William R. Clark, Ph.D - US grants

The experiments in the present application are directed toward resolving: 1.) The mechanism of CTL-mediated lysis. The mechanism by which cytotoxic T lymphocytes kill specific target cells in still unknown. A study of lysis in lectin-mediated cytolysis (LDCC) led us to propose a new mechanism for CTL-mediated cytolysis, in which target cell death occurs as a result of distortion of target cell MHC proteins. Leakage at the interface between the transmembrane MHC proteins and surrounding lipids is postulated to lead to irreversible osmotic damage. Experiments are included in this proposal to test our hypothesis. Antibodies to MHC proteins, other transmembrane proteins, non-transmembrane proteins, and purely lipid antigens will be coupled to the surface of inert microspheres, microtiter wells, RBC or other nonlytic cell types. These will then be incubated with 51Cr-labeled target cells, and the rate of 51Cr release monitored. 2.) The relationship of lectin-mediated polyclonal activation of CTL function to LDCC and to antigen activation of CTL function. Certain plant lectins have been used both to activate (CTL function, and to mediate lysis in cases where MHC-restricted recognition is presumed not to occur. We have recently shown that target cell lysis in LDCC is in fact MHC-restricted, and we have obtained preliminary data indicating that lectin-mediated, polyclonal generation of CTL function is also controlled by MHC proteins involved in lectin presentation. We propose experiments to explore this point further, and to analyze its significance for CTL function generally. Using specific MHC antibodies, appropriate H-2 recombinant and congenic strains, and MHC positive and negative cell lines, we will probe the involvement of MHC proteins in activation of CTL function in primary and secondary reactions, in both syngeneic and allogeneic combination. We will also clone out individual CTL generated by lectin and compare their properties will CTL generated by specific antigen.

As households move among housing units, the geographic patterns of metropolitan populations change. Over time, these changes have profound impacts on the location of residents and of the services and facilities that serve those residents. Equally important, those changes also alter the character and quality of the housing units themselves. Considerable attention has been focused by geographers and other scholars on residential mobility from the perspective of households, but relatively little research has highlighted the ways in which movements of households have affected housing units. This project will analyze mobility and related factors for ten American metropolises using longitudinal data from the American Housing Survey collected between 1974 and 1986. The research will focus on two major questions: (1) How do patterns of residential mobility within metropolises change as the overall level of mobility changes? and (2) What are the impacts of changing levels and patterns of mobility within metropolises on the geographic distributions of residential populations? Variables describing the mobility and demographic characteristics of households occupying housing units and of related variables reflecting the constitution of housing submarkets will be fit into a logit model in order to test a number of hypotheses related to the two central questions. The results of this research will be significant from both scholarly and practical standpoints. In terms of basic research, the project will provide a firmer basis for understanding the relationship between local mobility and the changing socioeconomic and demographic patterns of populations within metropolises, and it will clarify the relationship between households and housing units. These new understandings will also provide a firmer foundation for analyses of the evolving residential structure of specific cities, thereby enabling civic leaders to better assess the possible impacts of various policies.

Recent initiatives to monitor and model the complex relationships between geophysical, biological, and climatic processes throughout the world have emphasized the need to understand how people and human institutions modify and respond to global environmental change. Multi- disciplinary, integrated research on the human dimensions of global environmental change has been slow to develop, however, in part because most social and natural scientists have had little experience in working with scholars from other disciplines on large-scale analyses of complex human and environmental interrelationships. This project will convene a small group of social and natural scientists from throughout the nation for a conference at the University of California at Los Angeles to assess how institutional structures at universities can be altered to facilitate research and teaching on human and natural dimensions of global environmental change. Discussions at the conference will focus on identifying disciplinary and organizational barriers that inhibit cooperative research and teaching. Alternative arrangements for enhancing cooperative work will be proposed and evaluated. A written report about the conference will be prepared for distribution to scholars and administrators not in attendance. This conference will examine an important facet of the process of encouraging and conducting research on a topic of rapidly growing importance from both scholarly and applied perspectives. Publication of the results of this conference will enable the conclusions reached by scholars in attendance to be shared with interested persons elsewhere. As a result, the conference likely will have beneficial impacts on research and teaching on global environmental change throughout the nation.

Cytotoxic T lymphocytes (CTLs) that have been exposed for several days to high concentrations of IL-2 either in vitro or in vivo become highly granular in nature. Considerable attention has been focused on the possibility that these IL-2 induced granules might contain a cytotoxin that could explain how CTLs kill their target cells. How such a mechanism would fit into CTL killing in general is still controversial. What cannot be questioned, however, is that CTLs do not undergo a degranulation process during target cell killing. The contents of CTL granules have been only crudely analyzed. While it is certain that a number of different serine esterases reside in granules, little else is known. We recently began an extensive search for biologically interesting activities released during CTL degranulation. We have defined three activities functionally, and now propose detailed biological, biochemical and molecular genetic analyses of these activities. The three activities we have defined are: CTL inhibition, which is probably a feedback regulatory mechanism for controlling CTL function; T helper cell inhibitin, which may be involved in CD8+ T cell suppression of helper function; and viral inhibitin, which drastically inhibits the ability of mature viral particles to infect cells. Understanding the biochemical basis of these activities will greatly broaden our understanding of CTL function.

