expression of an additional copy of the wild-type CpPI4K gene conferred a moderate resistance phenotype in the presence of a naphthyridine PI4Ki and a separate imidazopyrazine PI4Ki by about 3-fold. These results provide compelling evidence that CpPI4K is a molecular target of the imidazopyrazine and novel naphthyridine PI4Ki lead series. In summary, we have identified and validated CpPI4K and CpPDE1 as molecular targets of our PI4Ki and PDEi lead series, respectively. Our target identification efforts on CpPDE1 marks the first characterization of the CpPDE1 as a druggable target in C. parvum. Meanwhile, our genetic validation of CpPI4K druggability will build on existing research in the anti-Cryptosporidium drug discovery field. Collectively, the results from this work will inform medicinal chemistry lead optimization efforts to advance anticryptosporidial drug development.Cellular, Molecular and Biomedical SciencesDoctor of Philosophy (PhD
The fossil record of Vermont: What we can learn from the cataloguing efforts of the Vermont fossil record?
No full textUndergraduateThis poster presentation explores the work done by myself, combined with previous data collected by other interns working within the Geology/Paleontology collections in Delehanty Hall. This presentation focuses on what conclusions and observations can be made about the fossils from Vermont that have been catalogued so far in the extensive cataloguing process. A map aims to show the geographic and temporal distribution of fossils throughout the state of Vermont, and observations on the prevalence of certain species. Participation in this student research conference is required as part of the curriculum of BIOL3991B, Advanced Natural History Collections Internship
Transformer Temperature Management and Voltage Control in Electric Distribution Systems with High Solar PV Penetration
No full textThe increasing penetration of photovoltaic (PV) systems in distribution grids can lead to overvoltage and transformer overloading issues. While voltage regulation has been extensively studied and some research has addressed transformer temperature control, there is limited work on simultaneously managing both challenges. This thesis ad dresses this gap by proposing an optimization-based strategy that efficiently manages voltage regulation and transformer temperature while minimizing the curtailment of PV generation. In order to make this problem convex, a relaxation is applied to the transformer temperature dynamics constraint. We also provide analysis to determine under which conditions this relaxation remains tight. The proposed approach is val idated through simulations, demonstrating its effectiveness in achieving the desired control objectives.Electrical EngineeringMaster of Science (MS
The Last Director
No full textARRAY(0x5d004ea214d0)This article will highlight the personal narrative of the author’s final months as the Director of Multicultural Affairs as their institution began to comply and implement Anti-DEI policies and shutter cultural centers. The narrative explores the author’s initial feelings of hopelessness while highlighting the community presence and support that will remain in the face of these policies Throughout this article, the author provides an exploration of the impact of these policies on student sense of belonging as well as their potential identity development throughout their college experience while also exemplifying the importance of Cultural Centers and DEI-focused staff and spaces
Greenhouse Gas Emissions from Agricultural Soils are Shaped by Management and Topography in a Changing Climate
No full textAgricultural soils are sources of nitrous oxide (N2O) and methane (CH4), two potentgreenhouse gases (GHG). Soil management practices, topographic position, and environmental factors can influence the magnitude of GHG emissions, yet few studies have investigated how these factors interact. Because soil conditions vary across topographic gradients and extreme weather events are becoming more frequent, interactions among management, landscape position, and climate may amplify or mitigate GHG emissions. This thesis investigates how agricultural soil management practices and topographic variation influence N2O and CH4 emissions in both field conditions and a controlled laboratory setting. In Chapter One, we conducted a 17-month study across a 21-hectare corn silage field in Vermont, measuring GHG emissions, inorganic nitrogen availability, and environmental conditions across three different management systems (business-as-usual, a soil health management system, and a novel manure- derived amendment). Each treatment contained topographically high and low plots. We found that emissions varied strongly by topography, with low-lying areas consistently producing greater N2O and CH4 emissions, especially in the soil health management system. These patterns were driven primarily by increased soil moisture, inorganic nitrogen, and labile carbon in low areas. In Chapter Two, we conducted a 40-day incubation where