Natural Killer (NK) cell, a crucial player of the human innate immune defense system, detects and kills virus-infected cells and cancer cells. Although the relevant molecular machineries involved in NK cell activation and NK-target cell interactions are largely known, how their collected dynamics regulate fast yet highly selective target cell killing in the complex environment of tissues is poorly understood. In traditional bulk killing assays, heterogeneity and kinetic details of individual NK-target cell interactions are masked, seriously limiting analysis of the underlying dynamic mechanisms. Therefore, the aim of my PhD study is to develop quantitative microscopy assays to elucidate, at the single cell level, real-time killing dynamics of epithelial cancer cells by primary NK cells purified from human blood. Results from my study not only identified the rate-limiting kinetics in NK-cancer cell interaction and mechanistically relevant heterogeneity in the process, but also characterized key molecular events and regulatory components of the NK cell machinery that were associated with the observed cytotoxic dynamics and heterogeneity. NK cells are considered promising candidate for cancer treatment, especially for eliminating residual cancer cells after conventional therapy. The fundamental knowledge acquired from my PhD study, in particular regarding how killing by primary NK cell varies between different target cancer cell types, provides new mechanistic insight that may help to develop this treatment strategy. And the quantitative microscopy assays that I developed are readily extendable to analysis of other cell-cell interaction dynamics, e.g., involved in cytotoxic T cell function.

Thesis (Ph. D.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 163-179).

Thesis (M.E.S.)--Evergreen State College, 2009. / "June 2009." Title from title screen (viewed 4/8/2010). Includes bibliographical references (p. 41-48).

Underwater vocalizations were recorded from pods of wild killer whales (Oreinus orca) off Vancouver Island, British Columbia, during 1978-83. Acoustic exchanges within pods are dominated by repetitious, pulsed calls which can be organized into discrete categories. Repeated encounters with 16 photographically-identified 'resident' pods demonstrate that each pod produces a repertoire of 7 to 17 (mean = 10.7) discrete call types. Recordings of captive whales of known pod origin and historical field recordings indicate that pod repertoires remain stable for periods of at least 18 years (1965-83) and possibly 25 years (1958-83). Each individual whale appears capable of producing most or all of the calls in it's pod's repertoire. Repertoires are apparently learned. All discrete call types tend to be used in all 'active' contexts, which consist mainly of foraging and travelling. Few call types are clearly correlated with specific behaviours. Activities involving tight group formation and physical interaction among pod members were accompanied by an increase in the use of whistles and variable pulsed sounds. Significant differences exist among the call repertoires of different pods. The 16 resident pods on the B.C. coast can be arranged into 4 acoustic associations, each of which has a unique set of discrete call types. These associations are referred to as 'call traditions', and the pods belonging to a tradition form a 'clan'. Pods within each clan share some call types, but may also produce unique calls. Shared calls often have different pod-specific renditions. These differences form a system of related dialects within each call tradition. Three of the four resident clans belong to a single community, and pods from these clans frequently associate with one another. Observed patterns of association were often unrelated to acoustic relationships. The fourth resident clan forms a community with a separate range. A community of 17 'transient' pods is sympatric with but socially isolated from the resident communities. This community has a wide range, and appears to consist of a single call tradition. The call traditions and dialects described here are apparently unique among mammals. Various hypotheses to account for their origin and adaptive significance are discussed. Clans could represent independent lineages which arrived on the B.C. coast through a series of unrelated founding events. As the founding pod of each clan grew and divided, its group-specific call repertoire diverged, either through functionless cultural drift or by an active process promoting acoustic differentiation of related groups. Dialects may have no selective value, or they may serve as kin-recognition signals for maintaining pod cohesion and identity or avoiding excessive inbreeding. / Science, Faculty of / Zoology, Department of / Graduate

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 87-95).

Thesis (M.Sc.(Zoology and Entomology))--University of Pretoria, 2008. / The thesis is structured as three separate papers to be submitted to journals for publication, with a single reference list at the end. Includes bibliographical references (leaves 130-147).

Field observations were collected to assess the social behaviour and foraging strategies of free-ranging killer whales from the eastern North Pacific (near Vancouver Island, Canada) and the western South Atlantic (near Peninsula Valdez, Argentina). The Vancouver Island study concentrated on the environmental correlates of group size and the behavioural dynamics of social groups. There were no correlations between foraging behaviour and small-scale habitat use, however both group size and the spatial distribution of groups were correlated with foraging behaviour. In Argentina the subject whales intentionally stranded to capture pup sea lions. It was possible to observe details of prey choice and foraging strategy. Three social groups were observed in the study area. Area use suggested that the different groups were employing different strategies. Whales within social groups shared prey, but one group would exclude another from the best hunting areas. Whales invested the greatest effort in the area of highest yield, and on the prey-type that required the least effort to catch. Energetic calculations suggested that the rate at which these whales captured sea lion prey was just sufficient to sustain them. Two genetic components, the hypervariable 'minisatellite' loci, and the mitochondrial genome were investigated for each study population. In addition, further samples from Iceland and other populations near the sites at Peninsula Valdez and Vancouver Island were analysed. Whales within social groups at Peninsula Valdez were more closely related than between social groups. In general, whales within local populations had very high levels of genetic similarity compared to between population comparisons. This implies inbreeding within and genetic isolation between populations. Two genetically isolated populations (both near Vancouver Island) were sympatric, and the degree of genetic isolation was equal to the level seen for comparisons between the Atlantic and Pacific. A hypothesis is presented on the role of resource exploitation in the structuring of social groups, and the consequences for the genetic structuring of populations.

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

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