The Brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to DNA damage. Results from this study indicate that the checkpoint protein kinase ATM (mutated in ataxia telangiectasia) was required for phosphorylation of Brca1 in response to ionizing radiation. ATM resides in a complex with Brca1 and phosphorylated Brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated Brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a Brca1-deficient cell line. Thus, phosphorylation of Brca1 by the checkpoint kinase ATM may be critical for proper responses to DNA double-strand breaks and may provide a molecular explanation for the role of ATM in breast cancer.

Silver octahedra with edge lengths controlled in the range of 20-72 nm were synthesized via seed-mediated growth. The key to the success of this synthesis is the use of single-crystal Ag seeds with uniform and precisely controlled sizes to direct the growth and the use of citrate as a selective capping agent for the {111} facets. Our mechanistic studies demonstrated that Ag seeds with both cubic and quasi-spherical shapes could evolve into octahedra. For the first time, we were able to precisely control the edge lengths of Ag octahedra below 100 nm, and the lower limit of size could even be pushed down to 20 nm. Using the as-obtained Ag octahedra as sacrificial templates, Au nanocages with an octahedral shape and precisely tunable optical properties were synthesized through a galvanic replacement reaction. Such hollow nanostructures are promising candidates for a broad range of applications related to optics, catalysis, and biomedicine.

Objectives-Skeletal muscle mitochondrial dysfunction is associated with aging and diabetes, which decreases respiratory capacity and increases reactive oxygen species. Lipoic acid (LA) possesses antioxidative and antidiabetic properties. Metabolic action of LA ismediated by activation of AMP-activated protein kinase (AMPK), a cellular energy sensor that can regulate PGC-1α, a master regulator of mitochondrial biogenesis. We hypothesized that LA improves energy metabolism and mitochondrial biogenesis by enhancing AMPK-PGC-1α signalling in the skeletal muscle of aged mice.Methods-C57BL/6 mice (24-month old, male) were supplemented with or without α-LA (0.75% in drinking water) for one month. In addition, metabolic action and cellular signalling of LA were studied in cultured mouse myoblastoma C2C12 cells.Results-LA supplementation improved body composition, glucose tolerance, and energy expenditure in the aged mice. LA increased skeletal muscle mitochondrial biogenesis with increased phosphorylation of AMPK and mRNA expression of PGC-1α and glucose transporter-4 (GLUT-4). Besides body fat mass, LA decreased lean mass and attenuated phosphorylation of mammalian target of rapamycin (mTOR) signalling in the skeletal muscle. In cultured C2C12 cells, LA increased glucose uptake and palmitate β-oxidation, but decreased protein synthesis, which was associated with increased phosphorylation of AMPK and expression of PGC-1α and GLUT-4, and attenuated phosphorylation of mTOR and p70S6 kinase.Conclusions-We conclude that LA improves skeletal muscle energy metabolism in the aged mouse possibly through enhancing AMPK-PGC-1α-mediated mitochondrial biogenesis and function. Moreover, LA increases lean mass loss possibly by suppressing protein synthesis in the skeletal muscle by down-regulating the mTOR signalling pathway. Thus, LA may be a promising supplement for treatment of obesity and/or insulin resistance in older patients.