14,184 research outputs found

    The Biophysics Of Leukocyte Adhesion Deficiency

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    In order to perform an effective immune response, leukocytes must be able to exit the vasculature and enter the interstitial space. The leukocyte adhesion cascade has evolved to slow and stop cells to allow this access. Despite extensive molecular characterization, there are still significant questions regarding the biophysical constraints of the cascade. In this thesis, we explore the requirements for cells to physically complete the adhesion cascade. In the first aim, we confirm previously published predictions regarding the synergy between E-selectin and ICAM-1, showing that a consistent level of leukocyte adhesion can be maintained using varying ratios of the two molecules. We also show that T cells require O(10^0) sites/µm^2 to support tethering, O(10^1) sites/µm^2 to support rolling, and O(10^2) sites/µm^2 to cause arrest. In addition, we characterized the migration of T cells against the direction of flow. We discovered that cells determine their direction of migration within 30 seconds of arrest. We also found that cells migrating upstream transmigrate across a HUVEC monolayer faster than cells crawling downstream. In the second aim, we determined that cells attached to a surface through a series of linkages show a non-linear decrease in the critical detachment force as the number of linkages increases. We also showed that the intrinsic off rate of the linkages can control the critical force, while the spring constant of the linkages causes less of a change. Finally, in the third aim we used simulations to quantitatively predict the effect of depletion of kindlin-3 on cellular adhesion. We predicted that adhesion would be hypersensitive to kindlin-3 expression, requiring a reduction to below 20% of normal expression levels to see an effect. We also predicted that rolling velocity would be independent of kindlin-3 expression, while both time and distance to stop would increase with decreasing kindlin-3 expression. Experiments using the Jurkat T cell line supported these predictions, with a significant decrease in cell adhesion, no change in rolling velocity, and an increase in the time to stop. Together, these aims suggest that we now have the knowledge to improve leukocyte targeting through engineering the leukocyte adhesion cascade

    Damages for Sellers under the Code\u27s Profit Formula

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    London government in transition : L.C.C. to G.L.C. 1962-1967

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    A thesis submitted for the degree of Doctor of Philosophy of the University of LutonThis thesis concentrates upon a largely neglected subject wi thin contemporary political history, that is the transition in London government from the London County Council (L.C.C.) to the Greater London Council (G.L.C.). It is a study of the actions and reactions of poli tical parties at central government, county council, and district council level, and incorporates the role of non-political party pressure groups. The bulk of the thesis is concerned with the L.C.C. area. Consideration is, however, given to the non-L.C.C. area incorporated into the larger C.L.C. This work demonstrates that there was no consensus regarding the need for reform. It is argued that the lack of consensus led to compromises that failed to satisfy many interested groups and thus the C.L.C. was often perceived to be flawed. This thesis derives from an exhaustive literature search and extensive reading. The records of political parties were very useful. Newspapers and journals aided research, as did a series of interviews with key surviving individuals. A further source of information were the minutes of various local authorities and connected bodies. Previously unavailable records have been used, for example, Conservative Party and Government records. With the aid of these new sources this work uniquely concentrates on exposing the political constraints and biases that caused a flawed local government system to be introduced

    Of Mack Trucks, Road Bugs, Gilmore and Danzig: Happy Birthday Hadley v. Baxendale

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    It is testimony to the status of the great case of Hadley v. Baxendale\u27 that even after 150 years helpful discussion and learning can result from a two-day conference of experienced contracts teachers with the case itself as the centerpiece. As the renderings in the pages of this volume attest, such indeed resulted from a merry gathering in Gloucester, England in June 2004
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