A Lac؊ strain of Escherichia coli that reverts by the addition of a G to a G-G-G-G-G-G sequence was used to study the proliferation of mutators in a bacterial culture. Selection for the Lac ؉ phenotype, which is greatly stimulated in mismatch repair-deficient strains, results in an increase in the percentage of mutators in the selected population from less than 1 per 100,000 cells to 1 per 200 cells. All the mutators detected were deficient in the mismatch repair system. Mutagenesis results in a similar increase in the percentage of mutators. Mutagenesis combined with a single selection can result in a population of more than 50% mutators when a sample of several thousand cells is grown out and selected. Mutagenesis combined with two or more successive selections can generate a population that is 100% mutator. These experiments are discussed in relation to ideas that an early step in carcinogenesis is the creation of a mutator phenotype.Although cells with higher spontaneous mutation rates, or mutators, have been studied for many years, the recent finding that the inherited form of human nonpolyposis colon cancer results from a defect in the human counterpart to the bacterial mismatch repair system and that this defect creates a mutator phenotype (1,7,18,33) has generated new excitement in the field of repair systems in general and focused renewed attention on mutators in particular. Loeb has suggested (21, 22) that tumor progression may require the creation of a mutator cell, since the multistage process of carcinogenesis (32), which probably occurs by genetic instability and clonal selection (8), depends on a series of mutations. The spontaneous mutation rate cannot account for the multiple mutations observed in human tumors, but if creation of a mutator occurs early in tumor progression, then the multiple mutations could be generated (21,22). Can mutators arise and proliferate rapidly enough in a cell population to play a role in carcinogenesis? The first mutators discovered in bacteria were found in existing laboratory strains (27,37). Early experiments on detecting mutators dealt with screening isolates in the wild (12, 16) and also involved mutagenized populations of bacteria, sometimes coupled to different selections (6,13,14,19). For example, Jyssum (16) found that 4 of 110 natural isolates of Escherichia coli from patients were mutators, while Gross and Siegel (12) detected mutator activity in 1 of 408 natural E. coli isolates. Such findings suggested that natural populations might be undergoing constant selection, since competition experiments in chemostats showed that under certain conditions mutators have increased fitness in a population (2,4,11,29). Siegel and Bryson (35,36) discovered the mutS gene after observing the mutator phenotype of a strain selected to be azaserine resistant. Also, Helling (13) mutagenized cells and selected for streptomycin-resistant cells and then screened for mutator activity and detected examples of mutators carrying mutT defects, and Hoess and Herman utilized a multip...

Abstract-In response to the increasing variations in integrated-circuit manufacturing, the current trend is to create designs that take these variations into account statistically. In this paper, we quantify the difference between the statistical and deterministic optima of leakage power while making no assumptions about the delay model. We develop a framework for deriving a theoretical upper bound on the suboptimality that is incurred by using the deterministic optimum as an approximation for the statistical optimum. We show that for the mean power measure, the deterministic optima is an excellent approximation, and for the mean plus standard deviation measures, the optimality gap increases as the amount of inter-die variation grows, for a suite of benchmark circuits in a 45 nm technology. For large variations, we show that there are excellent linear approximations that can be used to approximate the effects of variation. Therefore, the need to develop special statistical power optimization algorithms is questionable.

Background: Morselized bone components have been shown to induce an in ammatory response after long bone fracture. Given that similar components are often utilized in calvarial reconstruction, we hypothesized that a connection exists between the in ammatory response generated by these morselized bone components and subsequent bone healing. In the current study, we sought to determine the effects of speci c in ammatory mediators on osteogenic differentiation. Methods:A mouse myoblast cell line (C2C12) with an established response to BMP2 stimulation was utilized and their response to BMP2 alone, and BMP2 in combination with speci c in ammatory mediators was quanti ed. Treatment groups included proliferation medium (negative control), BMP2, and BMP2 in combination with TGFOE≤1, TGFOE≤2, TGFOE≤3, TNFOE±, IL-10, or HMGB1. After 24 hours, cells underwent alkaline phosphatase (ALP) staining, quantitative ALP activity assay, and MTS cell proliferation assay. Quantitative PCR was used to analyze gene expression of the bone-related genes RUNX2, OSX, TGFOE≤1, 2 & 3, and FGFR2. One-way ANOVA analysis was used, with p<0.05 being signi cant.