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Effect of Rexinoids on Inducing Effector T Cell Chemotaxis

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The retinoid-X receptor (RXR) can form heterodimers with both the retinoic-acid
receptor (RAR) and vitamin D receptor (VDR). The RXR/RAR dimer is activated by ligand all
trans retinoic acid (ATRA), which culminates in gut-specific effector T cell migration. Similarly,

The retinoid-X receptor (RXR) can form heterodimers with both the retinoic-acid
receptor (RAR) and vitamin D receptor (VDR). The RXR/RAR dimer is activated by ligand all
trans retinoic acid (ATRA), which culminates in gut-specific effector T cell migration. Similarly,
the VDR/RXR dimer binds 1,25(OH)2D3 to cause skin-specific effector T cell migration.
Targeted migration is a potent addition to current vaccines, as it would induce activated T cell
trafficking to appropriate areas of the immune system and ensure optimal stimulation (40).
ATRA, while in use clinically, is limited by toxicity and chemical instability. Rexinoids
are stable, synthetically developed ligands specific for the RXR. We have previously shown that
select rexinoids can enhance upregulation of gut tropic CCR9 receptors on effector T cells.
However, it is important to establish whether these cells can actually migrate, to show the
potential of rexinoids as vaccine adjuvants that can cause gut specific T cell migration.
Additionally, since the RXR is a major contributor to VDR-mediated transcription and
epidermotropism (15), it is worth investigating whether these compounds can also function as
adjuvants that promote migration by increasing expression of skin tropic CCR10 receptors on T
cells.
Prior experiments have demonstrated that select rexinoids can induce gut tropic migration
of CD8+ T cells in an in vitro assay and are comparable in effectiveness to ATRA (7). The effect
of rexinoids on CD4+ T cells is unknown however, so the aim of this project was to determine if
rexinoids can cause gut tropic migration in CD4+ T cells to a similar extent. A secondary aim
was to investigate whether varying concentrations in 1,25-Dihydroxyvitamin D3 can be linked to
increasing CCR10 upregulation on Jurkat CD4+ T cells, with the future aim to combine 1,25
Dihydroxyvitamin D3 with rexinoids.
These hypotheses were tested using murine splenocytes for the migration experiment, and
human Jurkat CD4+ T cells for the vitamin D experiment. Migration was assessed using a
Transwell chemotaxis assay. Our findings support the potential of rexinoids as compounds
capable of causing gut-tropic migration in murine CD4+ T cells in vitro, like ATRA. We did not
observe conclusive evidence that vitamin D3 causes upregulated CCR10 expression, but this
experiment must be repeated with a human primary T cell line.

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2020-05

Human Physiological Adaptations to Starvation and Caloric Restriction

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Throughout history humans have had to adapt to changing conditions in order to survive. Food shortages are one of the major pressures that have shaped past populations. Because of this, the human body has many physiological adaptations that allow

Throughout history humans have had to adapt to changing conditions in order to survive. Food shortages are one of the major pressures that have shaped past populations. Because of this, the human body has many physiological adaptations that allow it to go extended periods of time consuming little to no food. These adaptations also allow the body to recover quickly once food becomes available. They include changes in metabolism that allow different fuel sources to be used for energy, the storing of excess energy absorbed from food in the forms of glycogen and fat to be used in between meals, and a reduction in the basal metabolic rate in response to starvation, as well as physiological changes in the small intestines. Even in places where starvation is not a concern today, these adaptations are still important as they also have an effect on weight gain and dieting in addition to promoting survival when the body is in a starved state.

Disclaimer: The initial goal of this project was to present this information as a podcast episode as a part of a series aimed at teaching the general public about human physiological adaptations. Due to the circumstances with COVID-19 we were unable to meet to make a final recording of the podcast episode. A recording of a practice session recorded earlier in the year has been uploaded instead and is therefore only a rough draft.

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2020-05

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Precarious Fauna: An Art Exhibition

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Human nature drives us to focus primarily on the present or near-future, instead of considering what consequences our actions may have many years from now. However, in a new era that is increasingly dominated by humans and their ambitions, this

Human nature drives us to focus primarily on the present or near-future, instead of considering what consequences our actions may have many years from now. However, in a new era that is increasingly dominated by humans and their ambitions, this tendency has destructive repercussions on the very environment that once supported and nurtured humankind. Wild animals are highly susceptible to human activities that damage ecosystems, and a loss of animal diversity can have unforeseen consequences on future human populations. In the research, I examine the avoidable reasons for the severe decline in population of four animal species, and through my art, imagine the losses associated with their disappearance. The artwork created evokes an emotional response in the viewer through dramatic, contrasting imagery, making them reassess the relationship between humans, animals and the environment.

