58 research outputs found

    Disease-associated CAG·CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion

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    Artículo científico -- Universidad de Costa Rica, Instituto de Investigaciones en Salud. 2014Genetically unstable expanded CAG·CTG trinucleotide repeats are causal in a number of human disorders, including Huntington disease and myotonic dystrophy type 1. It is still widely assumed that DNA polymerase slippage during replication plays an important role in the accumulation of expansions. Nevertheless, somatic mosaicism correlates poorly with the proliferative capacity of the tissue and rates of cell turnover, suggesting that expansions can occur in the absence of replication. We monitored CAG·CTG repeat instability in transgenicmouse cells arrested by chemical or genetic manipulation of the cell cycle and generated unequivocal evidence for the continuous accumulation of repeat expansions in non-dividing cells. Importantly, the rates of expansion in non-dividing cells were at least as high as those of proliferating cells. These data are consistent with amajor role for cell division-independent expansion in generating somatic mosaicism in vivo. Although expansions can accrue in non-dividing cells, we also show that cell cycle arrest is not sufficient to drive instability, implicating other factors as the key regulators of tissue-specific instability. Our data reveal that de novo expansion events are not limited to S-phase and further support a cell divisionindependent mutational pathway.Universidad de Costa Rica. Instituto de Investigaciones en SaludInstitute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, GlasgowParis Descartes-Sorbonne Paris Cité UniversityUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

    Association analysis of ACE and ACTN3 in Elite Caucasian and East Asian Swimmers

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    Purpose: Polymorphic variation in the angiotensin-converting enzyme (ACE) and α-actinin-3 (ACTN3) genes has been reported to be associated with endurance and/or power-related human performance. Our aim was to investigate whether polymorphisms in ACE and ACTN3 are associated with elite swimmer status in Caucasian and East Asian populations. Methods: ACE I/D and ACTN3 R577X genotyping was carried out for 200 elite Caucasian swimmers from European, Commonwealth, Russian, and American cohorts (short and middle distance, ≤400 m, n = 130; long distance, >400 m, n = 70) and 326 elite Japanese and Taiwanese swimmers (short distance, ≤100 m, n = 166; middle distance, 200-400 m, n = 160). Genetic associations were evaluated by logistic regression and other tests accommodating multiple testing adjustment. Results: ACE I/D was associated with swimmer status in Caucasians, with the D allele being overrepresented in short-and-middle-distance swimmers under both additive and I-allele-dominant models (permutation test P = 0.003 and P = 0.0005, respectively). ACE I/D was also associated with swimmer status in East Asians. In this group, however, the I allele was overrepresented in the short-distance swimmer group (permutation test P = 0.041 and P = 0.0098 under the additive and the D-allele-dominant models, respectively). ACTN3 R577X was not significantly associated with swimmer status in either Caucasians or East Asians. Conclusions: ACE I/D associations were observed in these elite swimmer cohorts, with different risk alleles responsible for the associations in swimmers of different ethnicities. The functional ACTN3 R577X polymorphism did not show any significant association with elite swimmer status, despite numerous previous reports of associations with "power/sprint" performance in other sports

    The Scaling Relationship between Self-Potential and Fluid Flow on Masaya Volcano, Nicaragua

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    The concurrent measurement of self-potential (SP) and soil CO2 flux (FCO2s) in volcanic sys- tems may be an important tool to monitor intrusive activity and understand interaction between magmatic and groundwater systems. However, quantitative relationships between these parameters must be established to apply them toward understanding processes operating at depth. Power-law scaling exponents calculated for SP and FCO2s measured along a fault on the flanks of Masaya volcano, Nicaragua indicate a nonlinear relationship between these parameters. Scaling exponents suggest that there is a declining increase in SP with a given increase in FCO2s, until a threshold (log FCO2s ≈ 2.5 g m−2d−1) above which SP remains constant with increasing FCO2s. Implications for subsurface processes that may influence SP at Masaya are discussed

    A framework for predicting global silicate weathering and CO2 drawdown rates over geologic time-scales

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    Global silicate weathering drives long-time-scale fluctuations in atmospheric CO2. While tectonics, climate, and rock-type influence silicate weathering, it is unclear how these factors combine to drive global rates. Here, we explore whether local erosion rates, GCM-derived dust fluxes, temperature, and water balance can capture global variation in silicate weathering. Our spatially explicit approach predicts 1.9–4.6 × 1013 mols of Si weathered globally per year, within a factor of 4–10 of estimates of global silicate fluxes derived from riverine measurements. Similarly, our watershed-based estimates are within a factor of 4–18 (mean of 5.3) of the silica fluxes measured in the world's ten largest rivers. Eighty percent of total global silicate weathering product traveling as dissolved load occurs within a narrow range (0.01–0.5 mm/year) of erosion rates. Assuming each mol of Mg or Ca reacts with 1 mol of CO2, 1.5–3.3 × 108 tons/year of CO2 is consumed by silicate weathering, consistent with previously published estimates. Approximately 50% of this drawdown occurs in the world's active mountain belts, emphasizing the importance of tectonic regulation of global climate over geologic timescales
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