Cells integrate signals from environmental inputs to regulate cellular programming, such as protein production, differentiation, and proliferation. This cellular decision making process occurs across multiple time and length scales, during which a cascade of biochemical reactions transduces signal from inputs to a functional outcome. T cells are a prototypical example of cells that make activation decisions based on discriminating a low level of agonist ligands, which is a peptide fragment presented on Major Histocompatibility Complex (pMHC). In recent years it has become evident that only a handful of ligands are sufficient to activate T cells to secrete cytokines or cytotoxic granules. In this low density pMHC regime, the sequence of T cell receptor (TCR) binding events that a T cell collects is highly stochastic, and the physical mechanism of input integration that overcomes the noise and accurately translates the signal remains unknown.

This work investigates the molecular processes underlying how T cell input integration results in a cellular activation outcome. First, an imaging assay based on a live cell-supported membrane platform is introduced to directly observe the sequence of single molecule pMHC:TCR bindings (inputs) and the presence of ligand:receptor:kinase complexes. Titrations of pMHC densities are performed to study the effect of initial binding events on subsequent binding events. Similar measurements were extended to auto-reactive human T cells to compare their binding affinities to normal human T cells. We further map the sequence of pMHC:TCR binding events to early T cell activation, as read out by the translocation of the transcription factor NFAT. Results from the input-outcome assay indicates that T cells may coordinate input accumulation. We then investigate protein assemblies as a potential mechanism of coordinated input accumulation. This work highlights the common feature of spatiotemporally coordinated input accumulation as a general design principle in cellular decision making.

Shanghai (translated as Above Sea) has long been characterized as Mainland China's most East meets West, and modern metropolis. Throughout the twentieth and twenty-first centuries, artists, designers, and filmmakers have confronted this identity, formulating diverging notions of Chinese modernity and contemporaneity vis-à-vis Shanghai's cultural hybridity. This dissertation examines these formulations by analyzing examples of art, as well as fashion, print media, and film produced in dialogue with cross-cultural Shanghai in three key periods: the 1920s-30s during the city's semi-colonial modernist heyday, the 1960s-70s during the Cultural Revolution (Wenhua dageming), and the 1990s-2000s as Shanghai has re-emerged as a global center. My analyses problematize the trope of East meets West that has long informed the discourses both on Shanghai and modern and contemporary Chinese art, by exposing other cultural collisions (e.g., semi-colonial cosmopolitanism vs. anti-imperialist nationalism in the 1920s-30s, Maoist collectivity vs. individualism in the 1960s-70s, and local identities vs. globalization in the 1990s-2000s). The examples explored (e.g., Liang You/Young Companion magazine, revolutionary woodcuts, and painting by Parisian-trained artist, Pang Xunqin, in the 1920s-30s, socialist realist murals, revolutionary Peking opera, and a documentary by Italian auteur, Michelangelo Antonioni, in the 1960s-70s, installations by transnational artists, Xu Bing and Gu Wenda, and films by Shanghai-based artists, Zhou Tiehai and Yang Fudong, in the 1990s-2000s) span time, media, and national boundaries, allowing for analyses of diverging notions of Chinese modernity and contemporaneity vis-à-vis visual culture and its transnational movements. Many of these examples are locationally linked through a particular neighborhood said to epitomize contemporary Shanghai. Today the site of Xintiandi (translated as New Heaven on Earth), a retail and cultural complex in Shanghai's former French Concession, this neighborhood encompasses an underground history of revolutionary art, film, and design, which this dissertation uncovers. While filtered through the lens of Shanghai, this dissertation confronts broader issues, including the stakes of non-Western art's integration into art historical canons, and the role modern and contemporary Chinese art plays in the emergence of a globalized culture industry.

Cerebral Cavernous Malformations (CCMs) are common vascular disruptions occurring mainly in the brain and spinal cord in which chronic hemorrhage leads to neurological deficits, headaches, seizures, and sometimes death. The 3 genes known to cause CCM when mutated include Krit1 (Krev Interaction Trapped 1), CCM2, and PDCD10 (Programmed Cell Death 10, also known as CCM3). Heg1 (Heart of Glass) is a transmembrane protein known to recruit and anchor both Krit1 and Rasip1 (Ras Interacting Protein 1) to the membrane, maintaining vascular homeostasis by stabilizing endothelial cell-cell junctions. It has been shown that endothelial deficiency of Krit1, CCM2, or PDCD10 will lead to CCM lesion formation in various mouse models. Interestingly, although deletion of Heg1 alone does not lead to CCM development, when Heg1 is deleted in combination with Krit1, lesions formation is exacerbated. Our task was to find the potential pathways Heg1 is involved in that lead to the exacerbation of CCM lesion formation. Through in vivo and in vitro experiments, we found that when both Krit1 and Heg1 are depleted, lesion volume in mouse hindbrains increases, and Klf4 expression is drastically amplified in retinal endothelial cells. We found that Rasip1, an important Heg1 interactor, functions in the same pathway as Krit1 and Heg1. In addition, Mekk3 is important in the regulation of Klf2/4 expression, and knockdown of Mekk3 can rescue the increased Klf2/4 expression caused by Krit1/Heg1 knockdown. Further experiments are needed to better understand the role of Heg1 in the development of CCMs and elucidate the pathways involved.