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2018-05

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Utilizing Confocal Laser Scanning Microscopy to Visualize Origami Nanostructure Transfection in Primary Immune Cells

Description

An aim of fundamental immunology is quantifying the diversity of the T cell receptor (TCR) repertoire to elucidate the vast recognition by T cells for protection against pathogen and cancer. The utilization of DNA origami nanostructures engineered to capture single

An aim of fundamental immunology is quantifying the diversity of the T cell receptor (TCR) repertoire to elucidate the vast recognition by T cells for protection against pathogen and cancer. The utilization of DNA origami nanostructures engineered to capture single cell paired TCR mRNA sequences has transformed the financial and time requirements of repertoire establishment. To further support this protocol, confocal laser scanning microscopy was implemented following transfection to visualize the stability of the DNA origami within primary immune lymphocytes.

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2018-05

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CXCL10-Induced Migration of Triple-Negative Breast Cancer Cells

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Inhibitor of growth factor 4 (ING4) is a tumor suppressor of which low expression has been associated with poor patient survival and aggressive tumor progression in breast cancer. ING4 is characterized as a transcription regulator of inflammatory genes. Among the

Inhibitor of growth factor 4 (ING4) is a tumor suppressor of which low expression has been associated with poor patient survival and aggressive tumor progression in breast cancer. ING4 is characterized as a transcription regulator of inflammatory genes. Among the ING4-regulated genes is CXCL10, a chemokine secreted by endothelial cells during normal inflammation response, which induces chemotactic migration of immune cells to the site. High expression of CXCL10 has been implicated in aggressive breast cancer, but the mechanism is not well understood. A potential signaling molecule downstream of Cxcl10 is Janus Kinase 2 (Jak2), a kinase activated in normal immune response. Deregulation of Jak2 is associated with metastasis, immune evasion, and tumor progression in breast cancer. Thus, we hypothesized that the Ing4/Cxcl10/Jak2 axis plays a key role in breast cancer progression. We first investigated whether Cxcl10 affected breast cancer cell migration. We also investigated whether Cxcl10-mediated migration is dependent on ING4 expression levels. We utilized genetically engineered MDAmb231 breast cancer cells with a CRISPR/Cas9 ING4-knockout construct or a viral ING4 overexpression construct. We performed Western blot analysis to confirm Ing4 expression. Cell migration was assessed using Boyden Chamber assay with or without exogenous Cxcl10 treatment. The results showed that in the presence of Cxcl10, ING4-deficient cells had a two-fold increase in migration as compared to the vector controls, suggesting Ing4 inhibits Cxcl10-induced migration. These findings support our hypothesis that ING4-deficient tumor cells have increased migration when Cxcl10 signaling is present in breast cancer. These results implicate Ing4 is a key regulator of a chemokine-induced tumor migration. Our future plan includes evaluation of Jak2 as an intermediate signaling molecule in Cxcl10/Ing4 pathway. Therapeutic implications of these findings are targeting Cxcl10 and/or Jak2 may be effective in treating ING4-deficient aggressive breast cancer.

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2019-05

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Cloning and expression of antigen-specific T cell receptors

Description

Cancer poses a significant burden on the global health system and represents a leading cause of death worldwide. For late-stage cancers, the traditional treatments of chemotherapy, radiation, and surgery are not always viable, and they can pose unnecessary health risks

Cancer poses a significant burden on the global health system and represents a leading cause of death worldwide. For late-stage cancers, the traditional treatments of chemotherapy, radiation, and surgery are not always viable, and they can pose unnecessary health risks to the patients. New immunotherapies, such as adoptive cell transfer, are being developed and refined to treat such cancers. T cell immunotherapies in particular, where a patient’s T cell lymphocytes are isolated and amplified to be re-infused into the patient or where human cell lines are engineered to express T cell receptors for the recognition of common cancer antigens, are being expanded on because for some cancers, they could be the only option. Constructing an optimal pipeline for cloning and expression of antigen-specific TCRs has significant bearing on the efficacy of engineered cell lines for ACT. Adoptive T cell transfer, while making great strides, has to overcome a diverse T cell repertoire – cloning and expressing antigen-specific TCRs can mediate this understanding. Having identified the high frequency FluM1-specific TCR sequences in stimulated donor PBMCs, it was hypothesized that the antigen-specific TCR could be reconstructed via Gateway cloning methods and tested for expression and functionality. Establishing this pipeline would confirm an ability to properly pair and express the heterodimeric chains. In the context of downstream applications, neoantigens would be used to stimulate T cells, the α and β chains would be paired via single-cell or bulk methods, and instead of Gateway cloning, the CDR3 hypervariable regions α and β chains alone would be co-expressed using Golden Gate assembly methods.

