![156939-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/156939-Thumbnail%20Image.png?versionId=eEhzVS14PsCU71eklRJdKWnaQGoYqViV&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240615/us-west-2/s3/aws4_request&X-Amz-Date=20240615T203306Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=f31fdb1cc7b2930e6873c904143d6ba39696f32af813fc5319c98087114ea48d&itok=2bPKT4iC)
![154259-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-08/154259-Thumbnail%20Image.png?versionId=n3KfFG1r4.PXOGUT1lb8Uvx83wGGQOF8&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240615/us-west-2/s3/aws4_request&X-Amz-Date=20240615T135737Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=e7eae2e7822dae02a5155a71afd70f89f7d70a5dce89ab15a691b9a099074200&itok=Sk5Cnr94)
The goal of this research was to identify and characterize biologically active small molecule inhibitors for QSOX1. Chemical inhibition of QSOX1 enzymatic activity was hypothesized to reduce growth and invasion of tumor cells. Recombinant QSOX1 was screened against libraries of small molecules using an enzymatic activity assay to identify potential QSOX1 inhibitors. Two lead QSOX1 inhibitors were confirmed, 2-phenyl-1, 2-benzisoselenazol-3-one (ebselen), and 3-methoxy-n-[4-(1 pyrrolidinyl)phenyl]benzamide. The biological activity of these compounds is consistent with QSOX1 knockdown in tumor cell lines, reducing growth and invasion in vitro. Treatment of tumor cells with these compounds also resulted in specific ECM defects, a phenotype associated with QSOX1 knockdown. Additionally, these compounds were shown to be active in pancreatic and renal cancer xenografts, reducing tumor growth with daily treatment. For ebselen, the molecular mechanism of inhibition was determined using a combination of biochemical and mass spectrometric techniques. The results obtained in these studies provide proof-of-principle that targeting QSOX1 enzymatic activity with chemical compounds represents a novel potential therapeutic avenue worthy of further investigation in cancer. Additionally, the utility of these small molecules as chemical probes will yield future insight into the general biology of QSOX1, including the identification of novel substrates of QSOX1.
![154018-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/154018-Thumbnail%20Image.png?versionId=RzWd4VrJvWb2agWd0CYt4i9inZDnvUzd&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240616/us-west-2/s3/aws4_request&X-Amz-Date=20240616T032005Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=9be3b5a1b755d9b52ec6d6f05eaea5b8136ccae14a6e55b6fd8dd672747ad727&itok=a2J6fMyg)
![155098-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/155098-Thumbnail%20Image.png?versionId=fHVTvPO9Rv4J.uT1jfabTNNkUprhn6Yz&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240615/us-west-2/s3/aws4_request&X-Amz-Date=20240615T155955Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=77d15b3cdb51ae676914459701c8df5363e821eaab41f5021223e5e879aeb949&itok=8_lJwVb7)
Findings indicate that the deployment of green roofs will cool the urban environment in daytime and warm it at night, via evapotranspiration and soil insulation. At the annual scale, green roofs are effective in decreasing building energy demands for both summer cooling and winter heating. For cities in arid and semiarid environments, an optimal trade-off between water and energy resources can be achieved via innovative design of smart urban irrigation schemes, enabled by meticulous analysis of the water-energy nexus. Using water-saving plants alleviates water shortage induced by population growth, but comes at the price of an exacerbated urban thermal environment. Realizing the potential water buffering capacity of urban green infrastructure is crucial for the long-term water sustainability and subsequently multisector sustainability of cities. Environmental performance of urban green infrastructure is determined by land-atmosphere interactions, geographic and meteorological conditions, and hence it is recommended that analysis should be conducted on a city-by-city basis before actual implementation of green infrastructure.
