Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.

In eukaryotic chromosomes, DNA replication initiates at multiple origins. Large inter-origin gaps arise when several adjacent origins fail to fire. Little is known about how cells cope with this situation. We created a derivative of Saccharomyces cerevisiae chromosome III lacking all efficient origins, the 5ORIΔ-ΔR fragment, as a model for chromosomes with large inter-origin gaps. We used this construct in a modified synthetic genetic array screen to identify genes whose products facilitate replication of long inter-origin gaps. Genes identified are enriched in components of the DNA damage and replication stress signaling pathways. Mrc1p is activated by replication stress and mediates transduction of the replication stress signal to downstream proteins; however, the response-defective mrc1AQ allele did not affect 5ORIΔ-ΔR fragment maintenance, indicating that this pathway does not contribute to its stability. Deletions of genes encoding the DNA-damage-specific mediator, Rad9p, and several components shared between the two signaling pathways preferentially destabilized the 5ORIΔ-ΔR fragment, implicating the DNA damage response pathway in its maintenance. We found unexpected differences between contributions of components of the DNA damage response pathway to maintenance of ORIΔ chromosome derivatives and their contributions to DNA repair. Of the effector kinases encoded by RAD53 and CHK1, Chk1p appears to be more important in wild-type cells for reducing chromosomal instability caused by origin depletion, while Rad53p becomes important in the absence of Chk1p. In contrast, RAD53 plays a more important role than CHK1 in cell survival and replication fork stability following treatment with DNA damaging agents and hydroxyurea. Maintenance of ORIΔ chromosomes does not depend on homologous recombination. These observations suggest that a DNA-damage-independent mechanism enhances ORIΔ chromosome stability. Thus, components of the DNA damage response pathway contribute to genome stability, not simply by detecting and responding to DNA template damage, but also by facilitating replication of large inter-origin gaps.

Eukaryotic chromosomes are duplicated during S phase and transmitted to progeny during mitosis with high fidelity. Chromosome duplication is controlled at the level of replication initiation, which occurs at cis-acting replicator sequences that are spaced at intervals of $40 kb along the chromosomes of the budding yeast Saccharomyces cerevisiae. Surprisingly, we found that derivatives of yeast chromosome III that lack known replicators were replicated and segregated properly in at least 96% of cell divisions. To gain insight into the mechanisms that maintain these ''originless'' chromosome fragments, we screened for mutants defective in the maintenance of an ''originless'' chromosome fragment, but proficient in the maintenance of the same fragment that carries its normal complement of replicators (originless fragment maintenance mutants, or ofm). We show that three of these Ofm mutations appear to disrupt different processes involved in chromosome transmission. The OFM1-1 mutant seems to disrupt an alternative initiation mechanism, and the ofm6 mutant appears to be defective in replication fork progression. ofm14 is an allele of RAD9, which is required for the activation of the DNA damage checkpoint, suggesting that this checkpoint plays a key role in the maintenance of the ''originless'' fragment.

The first experiments on the National Ignition Facility (NIF) have employed the first four beams to measure propagation and laser backscattering losses in large ignition-size plasmas. Gas-filled targets between 2 and 7 mm length have been heated from one side by overlapping the focal spots of the four beams from one quad operated at 351 nm (3ω) with a total intensity of 2 × 1015 W cm−2. The targets were filled with 1 atm of CO2 producing up to 7 mm long homogeneously heated plasmas with densities of ne = 6 × 1020 cm−3 and temperatures of Te = 2 keV. The high energy in an NIF quad of beams of 16 kJ, illuminating the target from one direction, creates unique conditions for the study of laser–plasma interactions at scale lengths not previously accessible. The propagation through the large-scale plasma was measured with a gated x-ray imager that was filtered for 3.5 keV x-rays. These data indicate that the beams interact with the full length of this ignition-scale plasma during the last ∼1 ns of the experiment. During that time, the full aperture measurements of the stimulated Brillouin scattering and stimulated Raman scattering show scattering into the four focusing lenses of 3% for the smallest length (∼2 mm), increasing to 10–12% for ∼7 mm. These results demonstrate the NIF experimental capabilities and further provide a benchmark for three-dimensional modelling of the laser–plasma interactions at ignition-size scale lengths.

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