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      A branching process model for flow cytometry and budding index measurements in cell synchrony experiments

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          Abstract

          We present a flexible branching process model for cell population dynamics in synchrony/time-series experiments used to study important cellular processes. Its formulation is constructive, based on an accounting of the unique cohorts in the population as they arise and evolve over time, allowing it to be written in closed form. The model can attribute effects to subsets of the population, providing flexibility not available using the models historically applied to these populations. It provides a tool for in silico synchronization of the population and can be used to deconvolve population-level experimental measurements, such as temporal expression profiles. It also allows for the direct comparison of assay measurements made from multiple experiments. The model can be fit either to budding index or DNA content measurements, or both, and is easily adaptable to new forms of data. The ability to use DNA content data makes the model applicable to almost any organism. We describe the model and illustrate its utility and flexibility in a study of cell cycle progression in the yeast Saccharomyces cerevisiae.

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          Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division

          The budding yeast, Saccharomyces cerevisiae, was grown exponentially at different rates in the presence of growth rate-limiting concentrations of a protein synthesis inhibitor, cycloheximide. The volumes of the parent cell and the bud were determined as were the intervals of the cell cycle devoted to the unbudded and budded periods. We found that S. cerevisiae cells divide unequally. The daughter cell (the cell produced at division by the bud of the previous cycle) is smaller and has a longer subsequent cell cycle than the parent cell which produced it. During the budded period most of the volume increase occurs in the bud and very little in the parent cell, while during the unbudded period both the daughter and the parent cell increase significantly in volume. The length of the budded interval of the cell cycle varies little as a function of population doubling time; the unbudded interval of the parent cell varies moderately; and the unbudded interval for the daughter cell varies greatly (in the latter case an increase of 100 min in population doubling time results in an increase of 124 min in the daughter cell's unbudded interval). All of the increase in the unbudded period occurs in that interval of G1 that precedes the point of cell cycle arrest by the S. cerevisiae alpha-mating factor. These results are qualitatively consistent with and support the model for the coordination of growth and division (Johnston, G. C., J. R. Pringle, and L. H. Hartwell. 1977. Exp. Cell. Res. 105:79-98.) This model states that growth and not the events of the DNA division cycle are rate limiting for cellular proliferation and that the attainment of a critical cell size is a necessary prerequisite for the "start" event in the DNA-division cycle, the event that requires the cdc 28 gene product, is inhibited by mating factor and results in duplication of the spindle pole body.
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            Butyrolactone: more than a kinase inhibitor?

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              Statistical resynchronization and Bayesian detection of periodically expressed genes.

              We propose a periodic-normal mixture (PNM) model to fit transcription profiles of periodically expressed (PE) genes in cell cycle microarray experiments. The model leads to a principled statistical estimation procedure that produces more accurate estimates of the mean cell cycle length and the gene expression periodicity than existing heuristic approaches. A central component of the proposed procedure is the resynchronization of the observed transcription profile of each PE gene according to the PNM with estimated periodicity parameters. By using a two-component mixture-Beta model to approximate the PNM fitting residuals, we employ an empirical Bayes method to detect PE genes. We estimate that about one-third of the genes in the genome of Saccharomyces cerevisiae are likely to be transcribed periodically, and identify 822 genes whose posterior probabilities of being PE are greater than 0.95. Among these 822 genes, 540 are also in the list of 800 genes detected by Spellman. Gene ontology annotation analysis shows that many of the 822 genes were involved in important cell cycle-related processes, functions and components. When matching the 822 resynchronized expression profiles of three independent experiments, little phase shifts were observed, indicating that the three synchronization methods might have brought cells to the same phase at the time of release.
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                Author and article information

                Journal
                2010-09-28
                Article
                10.1214/09-AOAS264
                1009.5745
                56de56a1-a488-475c-8e2b-ea24fe370304

                http://arxiv.org/licenses/nonexclusive-distrib/1.0/

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                IMS-AOAS-AOAS264
                Annals of Applied Statistics 2009, Vol. 3, No. 4, 1521-1541
                Published in at http://dx.doi.org/10.1214/09-AOAS264 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)
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