THE ROLE OF THE MECHANICAL ENVIRONMENT ON CANCER CELL TRANSMIGRATION AND MRNA LOCALIZATION

Most cancer-related deaths are due to metastasis formation, the ability of cancer cells to break away from the primary tumor site, transmigrate through the endothelium, and form secondary tumors in distant areas. Many studies have identified links between the mechanical properties of the cellular microenvironment and the behavior of cancer cells. Cells may experience heterogeneous microenvironments of varying stiffness during tumor progression, transmigration, and invasion into the basement membrane. In addition to mechanical factors, the localization of RNAs to lamellipodial regions has been proposed to play an important part in metastasis. This dissertation provides a quantitative evaluation of the biophysical effects on cancer cell transmigration and RNA localization. In the first part of this dissertation, we sought to compare cancer cell and leukocyte transmigration and investigate the impact of matrix stiffness on transmigration process. We found that cancer cell transmigration includes an additional step, ‘incorporation’, into the endothelial cell (EC) monolayer. During this phase, cancer cells physically displace ECs and spread into the monolayer. Furthermore, the effects of subendothelial matrix stiffness and endothelial activation on cancer cell incorporation are cell-specific, a notable difference from the process by which leukocytes transmigrate. Collectively, our results provide mechanistic insights into tumor cell extravasation and demonstrate that incorporation into the endothelium is one of the earliest steps. In the next part of this work, we investigated how matrix stiffness impacts RNA localization and its relevance to cancer metastasis. In migrating cells, the tumor suppressor protein, adenomatous polyposis coli (APC) targets RNAs to cellular protrusions. We observed that increasing stiffness promotes the peripheral localization of these APC-dependent RNAs and that cellular contractility plays a role in regulating this pathway. We next investigated the mechanism underlying the effect of substrate stiffness and cellular contractility. We found that contractility drives localization of RNAs to protrusions through modulation of detyrosinated microtubules, a network of modified microtubules that associate with, and are required for localization of APC-dependent RNAs. These results raise the possibility that as the matrix environment becomes stiffer during tumor progression, it promotes the localization of RNAs and ultimately induces a metastatic phenotype.

ESSAYS IN ENERGY, ENVIRONMENT AND TECHNOLOGICAL CHANGE

This dissertation studies technological change in the context of energy and environmental economics. Technology plays a key role in reducing greenhouse gas emissions from the transportation sector. Chapter 1 estimates a structural model of the car industry that allows for endogenous product characteristics to investigate how gasoline taxes, R&D subsidies and competition affect fuel efficiency and vehicle prices in the medium-run, both through car-makers' decisions to adopt technologies and through their investments in knowledge capital. I use technology adoption and automotive patents data for 1986-2006 to estimate this model. I show that 92% of fuel efficiency improvements between 1986 and 2006 were driven by technology adoption, while the role of knowledge capital is largely to reduce the marginal production costs of fuel-efficient cars. A counterfactual predicts that an additional $1/gallon gasoline tax in 2006 would have increased the technology adoption rate, and raised average fuel efficiency by 0.47 miles/gallon, twice the annual fuel efficiency improvement in 2003-2006. An R&D subsidy that would reduce the marginal cost of knowledge capital by 25% in 2006 would have raised investment in knowledge capital. This subsidy would have raised fuel efficiency only by 0.06 miles/gallon in 2006, but would have increased variable profits by $2.3 billion over all firms that year. Passenger vehicle fuel economy standards in the United States will require substantial improvements in new vehicle fuel economy over the next decade. Economic theory suggests that vehicle manufacturers adopt greater fuel-saving technologies for vehicles with larger market size. Chapter 2 documents a strong connection between market size, measured by sales, and technology adoption. Using variation consumer demographics and purchasing pattern to account for the endogeneity of market size, we find that a 10 percent increase in market size raises vehicle fuel efficiency by 0.3 percent, as compared to a mean improvement of 1.4 percent per year over 1997-2013. Historically, fuel price and demographic-driven market size changes have had large effects on technology adoption. Furthermore, fuel taxes would induce firms to adopt fuel-saving technologies on their most efficient cars, thereby polarizing the fuel efficiency distribution of the new vehicle fleet.

Contested Play and Clean Water: McMillan Park, Race, and the Built Environment in Washington, D.C., 1900-1941

This study focuses on the intersection of the politics and culture of open public space with race relations in the United States from 1900 to 1941. The history of McMillan Park in Washington, D.C. serves as a lens to examine these themes. Ultimately, the park’s history, as documented in newspapers, interviews, reports, and photographs, reveals how white residents attempted to protect their dominance in a racial hierarchy through the control of both the physical and cultural elements of public recreation space. White use of discrimination through seemingly neutral desires to protect health, safety, and property values, establishes a congruence with their defense of residential property. Without similar access to legal methods, African Americans acted through direct action in gaps of governmental control. Their use of this space demonstrates how African-American residents of Washington and the United States contested their race, recreation, and spatial privileges in the pre-World War II era.

The Impact of Motor Learning on Motor Behavior and Cortical Dynamics in a Complex Stressful Social Environment

An economy of effort is a core characteristic of highly skilled motor performance often described as being effortless or automatic. Electroencephalographic (EEG) evaluation of cortical activity in elite performers has consistently revealed a reduction in extraneous associative cortical activity and an enhancement of task-relevant cortical processes. However, this has only been demonstrated under what are essentially practice-like conditions. Recently it has been shown that cerebral cortical activity becomes less efficient when performance occurs in a stressful, complex social environment. This dissertation examines the impact of motor skill training or practice on the EEG cortical dynamics that underlie performance in a stressful, complex social environment. Sixteen ROTC cadets participated in head-to-head pistol shooting competitions before and after completing nine sessions of skill training over three weeks. Spectral power increased in the theta frequency band and decreased in the low alpha frequency band after skill training. EEG Coherence increased in the left frontal region and decreased in the left temporal region after the practice intervention. These suggest a refinement of cerebral cortical dynamics with a reduction of task extraneous processing in the left frontal region and an enhancement of task related processing in the left temporal region consistent with the skill level reached by participants. Partitioning performance into ‘best’ and ‘worst’ based on shot score revealed that deliberate practice appears to optimize cerebral cortical activity of ‘best’ performances which are accompanied by a reduction in task-specific processes reflected by increased high-alpha power, while ‘worst’ performances are characterized by an inappropriate reduction in task-specific processing resulting in a loss of focus reflected by higher high-alpha power after training when compared to ‘best’ performances. Together, these studies demonstrate the power of experience afforded by practice, as a controllable factor, to promote resilience of cerebral cortical efficiency in complex environments.