The first on-line laser spectroscopy of cooled fission fragments is reported. The r ions, produced in uranium fission, were extracted and separated using an ion guide isotope separator. The ions were cooled and bunched for collinear laser spectroscopy by a gas-filled linear Paul trap. New results for nuclear mean-square charge radii, dipole, and quadrupole moments are reported across the N=60 shape change. The mean-square charge radii are found to be almost identical to those of the Sr isotones and previously offered modeling of the radial changes is critically reviewed.

A new method has been developed for increasing the sensitivity of collinear laser spectroscopy. The method utilizes an ion-trapping technique in which a continuous low-energy ion beam is cooled and accumulated in a linear Paul trap and subsequently released as a short (10-20 micros) bunch. In collinear laser measurements the signal-to-noise ratio has been improved by a factor of 2 x 10(4), allowing spectroscopic measurements to be made with ion-beam fluxes of approximately 50 ions s(-1). The bunching method has been demonstrated in an on-line isotope shift and hyperfine structure measurement on radioactive (175)Hf.

PURPOSE. Previous studies have demonstrated that peroxisome proliferator-activated receptoralpha (PPARa) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARa's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS.For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARa knockout (PPARa À/À ) mice were exposed to 75% O 2 from postnatal day 7 (P7) to P12 and treated with the PPARa agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl 2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2 0 ,7 0 -dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS. Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARaÀ/À OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARa overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-a (HIF-1a) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARa À/À mice.CONCLUSIONS. Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1a/Nox 4 and consequently alleviation of oxidative stress.

Sirtuins, which are class III NAD-dependent histone deacetylases (HDACs) that regulate a number of physiological processes, play important roles in the regulation of metabolism, aging, oncogenesis and cancer progression. More recently, a role for the sirtuins in the regulation of steroid hormone receptor signaling is emerging. In this mini-review, we will summarize current research into the regulation of estrogen, androgen, progesterone, mineralocorticoid and glucocorticoid signaling by sirtuins in cancer. Sirtuins can regulate steroid hormone signaling through a variety of molecular mechanisms, including acting as co-regulatory transcription factors, deacetylating histones in the promoters of genes with nuclear receptor binding sites, directly deacetylating steroid hormone nuclear receptors, and regulating pathways which modify steroid hormone receptors through phosphorylation. Furthermore, disruption of sirtuin activity may be an important step in the development of steroid hormone-refractory cancers.

In prostate and breast cancer, the androgen and estrogen receptors mediate induction of androgen- and estrogen-responsive genes respectively, and stimulate cell proliferation in response to the binding of their cognate steroid hormones. Sirtuin 1 (SIRT1) is a nicotinamide adenosine dinucleotide (NAD+)-dependent class III histone deacetylase (HDAC) that has been linked to gene silencing, control of the cell cycle, apoptosis and energy homeostasis. In prostate cancer, SIRT1 is required for androgen-antagonist-mediated transcriptional repression and growth suppression of prostate cancer cells. Whether SIRT1 plays a similar role in the actions of estrogen or antagonists had not been determined. We report here that SIRT1 represses the transcriptional and proliferative response of breast cancer cells to estrogens, and this repression is estrogen receptor-alpha (ERα)-dependent. Inhibition of SIRT1 activity results in the phosphorylation of ERα in an AKT-dependent manner, and this activation requires phosphoinositide 3-kinase (PI3K) activity. Phosphorylated ERα subsequently accumulates in the nucleus, where ERα binds DNA ER-response elements and activates transcription of estrogen-responsive genes. This ER-dependent transcriptional activation augments estrogen-induced signaling, but also activates ER-signaling in the absence of estrogen, thus defining a novel and unexpected mechanism of ligand-independent ERα-mediated activation and target gene transcription. Like ligand-dependent activation of ERα, SIRT1 inhibition-mediated ERα activation in the absence of estrogen also results in breast cancer cell proliferation. Together, these data demonstrate that SIRT1 regulates the most important cell signaling pathway for the growth of breast cancer cells, both in the presence and the absence of estrogen.