It has been shown that, during the S-phase of the cell cycle, the mouse DNA methyltransferase (DNA MTase) is targeted to sites of DNA replication by an amino acid sequence (aa 207-455) lying in the N-terminal domain of the enzyme [Leonhardt, H., Page, A. W., Weier, H. U. and Bestor, T. H. (1992) Cell , 71, 865-873]. In this paper it is shown, by using enhanced green fluorescent protein (EGFP) fusions, that other peptide sequences of DNA MTase are also involved in this targeting. The work focuses on a sequence, downstream of the reported targeting sequence (TS), which is homologous to the Polybromo-1 protein. This motif (designated as PBHD) is separated from the reported targeting sequence by a zinc-binding motif [Bestor , T. H. (1992) EMBO J , 11, 2611-2617]. Primed in situ extension using centromeric-specific primers was used to show that both the host DNA MTase and EGFP fusion proteins containing the targeting sequences were localized to centromeric, but not telomeric, regions during late S-phase and mitosis. Also found was that, in approximately 10% of the S-phase cells, the EGFP fusions did not co-localize with the centromeric regions. Mutants containing either, or both, of these targeting sequences could act as dominant negative mutants against the host DNA MTase. EGFP fusion proteins, containing the reported TS (aa 207-455), were targeted to centromeric regions throughout the mitotic stage which lead to the discovery of a similar behavior of the endogenous DNA MTase although the host MTase showed much less intense staining than in S-phase cells. The biological role of the centromeric localization of DNA MTase during mitosis is currently unknown.
The mean residual life function is an attractive alternative to the survival function or the hazard function of a survival time in practice. It provides the remaining life expectancy of a subject surviving up to time t. In this study, we propose a class of transformed mean residual life models for fitting survival data under right censoring. To estimate the model parameters, we make use of the inverse probability of censoring weighting approach and develop a system of estimating equations. Efficiency and robustness of the estimators are also studied. Both asymptotic and finite sample properties of the proposed estimators are established and the approach is applied to two real-life datasets collected from clinical trials.
Multivariate failure time data frequently occur in medical studies and the dependence or association among survival variables is often of interest ("Biometrics", 51 , 1995, 1384; "Stat. Med.", 18 , 1999, 3101; "Biometrika", 87 , 2000, 879; "J. Roy. Statist. Soc. Ser. B", 65 , 2003, 257). We study the problem of estimating the association between two related survival variables when they follow a copula model and only bivariate interval-censored failure time data are available. For the problem, a two-stage estimation procedure is proposed and the asymptotic properties of the proposed estimator are established. Simulation studies are conducted to assess the finite sample properties of the presented estimate and the results suggest that the method works well for practical situations. An example from an acquired immunodeficiency syndrome clinical trial is discussed. Copyright 2006 Board of the Foundation of the Scandinavian Journal of Statistics..
We have previously shown that in developing chicken embryos and differentiating mouse myoblasts, the demethylation of 5-metCpGs occurs through the replacement of 5-methylcytosine by cytosine (Jost, J. P. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 4685-4688; Jost, J. P. & Jost, Y.C. (1994) J. Biol. Chem. 269, 10040-10043). We have now purified over 30,000-fold a 5-methylcytosine-DNA glycosylase from 12-day-old chicken embryos. The enzyme copurifies with a mismatch-specific thymine-DNA glycosylase and an apyrimidic-endonuclease. The reaction product of the highly purified 5-methylcytosine-DNA glycosylase is 5-methylcytosine. The copurified apyrimidic-endonuclease activity cleaves 3' from the apyrimidic sugar. A 52.5-kDa peptide, isolated as a single band from preparative SDS-polyacrylamide gels, has both the 5-methylcytosine-DNA glycosylase and the mismatch-specific thymine-DNA glycosylase activities. 5-Methylcytosine-DNA glycosylase has an apparent pI of 5.5-7.5 and maximal activity between pH 6.5 and 7.5. The Km for hemimethylated oligonucleotide substrate is 8 x 10(-8) M with a Vmax of 4 x 10(-11) mol/h/micrograms proteins. 5-Methylcytosine-DNA glycosylase binds equally well to methylated and non-methylated DNA. The enzyme reacts six times faster with the hemimethylated DNA than with the same bifilarly methylated DNA sequence, and single-stranded methylated DNA is not a substrate. The action of the enzyme is distributive.
The authors consider the estimation of regression parameters in the context of a class of generalized proportional hazards models, termed linear transformation models, in the presence of interval‐censored data. They present an estimating equation approach whose good performance is demonstrated through simulations and which they illustrate in a few concrete cases.
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