we applied identical soil moisture treatments to intact soil cores collected from topographically high and low plots, removing soil moisture as the differentiating factor between these positions. GHGs were measured every other day and inorganic nitrogen was extracted from soil samples at the start and end of the experiment. In contrast to the field results, high topography soils emitted substantially more N2O and CH4 under all moisture regimes. These soils also had higher inorganic nitrogen and microbial respiration rates, suggesting that available nutrient status and microbial communities strongly influenced emissions. Together, these studies demonstrate that soil moisture is a key environmental trigger for GHG emissions in the field, but that underlying soil properties shaped by topography and management determine the magnitude and trajectory of those emissions. This thesis advances our understanding of how N2O and CH4 emission behave under field and controlled conditions, and highlights the importance of considering spatial variability and hydrologic context when evaluating the climate impacts of agricultural management practices.Natural ResourcesMaster of Science (MS
Effect of Nozzle Translation on a Bounded Vortex Flow Field and Particle Removal from a Surface
No full textA bounded vortex flow is a hydrodynamic approach for removing particles from a surface without scattering them onto nearby surfaces. This flow is generated by a nozzle that combines azimuthally tilted downward jets in a circular array located about a central suction port. When the nozzle is directed toward a flat surface (called the impingement surface), a strong wall-normal intake vortex below the suction outlet is observed to develop, which generates a strong shear stress on the surface. This shear stress acts to remove particles adhered to the impingement surface, along with enhancement of heat or mass transfer. In a typical cleaning scenario, the nozzle would translate above the impingement surface to remove particulates over a region. This thesis first presents a computational study of the effects of nozzle translation on the bounded vortex flow field. The translation of the nozzle induces a bending of the vortex in the downstream direction, where the vortex bending increases as translation speed rises. An oscillatory motion was observed where the bounded vortex resists the induced bending and rotates about a mean position on the impingement surface downstream of the suction port. At sufficiently large translation speeds, a bifurcation occurs beyond which the vortex cannot sustain the oscillatory state and instead flows into the nozzle wake. In this latter state, the vortex detaches from the impingement surface and is carried downstream, effectively limiting the particle removal effectiveness of the device. In addition to the computational study of the bounded vortex flow field subject to nozzle translation, an experimental study was conducted to examine the effectiveness of the bounded vortex flow device for particle removal from a surface in the presence of nozzle translation along the surface. The cleaning effectiveness was analyzed as a function of flow rate through the nozzle, particle size, and nozzle translation velocity relative to the impingement surface. To complement these experiments on particle mitigation, numerical computations of the flow field were used to obtain a relationship between nozzle flow rate and maximum shear stress on the impingement surface. This shear stress is then used to theoretically predict the onset of particle motion. The combined computational and experimental findings provide insights into optimizing the bounded vortex flow for applications in surface cleaning and heat transfer enhancement, where the nozzle would move relative to a surface.Mechanical EngineeringMaster of Science (MS
Anticholinergic Burden in New Milford
No full textPatients in New Milford, Connecticut routinely report frequent use of prescription and over-the-counter medications that carry anticholinergic properties. Several of these medications have anticholinergic effects as a side effect and not as the primary drug class. A pamphlet was created using simple language and large text to provide accessible patient education to the population in New Milford that is at risk for adverse effects of common drugs that carry anticholinergic burdens
Comparison of the PHQ-9 and GDS-5 by Older Adult Patients in Middlebury, Vermont
No full textThis project examines the perspectives of older adult patients who provided their opinions on preference between the Public Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale-5 (GDS-5). Twenty three patients aged sixty-five and older participated in the study, and sixteen of the twenty-three preferred the GDS-5. Reasons for this preference included ease of use, brevity, and being able to answer with "yes" or "no" rather than a Likert scale. These results point to a potential solution that screens older adults for depression while reducing their overall paperwork burden