The number of wives in the labor force has doubled over the past three decades and household migration behavior is increasingly dependent on a complex process of joint decision making. This research examines, in a longitudinal context, the geographic and economic impacts of migration on dual-earner families, with specific focus on the labor-force experience of married women. Research on the impact of women's participation in the labor force has indicated that two-earner households are less likely to move than single-earner households due to their dual labor-force attachment. Traditional family migration research has argued that migration is associated frequently with the loss of earnings, interrupted careers, unemployment, underemployment or leaving the labor force on the part of the wife. In contrast, more recent work has raised questions about the disadvantaged effects and suggests that employment of married women increases with migration. Using the Panel Study of Income Dynamics (PSID) data this study considers the full range of potential labor force impacts on married women within the larger context of parallel careers in the life course of women and families. The study controls for the bias of migration self-selectivity. It explicitly considers the spatial variation in dual-earner family migration and the effects of migration on women in these families. Furthermore, this research uses longitudinal models to differentiate between the short-term and the long-term impacts of migration on married women. It addresses participation (employment, unemployment, underemployment, interrupted careers) and financial aspects of the impact of migration on married women.

A better understanding of the joint employment and location decisions of husbands and wives has the potential to improve the efficiency of the labor market. Women are the most dynamic supply sector of the labor market, and married women are an important component of spatial changes in the labor force, by virtue of their increased participation and their impact on family migration in general. Industry and organizations invest about 15 billion dollars annually in job relocations. Many of the transferees are married and dual earners, and relocating two earners is much more difficult than relocating a single earner. Spouses, relatives, and children are no longer considered mere appendages of the employee. Corporations are recognizing the need for greater incentives and support for the spousal job search process. Further, it is estimated that between ten and fifteen percent of all relocations are for the married woman's job, and there is reason to believe that this figure will continue to rise in the future. Given contemporary social changes it is an appropriate time to reassess family migration theory. New findings will enrich our knowledge of the temporal and spatial variations in the impact of family migration on women in dual-earner households.

As the volume of migration of people from one nation to another has increased around the globe, an equally significant facet of global economic transactions has become the remittance of funds from those who have emigrated to those who have been left behind. This is especially true in poorer nations, including those states whose state-run economies have not performed as well as market-based economies in other nations. This doctoral dissertation research project will examine the hypothesis that remittances sent to Cubans from relatives abroad play the positive role in Cuba of allowing their recipients to maintain an acceptable basic standard of living, thereby enabling them to continue to maintain their participation in relatively low-paying professional occupations. Studies of the rise of the informal economy have suggested that participation in the informal economy has increased during the time of transition from socialist to market economies. The opportunity to earn more money in this sector attracts workers to leave their trained profession to work in the informal economy. Do remittances play an important countervailing role? No previous studies have provided data regarding the ways that remittances may affect the motivation and actual participation in the informal economy. The project will combine a quantitative survey of 300 households followed by intensive in-depth personal interviews and household budgets for 15 households. The data will be used to test the links between the receipt of a steady and significant flow of remittances and type of employment.

The research will provide new insights and information regarding the potential for informal activities to draw away professionals from their occupations and lower the use of human capital in Cuban society and transitional socialist societies in general. Whereas other studies have argued that increased participation in the informal economy has been detrimental to the process of transformation from a socialist to a mixed market economy, this study will shed light on what motivates individuals to engage in or withdraw from the informal economy and where individuals place their primary occupational emphasis. The research also will broaden scholarly contacts with Cuba and facilitate future research in a nation that previously has been inaccessible for most U.S. researchers. As a Doctoral Dissertation Research Improvement award, this award will provide support to enable a promising student to establish a strong independent research career.

For most animal species, natural or man-made barriers such as waterways, roads, or habitat gaps often constrain the movement of individuals across a landscape, reducing genetic exchange and isolating members into distinct populations. But highly mobile, broadly distributed species may be less susceptible to such barriers and hence genetic subdivision. This study will identify if and how landscape characteristics mediate gene flow over three spatial scales in a mobile carnivore, the bobcat (Lynx rufus). At the local scale, telemetry, genetic, and landscape data will be combined to test whether habitat fragmentation influences movement and fine-scale genetic structuring of bobcats within an agricultural landscape. At the regional scale, genetic patterns will be used to delineate populations and identify landscape characteristics influencing recent expansions of bobcats into areas from which they had been extirpated. At the continental scale, DNA samples will be collected and analyzed from across the United States to determine whether landscape features also generate deeper, broad-scale genetic divergences that warrant recognition as distinct subspecies.

This project will lead to significant improvements in our understanding of how landscape characteristics may influence evolutionary and ecological processes in mobile species like bobcats. Such findings are important for evaluating the potential impact of landscape changes on population dynamics and species persistence, predicting the spread of emerging diseases, and effectively managing wildlife. This work will also foster science education through mentoring and outreach, and by providing a hands-on research experience for a high school biology teacher.