Possibilities for Refinement and Reduction: Future Improvements Within Regulatory Testing

Approaches and challenges to refining and reducing animal use in regulatory testing are reviewed. Regulatory testing accounts for the majority of animals reported in the most painful and/or distressful categories in the United States and Canada. Refinements in testing, including the use of humane endpoints, are of increasing concern. Traditional approaches to reduction (e.g., improving experimental design) are being supplemented with complementary approaches, such as the use of tier testing to eliminate some chemicals prior to in vivo testing. Technological advances in telemetry and noninvasive techniques will help decrease either the demand for animals in testing or animal suffering. Further decreases in animal use will stem from international harmonization and coordination of testing programs. Progress in refinement and reduction faces a variety of broad challenges, including limited funding for research. In the specific area of refinement, a key challenge is the issue of distress (as distinct from pain). In the area of reduction, the practice of using unjustifiably high numbers of animals from small species (e.g., rodents) should be challenged. One case study of the use of carbon dioxide as a euthanasia agent illustrates the need for further analysis and research. Notwithstanding the complexities and challenges, the potential for refinement and reduction in regulatory testing is encouraging

Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex

Peer reviewedPublisher PD

The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

Peer reviewedPublisher PD

Estilos de vida en personas con sobrepeso del Centro Médico Parroquial San Martín de Porres de Villa El Salvador, 2021

Objetivo: Determinar los estilos de vida en personas con sobrepeso del Centro Médico Parroquial San Martín de Porres de Villa El Salvador, 2021. Materiales y métodos: El enfoque fue cuantitativo, su diseño fue el descriptivo- transversal. La técnica de recolección de información fue la encuesta y el instrumento empleado fue el cuestionario FANTASTICO. Resultados: El nivel de estilo de vida tuvo mayor predomino el nivel regular con 38%, seguido del nivel excelente con 22,2%, nivel bueno con 16,7%, nivel malo con 15,7% y existe peligro con 7,4%. En cuanto a las dimensiones, familia y amigos el nivel excelente con un 83,3%,actividad física prevaleció el nivel excelente con 77,8%, nutrición el nivel malo con un 54,6%, tabaco y toxinas prevaleció el nivel existe peligro con 74,1%, alcohol el nivel existe peligro con 61,1%, sueño y estrés prevaleció el nivel malo con 38%, tipo de personalidad el nivel excelente con 59,3%,introspección prevaleció el nivel malo con 46,3% , control de la sexualidad el nivel excelente con 76,9% y en otros prevaleció el nivel regular con 38%. Conclusiones: El estilo de vida de los participantes, predomino el nivel regular, seguido del excelente, bueno, malo y existe peligro

Energia, Ambiente, Progettazione e Certificazioni

Organizzazione scientifica del Seminario "Energia, Ambiente, Progettazione e Certificazioni" tenutosi presso la sede dell'Ordine degli Architetti di Latina dal 16 al 30 marzo 2011. Programma del Seminario: - Normativa sul rendimento energetico in edilizia - Progetto e certificazione ambientale - Progetto e certificazione energetico- ambientale - Progetto di restauro e certificazione energetica - Innovazione tecnologica e risparmio energetic

The effects of manipulating levels of replication initiation factors on origin firing efficiency in yeast.

Chromosome replication in Saccharomyces cerevisiae is initiated from ~300 origins that are regulated by DNA sequence and by the limited abundance of six trans-acting initiation proteins (Sld2, Sld3, Dpb11, Dbf4, Sld7 and Cdc45). We set out to determine how the levels of individual factors contribute to time of origin activation and/or origin efficiency using induced depletion of single factors and overexpression of sets of multiple factors. Depletion of Sld2 or Sld3 slows growth and S phase progression, decreases origin efficiency across the genome and impairs viability as a result of incomplete replication of the rDNA. We find that the most efficient early origins are relatively unaffected by depletion of either Sld2 or Sld3. However, Sld3 levels, and to a lesser extent Sld2 levels, are critical for firing of the less efficient early origins. Overexpression of Sld3 simultaneously with Sld2, Dpb11 and Dbf4 preserves the relative efficiency of origins. Only when Cdc45 and Sld7 are also overexpressed is origin efficiency equalized between early- and late-firing origins. Our data support a model in which Sld3 together with Cdc45 (and/or Sld7) is responsible for the differential efficiencies of origins across the yeast genome

Replication in Hydroxyurea: It's a Matter of Time▿ †

Hydroxyurea (HU) is a DNA replication inhibitor that negatively affects both the elongation and initiation phases of replication and triggers the “intra-S phase checkpoint.” Previous work with budding yeast has shown that, during a short exposure to HU, MEC1/RAD53 prevent initiation at some late S phase origins. In this study, we have performed microarray experiments to follow the fate of all origins over an extended exposure to HU. We show that the genome-wide progression of DNA synthesis, including origin activation, follows the same pattern in the presence of HU as in its absence, although the time frames are very different. We find no evidence for a specific effect that excludes initiation from late origins. Rather, HU causes S phase to proceed in slow motion; all temporal classes of origins are affected, but the order in which they become active is maintained. We propose a revised model for the checkpoint response to HU that accounts for the continued but slowed pace of the temporal program of origin activation

A natural polymorphism in rDNA replication origins links origin activation with calorie restriction and lifespan.

Aging and longevity are complex traits influenced by genetic and environmental factors. To identify quantitative trait loci (QTLs) that control replicative lifespan, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard and a laboratory strain. The predominant QTL mapped to the rDNA, with the vineyard rDNA conferring a lifespan increase of 41%. The lifespan extension was independent of Sir2 and Fob1, but depended on a polymorphism in the rDNA origin of replication from the vineyard strain that reduced origin activation relative to the laboratory origin. Strains carrying vineyard rDNA origins have increased capacity for replication initiation at weak plasmid and genomic origins, suggesting that inability to complete genome replication presents a major impediment to replicative lifespan. Calorie restriction, a conserved mediator of lifespan extension that is also independent of Sir2 and Fob1, reduces rDNA origin firing in both laboratory and vineyard rDNA. Our results are consistent with the possibility that calorie restriction, similarly to the vineyard rDNA polymorphism, modulates replicative lifespan through control of rDNA origin activation, which in turn affects genome replication dynamics