Synthetic exogenous surfactant preparations have significant potential advantages as pharmacologic products compared to animal-derived clinical surfactants

reaction as h{ X,c{ ~c{ XDSBC, 2 2 2 4 Calculation methods for DSB-production model In this paper, we assume the following schemes of a stochastic production mechanism of DSBs and their repair processes: 1 DCADSB DSBzRP DSBC / c2c2z c1 h3 X,c3 ~c3 XDSBC: 1 5 DSBC DCARDSBzRP c3 The above equations allow us to calculate Xi for each molecular type i by using the Gillespie algorithm. For example, a time course of XDSB zXDSBC is shown in A Model for ATM Sensor state, but its 16483784 value is a little different from the theoretical value. The time until the ensemble approaches the steady state is larger than the theoretical value. In Comparison of theoretical and simulation results In this section, we compare simulation and theoretical results of mean values of DSBs and DSBCs. Methods for calculating the theoretical mean values of DSBs and DSBCs are shown in the Materials and Methods section. The precise mechanism of DNA damage processes induced by stress signals has not been clarified yet, and we cannot estimate the stochastic rate constants. In this paper, we assume that the stochastic rate constants cz, c{, and c3 2 2 are not affected by stress signals, and their values are defined in DSB module Description Xi c1 cz 2 c{ 2 c3 kDSB t The number of molecules of type i The stochastic 12504917 rate constant for the DSB production step The stochastic rate constant for the DSBC production step The stochastic rate constant for DSBC failure The stochastic rate constant for DSBC success DSB- and DSBC-dependent phosphorylation rate of ATM In higher eukaryotes, DNA double strand breaks are predominantly repaired by a simple end joining process mediated by ligation that operates without homology requirements and is therefore termed non-homologous end joining . The main task of NHEJ is the restoration of structural integrity in broken DNA molecules, as it has no build-in mechanisms ensuring the preservation of DNA sequence at the break. As a consequence, NHEJ is associated with additions or deletions of nucleotides at the junction that alter the genome leaving scarsbehind. Sequence preservation, when it occurs, is fortuitous and observed only for certain types of cleanDNA ends generated by restriction endonucleases – it is unlikely for the chemically complex, modified ends generated by ionizing radiation. The dominance of NHEJ in DSB processing that manifests in higher eukaryotes coincides with the evolutionary appearance of DNA-PKcs. Likely, DNA-PKcs optimized the functions of preexisting DNA end joining factors – mainly the orthologs of KU, DNA ligase IV as well as of polymerases m and l, in bacteria and yeast – to generate a highly efficient mechanism capable of sealing, with half times of only a few minutes, large numbers of DSBs. The NHEJ pathway that evolved in this way is frequently referred to as classical or canonical to distinguish it from other repair pathways operating on similar order BMS 650032 principles . We opt for the term DNA-PKcsdependent for this pathway to emphasize the significance of this kinase in its evolutionary development. D-NHEJ starts with the recognition and binding to the DNA ends of KU. DNA-bound KU recruits and activates DNA-PKcs, which in turn phosphorylates numerous proteins including most components of D-NHEJ and DNA-PKcs itself. The latter autophosphorylation releases DNA-PKcs from the DNA ends and facilitates their modification by DNA endprocessing activities such as Artemis, and PNK, as well as the addition of nucleotides by DNA polymerases m a