![153508-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/153508-Thumbnail%20Image.png?versionId=OZ7jvYo38QmjWi49hylBA2LGEQm5AtLk&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240616/us-west-2/s3/aws4_request&X-Amz-Date=20240616T042146Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=56daca8a5e01209475d706533c8ad62bd14223e9102fce02bae27a58123400a2&itok=KGePlCv3)
![155158-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/155158-Thumbnail%20Image.png?versionId=8ikpqAO27MywlbNL4sC6pKTu_cn1WqLp&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240615/us-west-2/s3/aws4_request&X-Amz-Date=20240615T222208Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=b144a0f0eddb40ea7cf39168623a4725a33a34a5f7e43f7343c2ad53cbbe710e&itok=6WSJTJT7)
I hypothesize that duplication events grant miRNA families with enhanced regulatory capabilities, specifically through distinct targeting preferences by family members. This has relevance for our understanding of vertebrate evolution, as well disease detection and personalized medicine. To test this hypothesis, I apply a conjunction of bioinformatic and experimental approaches, and design a novel high-throughput screening platform to identify human miRNA targets. Combined with conventional approaches, this tool allows systematic testing for functional targets of human miRNAs, and the identification of novel target genes on an unprecedented scale.
In this dissertation, I explore evolutionary signatures of 62 deeply conserved metazoan miRNA families, as well as the targeting preferences for several human miRNAs. I find that constraints on miRNA processing impact sequence evolution, creating evolutionary hotspots within families that guide distinct target preferences. I apply our novel screening platform to two cancer-relevant miRNAs, and identify hundreds of previously undescribed targets. I also analyze critical features of functional miRNA target sites, finding that each miRNA recognizes surprisingly distinct features of targets. To further explore the functional distinction between family members, I analyze miRNA expression patterns in multiple contexts, including mouse embryogenesis, RNA-seq data from human tissues, and cancer cell lines. Together, my results inform a model that describes the evolution of metazoan miRNAs, and suggests that highly similar miRNA family members possess distinct functions. These findings broaden our understanding of miRNA function in vertebrate evolution and development, and how their misexpression contributes to human disease.
![155884-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-08/155884-Thumbnail%20Image.png?versionId=ij0FKOy1H3OOcAHnQeAuaW1_CaGr57ER&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240615/us-west-2/s3/aws4_request&X-Amz-Date=20240615T084213Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=e31a60391578b47a853efe30e1ef37c8dd2017192a220fef60ab3a389cb7f354&itok=SHcdUK-O)
Trees serve as a natural umbrella to mitigate insolation absorbed by features of the urban environment, especially building structures and pavements. For a desert community, trees are a particularly valuable asset because they contribute to energy conservation efforts, improve home values, allow for cost savings, and promote enhanced health and well-being. The main obstacle in creating a sustainable urban community in a desert city with trees is the scarceness and cost of irrigation water. Thus, strategically located and arranged desert trees with the fewest tree numbers possible potentially translate into significant energy, water and long-term cost savings as well as conservation, economic, and health benefits. The objective of this dissertation is to achieve this research goal with integrated methods from both theoretical and empirical perspectives.
This dissertation includes three main parts. The first part proposes a spatial optimization method to optimize the tree locations with the objective to maximize shade coverage on building facades and open structures and minimize shade coverage on building rooftops in a 3-dimensional environment. Second, an outdoor urban physical scale model with field measurement is presented to understand the cooling and locational benefits of tree shade. The third part implements a microclimate numerical simulation model to analyze how the specific tree locations and arrangements influence outdoor microclimates and improve human thermal comfort. These three parts of the dissertation attempt to fill the research gap of how to strategically locate trees at the building to neighborhood scale, and quantifying the impact of such arrangements.
Results highlight the significance of arranging residential shade trees across different geographical scales. In both the building and neighborhood scales, research results recommend that trees should be arranged in the central part of the building south front yard. More cooling benefits are provided to the building structures and outdoor microclimates with a cluster tree arrangement without canopy overlap; however, if residents are interested in creating a better outdoor thermal environment, open space between trees is needed to enhance the wind environment for better human thermal comfort. Considering the rapid urbanization process, limited water resources supply, and the severe heat stress in the urban areas, judicious design and planning of trees is of increasing importance for improving the life quality and sustaining the urban environment.
