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Abstract: Estimation of division and death rates of lymphocytes in different conditionsis vital for quantitative understanding of the immune system. Deuterium, in theform of deuterated glucose or heavy water, can be used to measure rates ofproliferation and death of lymphocytes in vivo. Inferring these rates fromlabeling and delabeling curves has been subject to considerable debate withdifferent groups suggesting different mathematical models for that purpose. Weshow that the three models that are most commonly used are in factmathematically identical and differ only in their interpretation of theestimated parameters. By extending these previous models, we here propose amore mechanistic approach for the analysis of data from deuterium labelingexperiments. We construct a model of -kinetic heterogeneity- in which the totalcell population consists of many sub-populations with different rates of cellturnover. In this model, for a given distribution of the rates of turnover, thepredicted fraction of labeled DNA accumulated and lost can be calculated. Ourmodel reproduces several previously made experimental observations, such as anegative correlation between the length of the labeling period and the rate atwhich labeled DNA is lost after label cessation. We demonstrate the reliabilityof the new explicit kinetic heterogeneity model by applying it to artificiallygenerated datasets, and illustrate its usefulness by fitting experimental data.In contrast to previous models, the explicit kinetic heterogeneity model 1provides a mechanistic way of interpreting labeling data; 2 allows for anon-exponential loss of labeled cells during delabeling, and 3 can be used todescribe data with variable labeling length.



Author: Vitaly V. Ganusov, Jose Borghans, Rob De Boer

Source: https://arxiv.org/



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