![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/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T063358Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=0cb1af05eb91844098b16169ff17fffff4cfca8f53bfcbbec97f92e732898554&itok=a2J6fMyg)
![152574-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/152574-Thumbnail%20Image.png?versionId=W44s5AtwCblP7D0RIWJandXS59_hGaS6&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T044600Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=42426e3a9a7e73bdde2a2de870b29afb55d45b2ba836ae50716dfd1d1ce82287&itok=tNEdmG-j)
![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/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T043343Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=06b3faa4ab97abee7482c9967e6e2d5c9bfec29607b6659c82a46c39ff617bc4&itok=KGePlCv3)
![153018-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-08/153018-Thumbnail%20Image.png?versionId=EUkFEBTet.RCTdpSshdgmp8fBoaZ4ZJP&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T053523Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=af0b7163d4cde168a6a8be0d766bd08813f8f14df90376b1ed72f1dba6c7e4b7&itok=TgpWQV2w)
![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/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T031758Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=caefc0826c73bf771f13470bbb042d0914803ef65348bfcd65fa3bfdd232ba0c&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.
![155172-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/155172-Thumbnail%20Image.png?versionId=8S0RWHGBRZs_KsSK1bUQT4jbFXHHfkWC&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T051253Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=4af7794a4d993ad5f4bcacff2d65765b4722cc313a3bed3669074de7a4cafe77&itok=xTarV6T7)
Chapter 1 provides background information and motivation for infectious disease forecasting and outlines the rest of the thesis.
In chapter 2, logistic patch models are used to assess and forecast the 2013-2015 West Africa Zaire ebolavirus epidemic. In particular, this chapter is concerned with comparing and contrasting the effects that spatial heterogeneity has on the forecasting performance of the cumulative infected case counts reported during the epidemic.
In chapter 3, two simple phenomenological models inspired from population biology are used to assess the Research and Policy for Infectious Disease Dynamics (RAPIDD) Ebola Challenge; a simulated epidemic that generated 4 infectious disease scenarios. Because of the nature of the synthetically generated data, model predictions are compared to exact epidemiological quantities used in the simulation.
In chapter 4, these models are applied to the 1904 Plague epidemic that occurred in Bombay. This chapter provides evidence that these simple models may be applicable to infectious diseases no matter the disease transmission mechanism.
Chapter 5, uses the patch models from chapter 2 to explore how migration in the 1904 Plague epidemic changes the final epidemic size.
The final chapter is an interdisciplinary project concerning within-host dynamics of cereal yellow dwarf virus-RPV, a plant pathogen from a virus group that infects over 150 grass species. Motivated by environmental nutrient enrichment due to anthropological activities, mathematical models are employed to investigate the relevance of resource competition to pathogen and host dynamics.
![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/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T052420Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=4e2fa5af1b7e48b928e2abf515a6130f13d9a86541e24073ba1b4a9bb0eb1ebb&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.
![158842-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/158842-Thumbnail%20Image.png?versionId=ReJIvWKj0qBjCUwIYbdIL4v050YLyNsI&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240619/us-west-2/s3/aws4_request&X-Amz-Date=20240619T071857Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=4d8259762f6635939388c76e69f8cab6e59cbfca03157cd3807e12bc064ecef4&itok=of3dtsQr)
![129516-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-04/129516-Thumbnail%20Image.png?versionId=d55V_4_vRQje8cErBvsvbjtUgxriG3Oi&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240605/us-west-2/s3/aws4_request&X-Amz-Date=20240605T195240Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=30b88a9613ca602dd8197cfa85e849931c11e90758f32b43c2200b3fe3d4c914&itok=Irdlf-2W)
Deposits of dark material appear on Vesta’s surface as features of relatively low-albedo in the visible wavelength range of Dawn’s camera and spectrometer. Mixed with the regolith and partially excavated by younger impacts, the material is exposed as individual layered outcrops in crater walls or ejecta patches, having been uncovered and broken up by the impact. Dark fans on crater walls and dark deposits on crater floors are the result of gravity-driven mass wasting triggered by steep slopes and impact seismicity. The fact that dark material is mixed with impact ejecta indicates that it has been processed together with the ejected material. Some small craters display continuous dark ejecta similar to lunar dark-halo impact craters, indicating that the impact excavated the material from beneath a higher-albedo surface. The asymmetric distribution of dark material in impact craters and ejecta suggests non-continuous distribution in the local subsurface. Some positive-relief dark edifices appear to be impact-sculpted hills with dark material distributed over the hill slopes.
Dark features inside and outside of craters are in some places arranged as linear outcrops along scarps or as dark streaks perpendicular to the local topography. The spectral characteristics of the dark material resemble that of Vesta’s regolith. Dark material is distributed unevenly across Vesta’s surface with clusters of all types of dark material exposures. On a local scale, some craters expose or are associated with dark material, while others in the immediate vicinity do not show evidence for dark material. While the variety of surface exposures of dark material and their different geological correlations with surface features, as well as their uneven distribution, indicate a globally inhomogeneous distribution in the subsurface, the dark material seems to be correlated with the rim and ejecta of the older Veneneia south polar basin structure. The origin of the dark material is still being debated, however, the geological analysis suggests that it is exogenic, from carbon-rich low-velocity impactors, rather than endogenic, from freshly exposed mafic material or melt, exposed or created by impacts.