![158343-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/158343-Thumbnail%20Image.png?versionId=GthoRu22Rl3K3nHRKKUY_hbklOLuk5XN&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240617/us-west-2/s3/aws4_request&X-Amz-Date=20240617T094136Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=36b0bf4b1ab678815ac2d7e2b84f40999a9e407e46764f9616e089462d1f9419&itok=ZPXuGd_J)
The conservation of the dystrophin gene across metazoans suggests that both vertebrate and invertebrate model systems can provide valuable contributions to the understanding of DMD initiation and progression. Specifically, the invertebrate C. elegans possesses a dystrophin protein ortholog, dys-1, and a mild inflammatory response that is inactive in the muscle, allowing for the characterization of transcriptome rearrangements affecting disease progression independently of inflammation. Furthermore, C. elegans do not possess a satellite cell equivalent, meaning muscle regeneration does not occur. This makes C. elegans unique in that they allow for the study of dystrophin deficiencies without muscle regeneration that may obscure detection of subtle but consequential changes in gene expression.
I hypothesize that gaining a comprehensive definition of both the structural and signaling roles of dystrophin in C. elegans will improve the community’s understanding of the progression of DMD as a whole. To address this hypothesis, I have performed a phylogenetic analysis on the conservation of each member of the dystrophin associated protein complex (DAPC) across 10 species, established an in vivo system to identify muscle-specific changes in gene expression in the dystrophin-deficient C. elegans, and performed a functional analysis to test the biological significance of changes in gene expression identified in my sequencing results. The results from this study indicate that in C. elegans, dystrophin may have a signaling role early in development, and its absence may activate compensatory mechanisms that counteract disease progression. Furthermore, these findings allow for the identification of transcriptome changes that potentially serve as both independent drivers of disease and potential therapeutic targets for the treatment of DMD.
![157836-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/157836-Thumbnail%20Image.png?versionId=F.5l3oq_5uZqaCT90Y82oJFH2t.uNAap&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240615/us-west-2/s3/aws4_request&X-Amz-Date=20240615T090304Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=c2d3cd1b8be5803ce991748d9579a929116c3561369e748090e5d17eb09e45d4&itok=MJSyRCHH)
Domestic dogs have assisted humans for millennia. However, the extent to which these helpful behaviors are prosocially motivated remains unclear. To assess the propensity of pet dogs to spontaneously and actively rescue distressed humans, this study tested whether sixty pet dogs would release their seemingly trapped owners from a large box. To examine the causal mechanisms that shaped this behavior, the readiness of each dog to open the box was tested in three conditions: 1) the owner sat in the box and called for help (“Distress” test), 2) an experimenter placed high-value food rewards in the box (“Food” test), and 3) the owner sat in the box and calmly read aloud (“Reading” test).
Dogs were as likely to release their distressed owner as to retrieve treats from inside the box, indicating that rescuing an owner may be a highly rewarding action for dogs. After accounting for ability, dogs released the owner more often when the owner called for help than when the owner read aloud calmly. In addition, opening latencies decreased with test number in the Distress test but not the Reading test. Thus, rescuing the owner could not be attributed solely to social facilitation, stimulus enhancement, or social contact-seeking behavior.
Dogs displayed more stress behaviors in the Distress test than in the Reading test, and stress scores decreased with test number in the Reading test but not in the Distress test. This evidence of emotional contagion supports the hypothesis that rescuing the distressed owner was an empathetically-motivated prosocial behavior. Success in the Food task and previous (in-home) experience opening objects were both strong predictors of releasing the owner. Thus, prosocial behavior tests for dogs should control for physical ability and previous experience.