HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism.

Upon severe DNA damage a cellular signalling network initiates a cell death response through activating tumour suppressor p53 in association with promyelocytic leukaemia (PML) nuclear bodies. The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing p53 acetylation. To facilitate efficient p53 acetylation, SIRT1 function needs to be restricted. How SIRT1 activity is regulated under these conditions remains largely unclear. Here we provide evidence that SIRT1 activity is limited upon severe DNA damage through phosphorylation by the DNA damage-responsive kinase HIPK2. We found that DNA damage provokes interaction of SIRT1 and HIPK2, which phosphorylates SIRT1 at Serine 682 upon lethal damage. Furthermore, upon DNA damage SIRT1 and HIPK2 colocalize at PML nuclear bodies, and PML depletion abrogates DNA damage-induced SIRT1 Ser682 phosphorylation. We show that Ser682 phosphorylation inhibits SIRT1 activity and impacts on p53 acetylation, apoptotic p53 target gene expression and cell death. Mechanistically, we found that DNA damage-induced SIRT1 Ser682 phosphorylation provokes disruption of the complex between SIRT1 and its activator AROS. Our findings indicate that phosphorylation-dependent restriction of SIRT1 activity by HIPK2 shapes the p53 response.

Role of anxiety and depression in the onset of spontaneous preterm labor.

The aim of this cohort study conducted in France in 1997-1998 was to investigate the effects of antenatal anxiety and depression on spontaneous preterm labor. A consecutive series of 634 pregnant women with singleton pregnancies was included. Anxiety and depression were assessed using self-administered questionnaires: Spielberger's State-Trait Anxiety Inventory and the Edinburgh depression scale. Depression scores were dichotomized with a cutoff value suggestive of major depression. The 75th percentile was used for anxiety scores. A logistic regression analysis, controlling for sociodemographic and biomedical factors and including interaction terms, revealed that depression was positively associated with the outcome among underweight women, defined as women with a prepregnancy body mass index below 19 (adjusted odds ratio (OR) = 6.9, 95% confidence interval (CI): 1.8, 26.2). A similar result was observed for trait anxiety in women with a history of preterm labor (adjusted OR = 4.8, 95% CI: 1.1, 20.4). The association was close to significance for state anxiety in women with vaginal bleeding (adjusted OR = 3.6, 95% CI: 0.9, 14.7). These findings show that anxiety and depression, when combined with specific biomedical factors, are associated with spontaneous preterm labor. A synergic action of psychological and biomedical factors on the secretion of placental corticotropin-releasing factor is hypothesized.

Creosotebush vegetation after 50 years of lagomorph exclusion.

In 1939, an experiment was established on the Jornada Experimental Range to evaluate the effects of shrub removal, rabbit exclusion, furrowing, and seeding in creosotebush [Larrea tridentata (DC.) Cov] vegetation. Sixteen plots (21.3×21.3 m) were laid out in four rows of four plots per row with a buffer zone of 7.6 m between plots and rows. A barbed wire fence excluded cattle and poultry wire fencing excluded lagomorphs. Treatments were factorially applied at two levels. Plant cover in the plots was sampled in 1938 (before treatment), 1947, 1956, 1960, 1967 and 1989 with randomly located, line-intercept transects. Data from all sampling dates were analyzed as a split plot in time and main effects for 1989 tested by analysis of variance for a 2×4 factorial experiment. There were significant (P<0.10) year x treatment interactions. Seeding and furrowing treatments were ineffective but lagomorph exclusion and shrub clearing treatments resulted in significant treatment differences for several species. In 1989, basal area of spike dropseed (Sporobolus contractus A.S. Hitchc.) was 30-fold greater on the lagomorph excluded than on the lagomorph unexcluded treatment. Canopy cover of honey mesquite (Prosopis glandulosa Torr. var. glandulosa), tarbush (Flourensia cernua DC.) and mariola (Parthenium incanum H.B.K.) were affected by lagomorph exclusion. None of the responses were viewed as successional in nature. They principally represented individual species sensitivities to either absence of a primary herbivore or removal of aboveground shrub biomass. Though the physical treatments could be regarded as relatively severe disturbances of the system, the impacts on community vegetation dynamics were relatively insignificant.