We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymeraseβ. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA-β-gal staining (fourfold increase, P < 0.001), increased p16 transcript abundance (threefold increase, P < 0.01), and reduced HMGB1 nuclear localization (1.5-fold lower, P < 0.01). We also find that DNA polymerase β expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, P < 0.01). To evaluate whether DNA polymerase β might be causative in senescence induction, we evaluated the impact of murine DNA polymerase β nullizygosity on senescence. We find that unexposed DNA polymerase β -null primary fibroblasts exhibit a robust increase in the number of senescent cells compared to wild-type (11-fold, P < 0.001), demonstrating that loss DNA polymerase β is sufficient to induce senescence. We also see an additional increase in response to hydroxyurea (threefold greater than WT-HU, P < 0.05). These data demonstrate that loss of DNA polymerase β is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase β null MEFs (fivefold increase from wild-type, P < 0.0001). Our findings strongly suggest that DNA polymerase β is causative in senescence induction, reasonably pointing to DNA polymerase β as a likely factor driving the premature senescence in Down syndrome. Environ. Mol. Mutagen. 59:603-612, 2018. © 2018 Wiley Periodicals, Inc.
Pitx3 has been identified as the causative locus in a developmental eye mutation associated with mammalian anterior segment dysgenesis, congenital cataracts, and aphakia. In recent studies of frog eye development we discovered that pitx3 expresses symmetrically in the somites and lateral plate mesoderm and asymmetrically during cardiac and gut looping. We report that disruption of pitx3 activity on one side of an embryo relative to the other, either by over- or underexpression of pitx3, elicits a crooked dorsal axis in embryos that is a consequence of a retarded progression through somitogenesis. Unlike in amniotes, Xenopus somites form as cohorts of presomitic cells that rotate perpendicular to the dorsal axis. Since no vertebral anomalies have been reported in mouse and human Pitx3 mutants, we attempt to distinguish whether the segmentation clock is uniquely affected in frog or if the pitx3 perturbation inhibits the cellular changes that are necessary to rotation of presomitic cells. In Xenopus, pitx3 appears to inhibit the rotation of presomitic cell cohorts and to be necessary to the bilaterally symmetric expression of pitx2 in somites.
Background: Unexpected phenotypes resulting from morpholino-mediated translational knockdown of Pitx3 in Xenopus laevis required further investigation regarding the genetic networks in which the gene might play a role. Microarray analysis was, therefore, used to assess global transcriptional changes downstream of Pitx3. Results: From the large data set generated, selected candidate genes were confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization. Conclusions: We have identified four genes as likely direct targets of Pitx3 action: Pax6, b Crystallin-b1 (Crybb1), Hes7.1, and Hes4. Four others show equivocal promise worthy of consideration: Vent2, and Ripply2 (aka Ledgerline or Stripy), eFGF and RXRa. We also describe the expression pattern of additional and novel genes that are Pitx3-sensitive but that are unlikely to be direct targets. Developmental Dynamics 241:1487-1505, 2012. V C 2012 Wiley Periodicals, Inc.
This study investigated the influence of incorporating Biosilicate® on the physico-mechanical and biological properties of glass ionomer cement (GIC). This bioactive glass ceramic (23.75% Na2O, 23.75% CaO, 48.5% SiO2, and 4% P2O5) was incorporated by weight (5%, 10%, or 15%) into commercially available GICs (Maxxion R and Fuji IX GP). Surface characterization was made by SEM (n = 3), EDS (n = 3), and FTIR (n = 1). The setting and working (S/W time) times (n = 3) and compressive strength (CS) were analyzed (n = 10) according to ISO 9917-1:2007. The ion release (n = 6) was determined and quantified by ICP OES and by UV-Vis for Ca, Na, Al, Si, P, and F. To verify cell cytotoxicity, stem cells from the apical papilla (SCAP) were exposed to eluates (n = 3, at a ratio of 1.8 cm2/mL) and analyzed 24 h post-exposure. Antimicrobial activity against Streptococcus mutans (ATCC 25175, NCTC 10449) was analyzed by direct contact for 2 h (n = 5). The data were submitted for normality and lognormality testing. One-way ANOVA and Tukey’s test were applied for the working and setting time, compressive strength, and ion release data. Data from cytotoxicity and antimicrobial activity were submitted for Kruskal–Wallis’ testing and Dunn’s post hoc test (α = 0.05). Among all experimental groups, only those with 5% (wt) of Biosilicate® showed better surface quality. Only M5% showed a comparable W/S time to the original material (p = 0.7254 and p = 0.5912). CS was maintained for all Maxxion R groups (p > 0.0001) and declined for Fuji IX experimental groups (p < 0.0001). The Na, Si, P, and F ions released were significantly increased for all Maxxion R and Fuji IX groups (p < 0.0001). Cytotoxicity was increased only for Maxxion R with 5% and 10% of Biosilicate®. A higher inhibition of S. mutans growth was observed for Maxxion R with 5% of Biosilicate® (less than 100 CFU/mL), followed by Maxxion R with 10% of Biosilicate® (p = 0.0053) and Maxxion R without the glass ceramic (p = 0.0093). Maxxion R and Fuji IX presented different behaviors regarding Biosilicate® incorporation. The impacts on physico-mechanical and biological properties were different depending on the GIC, but therapeutic ion release was increased for both materials.
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