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2019-05

Tell It to the Frogs: Fukushima’s nuclear disaster and its impact on the Japanese Tree Frog

Description

“Tell It to the Frogs: Fukushima’s nuclear disaster and its impact on the Japanese Tree Frog” is a representation of the work from Giraudeau et. al’s “Carotenoid distribution in wild Japanese tree frogs (Hyla japonica) exposed to ionizing radiation in

“Tell It to the Frogs: Fukushima’s nuclear disaster and its impact on the Japanese Tree Frog” is a representation of the work from Giraudeau et. al’s “Carotenoid distribution in wild Japanese tree frogs (Hyla japonica) exposed to ionizing radiation in Fukushima.” This paper looked to see if carotenoid levels in the tree frog’s vocal sac, liver, and blood were affected by radiation from Fukushima’s power plant explosion. Without carotenoids, the pigment that gives the frogs their orange color on their necks, their courtship practices would be impacted and would not be as able to show off their fitness to potential mates. The artwork inspired by this research displayed the tree frog’s degradation over time due to radiation, starting with normal life and ending with their death and open on the table. The sculptures also pinpoint where the carotenoids were being measured with a brilliant orange glaze. Through ceramic hand building, the artist created larger than life frogs in hopes to elicit curiosity about them and their plight. While the paper did not conclude any changes in the frog’s physiology after 18 months of exposure, there are still questions that are left unanswered. Why did these frogs not have any reaction? Could there be any effects after more time has passed? Is radiation leakage as big of a problem as previously thought? The only way to get the answers to these questions is to be aware of these amphibians, the circumstances that led them to be involved, and continued research on them and radiation.

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2019-05

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DNA Origami as Novel Immune Adjuvants

Description

Cytokines induced by inflammasome has been used for blood cancer treatments, yet these treatments have been less successful in the solid tumor microenvironment. Here precise-morphology DNA origami structures were implemented to accurately test the effect and mechanism of activation in

Cytokines induced by inflammasome has been used for blood cancer treatments, yet these treatments have been less successful in the solid tumor microenvironment. Here precise-morphology DNA origami structures were implemented to accurately test the effect and mechanism of activation in the NLRP3 inflammasome. THP1 WT cells, a macrophage cell line, were treated with eleven different DNA origami structures. The inflammasome activation of two cytokines, Interleukin 1 beta (IL-1β) and Interferon beta (IFN-β), was measured using HEK Blue IL-1β cells, HEK Blue IFN-β cells, and enzyme linked immunosorbent assay (ELISA). Differences in activation signaling have the potential to provide the characterization required to address the intrinsic complexity of modulating an immune response. It is hoped that DNA origami will help induce more inflammation for solid tumors. The DNA origami was tested in three different volumes: 1 μL, 5 μL, and 10 μL. Overall, the origami that showed promising results were Mg Square. Tetrahedral and P53 block also showed potential but not as well as Mg square. Further testing of more DNA origami structures and testing them in mice are key to the success of targeted cancer immunotherapies in the neoadjuvant setting.

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2019-05

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Loose Lace Baby

Description

“Loose Lace Baby” is a multimedia creative project that includes the creation of a song, a music video, and cover art. The project began with the songwriting process, which became the inspiration for the video concept. The final cover art

“Loose Lace Baby” is a multimedia creative project that includes the creation of a song, a music video, and cover art. The project began with the songwriting process, which became the inspiration for the video concept. The final cover art is based on the themes and aesthetics of the song and video combined. This project’s purpose was to explore the creative process across multiple media forms and how those forms can work to inspire and enhance one another. The first stage of the project was the songwriting and recording stage. The song is a simple love song about feeling insecure in a relationship and is centered on the metaphor of “tripping over loose shoelaces”. The process in this stage included creative idea exchange, songwriting, music production, and research in different methods of song creation. This portion of the project was then used to inspire the second stage, which was the music video. The music video is about a young boy’s first major crush and follows him on his journey to tell her how he feels, which ultimately ends poorly for him, but goes to show that love can be a divisive but also binding force. The caveat to this boy’s crush is that it ends up being his babysitter, who is much older than him and therefore does not reciprocate his feeling despite having a meaningful connection of a different nature with him. This portion of the project involved many elements, namely using sound as a source of inspiration for moving visual art, production and design, learning about camera work, directing, scripting, screenplay, acting, editing, and most of all, collaboration. Finally, Once these stages of the project came together, the final stage was to draw on the core ideas of the two to create a piece of cover art that represented the messages from both the song and the music video, cohesively binding the multiple media forms into one final product. This stage involved photography, image editing, and pulling from the two other media forms to create a cohesive representative image The final product is a music video and song that are approximately four minutes long each, and a single cover art image. The main software used for music production was Ableton Live. The camera used was a Sony A6300 and the main video editing software used was Adobe Premiere. Many learning outcomes were reached, including multiple filming and editing techniques, video production and the work that goes into organizing and directing a film project, music production methods such as vocal recording and processing, live instrument recording, song arrangement and the use of a Digital Audio Workstation for production and mixing. An in-depth analysis of the entire process is given in detail in the following pages.

"Loose Lace Baby" music video: https://www.youtube.com/watch?v=K5uPf7Psht8&feature=youtu.be

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2020-05

Functional Art as a Representative Medium

Description

Items that have once served as tools in the past become something of greater value in the future: art. Ceramics is a craft that has gone beyond its simple functions to become a representative medium. This ability makes ceramics an

Items that have once served as tools in the past become something of greater value in the future: art. Ceramics is a craft that has gone beyond its simple functions to become a representative medium. This ability makes ceramics an art. This will be demonstrated by representing enzyme-substrate binding and inhibition through the use of a dinner set.

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2020-05