A Hole and One.
Ontology highlight
ABSTRACT:
SUBMITTER: Suliman A
PROVIDER: S-EPMC8712989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The distance of hole migration through DNA determines the degree to which radiation-induced lesions are clustered. It is the degree of clustering that confers to ionizing radiation its high toxicity. The migration distance is governed by a competition between hole transfer and irreversible trapping reactions. An important type of trapping is reactions that lead to the formation of deoxyribose radicals, which are precursors to free base release (fbr). Using HPLC, fbr was measured in X-irradiated films of d(CGCGCGCGCG)(2) and d(CGCGAATTCGCG)(2) as well as three genomic DNAs: M. luteus, calf thymus, and C. perfringens. The level of DNA hydration was varied from Gamma = 2.5 to 22 mol waters/mol nucleotide. The chemical yields of each base, G(base), were measured and used to calculate the modification factor, M(base). This factor compensates for differences in the GC/AT ratio, providing a measure of the degree to which a given base influences its own release. In the DNA oligomers, M(Gua) > M(Cyt), a result ascribed to the previously observed end effect in short oligomers. In the highly polymerized genomic DNA, we found that M(Cyt) > M(Gua) and that M(Thy) is consistently the smallest of the M factors. For these same DNA films, the yields of total DNA trapped radicals, G(tot)(fr), were measured using EPR spectroscopy. The yield of deoxyribose radicals was calculated using G(dRib)(fr) = approximately 0.11 x G(tot)(fr). Comparing G(dRib)(fr) with total fbr, we found that only about half of the fbr is accounted for by deoxyribose radical intermediates. We conclude that for a hole on cytosine, Cyt(*+), base-to-base hole transfer competes with irreversible trapping by the deoxyribose. In the case of a hole on thymine, Thy(*+), base-to-base hole transfer competes with irreversible trapping by methyl deprotonation. Close proximity of Gua protects the deoxyribose of Cyt but sensitizes the deoxyribose of Thy.
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Project description:The directionality of the hole-transfer processes between DNA backbone and base was investigated by using phosphorodithioate [P(S- )=S] components. ESR spectroscopy in homogeneous frozen aqueous solutions and pulse radiolysis in aqueous solution at ambient temperature confirmed initial formation of G.+ -P(S- )=S. The ionization potential of G-P(S- )=S was calculated to be slightly lower than that of guanine in 5'-dGMP. Subsequent thermally activated hole transfer from G.+ to P(S- )=S led to dithiyl radical (P-2S. ) formation on the μs timescale. In parallel, ESR spectroscopy, pulse radiolysis, and density functional theory (DFT) calculations confirmed P-2S. formation in an abasic phosphorodithioate model compound. ESR investigations at low temperatures and higher G-P(S- )=S concentrations showed a bimolecular conversion of P-2S. to the σ2 -σ*1 -bonded dimer anion radical [-P-2S -. 2S-P-]- [ΔG (150 K, DFT)=-7.2 kcal mol-1 ]. However, [-P-2S -. 2S-P-]- formation was not observed by pulse radiolysis [ΔG° (298 K, DFT)=-1.4 kcal mol-1 ]. Neither P-2S. nor [-P-2S -. 2S-P-]- oxidized guanine base; only base-to-backbone hole transfer occurs in phosphorodithioate.
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Project description:BackgroundEpithelia act as physical barriers protecting living organisms and their organs from the surrounding environment. Simple epithelial tissues have the capacity to efficiently repair wounds through a resealing mechanism. The known molecular mechanisms underlying this process appear to be conserved in both vertebrates and invertebrates, namely the involvement of the transcription factors Grainy head (Grh) and Fos. In Drosophila, Grh and Fos lead to the activation of wound response genes required for epithelial repair. ERK is upstream of this pathway and known to be one of the first kinases to be activated upon wounding. However, it is still unclear how ERK activation contributes to a proper wound response and which molecular mechanisms regulate its activation.Methodology/principal findingsIn a previous screen, we isolated mutants with defects in wound healing. Here, we describe the role of one of these genes, hole-in-one (holn1), in the wound healing process. Holn1 is a GYF domain containing protein that we found to be required for the activation of several Grh and Fos regulated wound response genes at the wound site. We also provide evidence suggesting that Holn1 may be involved in the Ras/ERK signaling pathway, by acting downstream of ERK. Finally, we show that wound healing requires the function of EGFR and ERK signaling.Conclusions/significanceBased on these data, we conclude that holn1 is a novel gene required for a proper wound healing response. We further propose and discuss a model whereby Holn1 acts downstream of EGFR and ERK signaling in the Grh/Fos mediated wound closure pathway.
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Project description:Finite element analysis has been an increasingly widely applied biomechanical modeling method in many different science and engineering fields over the last decade. In the biological sciences, there are many examples of FEA in areas such as paleontology and functional morphology. Despite this common use, the modeling of trabecular bone remains a key issue because their highly complex and porous geometries are difficult to replicate in the solid mesh format required for many simulations. A common practice is to assign uniform model material properties to whole or portions of models that represent trabecular bone. In this study we aimed to demonstrate that a physical, element reduction approach constitutes a valid protocol for addressing this problem in addition to the wholesale mathematical approach. We tested a customized script for element reduction modeling on five exemplar trabecular geometry models of carnivoran temporomandibular joints, and compared stress and strain energy results of both physical and mathematical trabecular modeling to models incorporating actual trabecular geometry. Simulation results indicate that that the physical, element reduction approach generally outperformed the mathematical approach: physical changes in the internal structure of experimental cylindrical models had a major influence on the recorded stress values throughout the model, and more closely approximates values obtained in models containing actual trabecular geometry than solid models with modified trabecular material properties. In models with both physical and mathematical adjustments for bone porosity, the physical changes exhibit more weight than material properties changes in approximating values of control models. Therefore, we conclude that maintaining or mimicking the internal porosity of a trabecular structure is a more effective method of approximating trabecular bone behavior in finite element models than modifying material properties.
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Project description:Introduction: The migration of a dexamethasone implant to the anterior chamber is a vision-threatening complication which can happen in non-compartmentalized eyes treated with this device. Previous literature suggests that the solution to this complication is almost always surgical and in most cases cannot be delayed. Case description: We present the case of a 78-year-old woman with a scleral-fixated IOL and macular edema treated with Ozurdex®. She came to us complaining of blurred vision and was subsequently diagnosed with an anterior-chamber migration of her dexamethasone implant. Postural manoeuvres were performed until the dexamethasone implant returned to the vitreous cavity through the pupil. Pilocarpine drops were prescribed with a positive outcome and no further migrations were described. Discussion: This case shows a practical and efficient way of managing a potentially vision-threatening complication without placing the patient onto an operating table. It is interesting to see how it is possible to relocate a dexamethasone implant despite the presence of a scleral-fixated IOL. Conclusion: Postural manoeuvres are an interesting option in patients with a dexamethasone implant migrated to the anterior chamber. This approach can have very positive outcomes, in addition to avoiding surgery, with all the risks and complications involved.
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