14 research outputs found

### The time evolution of âŒ©<i>C</i><sub><i>n</i></sub>âŒª.

<p>Time evolution of âŒ©<i>C</i><sub><i>n</i></sub>âŒª corresponding to the three cases in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132397#pone.0132397.g002" target="_blank">Fig 2(A), 2(B) and 2(C)</a> shown in solid, dotted and dashed lines, respectively.</p

### <i>P</i>(<i>C</i><sub><i>n</i></sub>, <i>t</i>) converges on a stationary distribution.

<p><i>P</i>(<i>C</i><sub><i>n</i></sub>, <i>t</i>) for <i>C</i><sub>0</sub> = 1 and <i>t</i> = 0.001 + 0.4<i>n</i> where <i>n</i> = 0, 1, 2, 3, â€¦10 for the parameter values of <i>Î³</i> = 1, <i>Ïµ</i> = 0.5, <i>Î²</i> = 500 [panel (A)]; <i>Î³</i> = 1, <i>Ïµ</i> = 0.5, <i>Î²</i> = 50 [panel (B)]; <i>Î³</i> = 0.5, <i>Ïµ</i> = 0.5, <i>Î²</i> = 5 [panel (C)]. The initial PDF <i>P</i>(<i>C</i><sub>0</sub>, 0) = <i>Î´</i>(<i>C</i><sub>0</sub> âˆ’ 1) is shown in a vertical dotted line; the stationary PDF at <i>t</i> = 4 is shown in a thick solid line in panels (A)-(C). Stationary PDFs in panels (A)-(C) are superimposed in panel (D).</p

### Evolution under noisy selection regimes.

<p>Initial distributions (solid line) and fitness functions (dotted line) are plotted for various selection regimes. Panel (A) is representative of a directed (positive) selection regime, panel (B) is representative of a stabilizing selection regime, while panel (C) is representative of a selection regime representative of therapeutic treatment.</p

### High- and low-<i>Î²</i> limits for âŸ¨<i>C</i><sub><i>n</i></sub>âŸ©.

<p>Various trajectories for âŸ¨<i>C</i><sub><i>n</i></sub>âŸ© for increasing <i>Ïµ</i>/<i>Î·</i> plotted for various <i>Î²</i> at <i>Î³</i> = 0.5. Shown are <i>Î²</i> values where <i>Î²</i> = 10<sup><i>n</i></sup> (<i>n</i> = âˆ’0.5, 0, 0.5, â€¦, 2.0). Trajectories of âŸ¨<i>C</i><sub><i>n</i></sub>âŸ© approach a limit as <i>Î²</i> increases from small <i>Î²</i> = 10<sup>âˆ’0.5</sup> (long dashes) to large <i>Î²</i> = 10<sup>2</sup> (right-most solid).</p

### Growth rate variability of <i>C</i><sub><i>n</i></sub>.

<p>Local growth rates of <i>Ï‡</i>(<i>C</i><sub><i>n</i></sub>, <i>t</i>) corresponding to the three cases in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132397#pone.0132397.g002" target="_blank">Fig 2(A), 2(B) and 2(C)</a> shown in solid, dotted and dashed lines, respectively. Negative growth rates are not shown in panel (A)-(C). <i>Ï‡</i>(<i>C</i><sub><i>n</i></sub>, <i>t</i>) at <i>t</i> = 0.8 in panel (A), (B), and (C) are plotted together in panel (D).</p

### Variability of population is influenced by both the magnitude and auto-correlation properties of noise.

<p>Time evolution of <i>P</i>(<i>C</i><sub><i>l</i></sub>, <i>t</i>) shown at <i>t</i> = 0.001 + 0.4<i>n</i> (<i>n</i> = 0, 1, 2, â€¦10) for <i>C</i><sub>0</sub> = 1. <i>Ï„</i><sub><i>c</i></sub> = 0.01 and <i>D</i> = 100 in panel (A); <i>Ï„</i><sub><i>c</i></sub> = 1 and <i>D</i> = 1 in panel (B); <i>Ï„</i><sub><i>c</i></sub> = 0.01 and <i>D</i> = 1 in panel (C). Time increases from narrower to wider distributions in each panel.</p

### Biochemical Characterization of Eight Genetic Variants of Human DNA Polymerase Îº Involved in Error-Free Bypass across Bulky <i>N</i><sup>2</sup>â€‘Guanyl DNA Adducts

DNA polymerase (pol) Îº, one of the Y-family polymerases, has been shown to function in error-free translesion DNA synthesis (TLS) opposite the bulky <i>N</i><sup>2</sup>-guanyl DNA lesions induced by many carcinogens such as polycyclic aromatic hydrocarbons. We analyzed the biochemical properties of eight reported human pol Îº variants positioned in the polymerase core domain, using the recombinant pol Îº (residues 1â€“526) protein and the DNA template containing an <i>N</i><sup>2</sup>-CH<sub>2</sub>(9-anthracenyl)Â­G (<i>N</i><sup>2</sup>-AnthG). The truncation R219X was devoid of polymerase activity, and the E419G and Y432S variants showed much lower polymerase activity than wild-type pol Îº. In steady-state kinetic analyses, E419G and Y432S displayed 20- to 34-fold decreases in <i>k</i><sub>cat</sub>/<i>K</i><sub>m</sub> for dCTP insertion opposite G and <i>N</i><sup>2</sup>-AnthG compared to that of wild-type pol Îº. The L21F, I39T, and D189G variants, as well as E419G and Y432S, displayed 6- to 22-fold decreases in <i>k</i><sub>cat</sub>/<i>K</i><sub>m</sub> for next-base extension from C paired with <i>N</i><sup>2</sup>-AnthG, compared to that of wild-type pol Îº. The defective Y432S variant had 4- to 5-fold lower DNA-binding affinity than wild-type, while a slightly more efficient S423R variant possessed 2- to 3-fold higher DNA-binding affinity. These results suggest that R219X abolishes and the E419G, Y432S, L21F, I39T, and D189G variations substantially impair the TLS ability of pol Îº opposite bulky <i>N</i><sup>2</sup>-G lesions in the insertion step opposite the lesion and/or the subsequent extension step, raising the possibility that certain nonsynonymous pol Îº genetic variations translate into individual differences in susceptibility to genotoxic carcinogens

