Embryonic stem cell (ESC) abnormalities in genome methylation hamper the utility of their therapeutic derivatives; however, the underlying mechanisms are unknown. Here, we show that the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, Sirt1, selectively prevents abnormal DNA methylation of some developmental genes in murine ESCs by antagonizing Dnmt3l. Transcriptome and DNA methylome analyses demonstrated that Sirt1-null (Sirt1) ESCs repress expression of a subset of imprinted and germline genes concomitant with increased DNA methylation of regulatory elements. Dnmt3l was highly expressed in Sirt1 ESCs, and knockdown partially rescued abnormal DNA methylation of the Sirt1 target genes. The Sirt1 protein suppressed transcription of Dnmt3l and physically interacted with the Dnmt3l protein, deacetylating and destabilizing Dnmt3l protein. Sirt1 deficiency delayed neurogenesis and spermatogenesis. These differentiation delays were significantly or partially abolished by reintroduction of Sirt1 cDNA or Dnmt3l knockdown. This study sheds light on mechanisms that restrain DNA methylation of developmentally vital genes operating in ESCs.

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The immobilization of long-lived radionuclide wastes generated from nuclear power plants (NPPs) during NPP operation, fuel reprocessing, and decommissioning of nuclear reactors is of great environmental concern. Designing suitable matrices with high durability, stability, and resistivity to various physical and chemical conditions (temperature, pressure, radiation, acidity/alkalinity, etc.) are required for the safe disposal and effective immobilization of radioactive wastes. In this review, we highlight and discuss the key developments in the design and applications of major inorganic waste forms for radioactive waste immobilization. Specifically, we review (i) glasses (borosilicates, phosphates, and sintered glasses), (ii) cements (Portland cement, cast stone/saltstone, hydroceramics, and geopolymer), (iii) synrocs (hollandite, zirconolite, and perovskite), and (iv) ceramics (titanates, sodalite, apatite, monazites, and goethite/magnetite). Additionally, we present future challenges that should be addressed during the design and selection of suitable waste forms for the immobilization of radionuclides. We believe that this paper can deepen our understanding of various waste forms and their roles in radioactive waste immobilization.

Background/Aims: Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis. Methods: Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson’s trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF). Results: The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFβ in vitro. Conclusions: The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.