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.

Management of safety climate and the psychosocial work environment – new challenges for occupational health and safety professionals?

Introduction: The work environment and Occupational Health and Safety (OHS) practice have changed over the last number of years. A holistic OHS approach has been recommended by the authorities in this field (e.g. World Health Organisation (WHO), European Agency for Safety and Health at Work (EU-OSHA) and the International Labour Organisation (ILO)). This involves a unified action engaging elements of the physical and psychosocial workplace with greater focus on prevention and promotion of health and wellbeing. The health and safety practitioner (HSP) has been recognised as one of the main agents for implementation of OHS. Within an organisation they act as a leader of change and a professional who shapes health and safety while safeguarding the wellbeing of individuals at work. Additionally, safety climate (SC) has been developed as an essential concept for OHS of an organisation, its productivity and the wellbeing of its workforce. Scholars and practitioners have recognised the great need for further empirical evidence on the HSP’s role in a changing work environment that increasingly requires the use of preventative measures and the assessment and management of psychosocial work-related risks. This doctoral research brings together the different concepts used in OHS and Public Health including SC, Psychosocial workplace risks, Health Promotion and OHS performance. The associations between these concepts are analysed bearing in mind the WHO Healthy Workplace Framework and three of its main components (physical and psychosocial work environment and health resources). This thesis aims to establish a deeper understanding of the practice and management of OHS in Ireland and the UK, exploring the role of HSPs (employed in diverse sectors of activity) and of SC in the OHS of organisations. Methods: One systematic review and three cross-sectional research studies were performed. The systematic review focussed on the evidence compiled for the association of SC with accidents and injuries at work, clarifying this concept’s definition and its most relevant dimensions. The second article (chapter 3) explored the association of SC with accidents and injuries in a sample of workers (n=367) from a pharmaceutical industry and compared permanent with non-permanent workers. Associations of safety climate with employment status and with self-reported occupational accidents/injuries were studied through logistic regression modelling. The third and fourth papers in this thesis investigated the main tasks performed by HSPs, their perceptions of SC, health climate (HC), psychosocial risk factors and health outcomes as well as work efficacy. Validated questionnaires were applied to a sample of HSPs in Ireland and UK, members of the Institute of Occupational Safety and Health (n=1444). Chi-square analysis and logistic regression were used to assess the association between HSPs work characteristics and their involvement in the management of Psychosocial Risk Factors, Safety Culture and Health Promotion (paper 3). Multiple linear regression analysis was used to determine the association between SC, HC, psychosocial risk factors and health outcomes (general health and mental wellbeing) and self-efficacy. Results: As shown in the systematic review, scientific evidence is unable to establish the widely assumed causal link between SC and accidents and injuries. Nevertheless, the current results suggested that, particularly, the organisational dimensions of SC were associated with accidents and injuries and that SC is linked to health, wellbeing and safety performance in the organisation. According to the present research, contingent workers had lower SC perceptions but showed a lower accident/injury rate than their permanent colleagues. The associations of safety climate with accidents/injuries had opposite directions for the two types of workers as for permanent employees it showed an inverse relationship while for temporary workers, although not significant, a positive association was found. This thesis’ findings showed that HSPs are, to a very small degree, included in activities related to psychosocial risk management and assessment, to a moderate degree, involved in HP activities and, to a large degree, engaged in the management of safety culture in organisations. In the final research study, SC and HC were linked to job demands-control-support (JDCS), health, wellbeing and efficacy. JDCS were also associated with all three outcomes under study. Results also showed the contribution of psychosocial risk factors to the association of SC and HC with all the studied outcomes. These associations had rarely been recorded previously. Discussion & Conclusions: Health and safety climate showed a significant association with health, wellbeing and efficacy - a relationship which affects working conditions and the health and wellbeing of the workforce. This demonstrates the link of both SC and HC with the OHS and the general strength or viability of organisations. A division was noticed between the area of “health” and “safety” in the workplace and in the approach to the physical and psychosocial work environment. These findings highlighted the current challenge in ensuring a holistic and multidisciplinary approach for prevention of hazards and for an integrated OHS management. HSPs have shown to be a pivotal agent in the shaping and development of OHS in organisations. However, as observed in this thesis, the role of these professionals is still far from the recommended involvement in the management of psychosocial risk factors and could have a more complete engagement in other areas of OHS such as health promotion. Additionally, a strong culture of health and safety with supportive management and buy-in from all stakeholders is essential to achieve the ideal unified and prevention-focussed approach to OHS as recommended by the WHO, EU-OSHA and ILO.

The extracurriculum in an input-poor environment

This paper reports on the experiences of an extracurricular program in English language learning (ELL) that was implemented in an institute of technology in the hinterland of the People's Republic of China (PRC). Following the guidelines set out in an impact study of the reform of curriculum change in Hong Kong (Adamson & Morris, 2000), this study takes account of the context of the particular socio-cultural and political environment in which the research program takes place. Three distinct phases emerged in the career of the extracurricular program - the establishment of the program; successful implementation; and the decline. The study identifies three key factors that shaped these phases: teacher motivation; student motivation and its various influences; and available resources (including collegial and administrative support). The findings suggest that of the key factors impacting on the ELL extracurriculum, student motivation was the most influential.