### Biochemical Characterization of Eight Genetic Variants of Human DNA Polymerase Îº Involved in Error-Free Bypass across Bulky <i>N</i><sup>2</sup>â€‘Guanyl DNA Adducts

DNA polymerase (pol) Îº, one of the Y-family polymerases, has been shown to function in error-free translesion DNA synthesis (TLS) opposite the bulky <i>N</i><sup>2</sup>-guanyl DNA lesions induced by many carcinogens such as polycyclic aromatic hydrocarbons. We analyzed the biochemical properties of eight reported human pol Îº variants positioned in the polymerase core domain, using the recombinant pol Îº (residues 1â€“526) protein and the DNA template containing an <i>N</i><sup>2</sup>-CH<sub>2</sub>(9-anthracenyl)Â­G (<i>N</i><sup>2</sup>-AnthG). The truncation R219X was devoid of polymerase activity, and the E419G and Y432S variants showed much lower polymerase activity than wild-type pol Îº. In steady-state kinetic analyses, E419G and Y432S displayed 20- to 34-fold decreases in <i>k</i><sub>cat</sub>/<i>K</i><sub>m</sub> for dCTP insertion opposite G and <i>N</i><sup>2</sup>-AnthG compared to that of wild-type pol Îº. The L21F, I39T, and D189G variants, as well as E419G and Y432S, displayed 6- to 22-fold decreases in <i>k</i><sub>cat</sub>/<i>K</i><sub>m</sub> for next-base extension from C paired with <i>N</i><sup>2</sup>-AnthG, compared to that of wild-type pol Îº. The defective Y432S variant had 4- to 5-fold lower DNA-binding affinity than wild-type, while a slightly more efficient S423R variant possessed 2- to 3-fold higher DNA-binding affinity. These results suggest that R219X abolishes and the E419G, Y432S, L21F, I39T, and D189G variations substantially impair the TLS ability of pol Îº opposite bulky <i>N</i><sup>2</sup>-G lesions in the insertion step opposite the lesion and/or the subsequent extension step, raising the possibility that certain nonsynonymous pol Îº genetic variations translate into individual differences in susceptibility to genotoxic carcinogens

### ERRÎ³ inverse agonist GSK5182 down-regulates the hypoxia-induced PDK4 expression.

<p>(<b>Aâ€“B</b>) HepG2 cells were transfected with hPDK4-Luc. After transfection, the cells were exposed in hypoxia and treated with or without GSK5182. Harvested lysates were utilized for luciferase and Î²-galactosidase assay (A). Q-PCR was performed using isolated total RNA (B). Experiments were done in triplicate and data are expressed as the fold activation relative to the control. (<b>C</b>) HepG2 cells were seeded in 60-cm<sup>2</sup> dishes and incubated overnight. The cells were incubated in hypoxia and treated with or without GSK5182. Total protein was harvesed for Western blot analysis using indicated antibodies. (<b>D</b>) HepG2 cells were seeded in 60-cm<sup>2</sup> dishes and incubated overnight. The cells were treated with or without chemicals (DFO and GSK5182) for 6 hr. Total protein and mRNA were isolated for Western blot assay and RT-PCR and normalized with Î± or Î²-tubulin and Î²-actin. (<b>E</b>) A schematic representation. All data are representative of at least three independent experiments. Error bars show Â± S.E.M. <sup>**</sup><i>P</i><0.01, <sup>***</sup><i>P</i><0.001 by two-tailed Student <i>t</i>-test.</p

### Hypoxia induces the ERRÎ³ gene expression in hepatoma cell lines.

<p>(<b>Aâ€“B</b>), HepG2 cells were seeded in 60-cm<sup>2</sup> dishes and incubated overnight. Then cells were incubated under hypoxia at indicated time period. The expression of ERRÎ³ was analyzed by Western blot (<b>A</b>) and Q-PCR (<b>B</b>) analysis. (<b>Câ€“D</b>) HepG2 cells were seeded in 60-cm<sup>2</sup> dishes and incubated overnight and then treated with DFO at indicated concentration and time period. The expression of ERRs was analyzed by Western blot (<b>C</b>) and Q-PCR (<b>D</b>) analysis. ERRÎ³ gene expression was normalized to L32 gene expression, and Î± or Î²-tubulin expression. All data are representative of at least three independent experiments. Error bars show Â± S.E.M. <sup>*</sup><i>P</i><0.05, <sup>**</sup><i>P</i><0.01 by two-tailed Student <i>t</i>-test.</p