Old drug, New target:Ellipticines selectively inhibit RNA Polymerase I transcription

Transcription byRNApolymerase I (Pol-I) is the main driving force behind ribosome biogenesis, a fundamental cellular process that requires the coordinated transcription of all three nuclear polymerases. Increased Pol-I transcription and the concurrent increase in ribosome biogenesis has been linked to the high rates of proliferation in cancers. The ellipticine family contains a number of potent anticancer therapeutic agents, some having progressed to stage I and II clinical trials; however, the mechanism by which many of the compounds work remains unclear. It has long been thought that inhibition of Top2 is the main reason behind the drugs antiproliferative effects. Here we report that a number of the ellipticines, including 9-hydroxyellipticine, are potent and specific inhibitors of Pol-I transcription, with IC50 in vitro and in cells in the nanomolar range. Essentially, the drugs did not affect Pol-II and Pol-III transcription, demonstrating a high selectivity.Wehave shown that Pol-I inhibition occurs by a p53-, ATM/ATR-, and Top2-independent mechanism. We discovered that the drug influences the assembly and stability of preinitiation complexes by targeting the interaction between promoter recognition factor SL1 and the rRNA promoter. Our findings will have an impact on the design and development of novel therapeutic agents specifically targeting ribosome biogenesis.

Community-living nonagenarians in northern ireland have lower plasma homocysteine but similar methylenetetrahydrofolate reductase thermolabile genotype prevalence compared to 70-89-year-old subjects

This cross-sectional study assessed relationships between plasma homocysteine, 'thermolabile' methylenetetrahydrofolatereductase (MTHFR) genotype, B vitamin status and measures of renal function in elderly (70-89 years) and nonagenarian (90+ years) subjects, with the hypothesis that octo/nonagenarian subjects who remain healthy into old age as defined by 'Senieur' status might show reduced genetic or environmental risk factors usually associated with hyperhomocysteinaemia. Plasma homocysteine was 9.1 micromol/l (geometric mean [GM]) for all elderly subjects. Intriguingly, homocysteine was significantly lower in 90+ (GM; 8.2 micromol/l) compared to 70-89-year-old subjects (GM; 9.8 micromol/l) despite significantly lower glomerular filtration rate (GFR) and serum B12 in nonagenarian subjects and comparable MTHFR thermolabile (TT) genotype frequency, folate and B6 status to 70-89-year-olds. For all elderly subjects, the odds ratio and 95% confidence intervals for plasma homocysteine being in the highest versus lowest quartile was 4.27 (2.04-8.92) for age 90 years, 3.4 (1.5-7.8) for serum folate 10.7nmol/l, 3.0 (0.9-10.2) for creatinine >140 compared

Changes in lymphocyte subsets, interleukin 2, and soluble interleukin 2 receptor in old and very old age

In this study, the changes in some of the cellular components of the immune system and the activity of the cytokine interleukin 2, important for immune activation and lymphocyte proliferation, were measured in a large cross-sectional study of all age groups including octogenarian and nonagenarian subjects. In 206 apparently well community-living subjects, the absolute lymphocyte count and T and B cell numbers fell a little in old and very old subjects. Within the T cell compartment, helper/inducer CD4+ T cells, together with their subsets identified as 'naive' (CD4+/CD45RA+) and 'memory' (CD4+/CD45RO+) cells, also showed a decline with increased age. The suppressor/cytotoxic CD8+ subset showed no age-related change. The levels of the cytokine interleukin 2 were very low in octogenarian and nonagenarian subjects, while the soluble interleukin 2 receptor levels increased with increasing age. The interleukin 2 levels were associated with number and percentage of the 'memory' (CD4+/CD45RO+) subset of T cells which mediates the host response to previously met antigens. Since the interleukin 2 values were very low in the oldest groups and were associated with a reduced 'memory' (CD4+/CD45RO+) compartment, this suggests a possible mechanism of why the very elderly subject is more susceptible to morbidity and mortality from infectious or other agents.

A late-Middle Pleistocene (Marine Isotope Stage 6) vegetated surface buried by Old Crow tephra at the Palisades, interior Alaska

A 40 cm thick primary bed of Old Crow tephra (131 ± 11 ka), an important stratigraphic marker in eastern Beringia, directly overlies a vegetated surface at Palisades West, on the Yukon River in central Alaska. Analyses of insect, bryophyte, and vascular plant macrofossils from the buried surface and underlying organic-rich silt suggest the local presence of an aquatic environment and mesic shrub-tundra at the time of tephra deposition. Autochthonous plant and insect macrofossils from peat directly overlying Old Crow tephra suggest similar aquatic habitats and hydric to mesic tundra environments, though pollen counts indicate a substantial herbaceous component to the regional tundra vegetation. Trace amounts of arboreal pollen in sediments associated with the tephra probably reflect reworking from older deposits, rather than the local presence of trees. The revised glass fission-track age for Old Crow tephra places its deposition closer to the time of the last interglaciation than earlier age determinations, but stratigraphy and paleoecology of sites with Old Crow tephra indicate a late Marine Isotope Stage 6 age. Regional permafrost degradation and associated thaw slumping are responsible for the close stratigraphic and paleoecological relations between Old Crow tephra and last interglacial deposits at some sites in eastern Beringia. © 2009 Elsevier Ltd.

"New" and "Old" Social Risks: Life Cycle and Social Class Perspectives on Social Exclusion in Ireland

The life cycle concept has come to have considerable prominence in Irish social policy debate. However, this has occurred without any systematic effort to link its usage to the broader literature relating to the concept. Nor has there been any detailed consideration of how we should set about operationalising the concept. In this paper we argue the need for "macro" life cycle perspectives that have been influenced by recent challenges to the welfare state to be combined with "micro" perspectives focusing on the dynamic and multidimensional nature of social exclusion. We make use of Irish EU-SILC 2005 data in developing a life cycle schema and considering its relationship to a range of indicators of social exclusion. At the European level renewed interest in the life cycle concept is associated with the increasing emphasis on the distinction between "new" and "old" social risks and the notion that the former are more "individualised". Inequality and poverty rather than being differentially distributed between social classes are thought to vary between phases in the average work life. Our findings suggest the "death of social class" thesis is greatly overblown. A more accurate appreciation of the importance of new and old social risks requires that we systematically investigate the manner in which factors such as social class and the life cycle interact.

Hypothalamic-pituitary-adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure

Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic-pituitary-adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown.

Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications

Internalizing behaviors in children between 4 and 5 years of age who had been prenatally exposed to psychotropic medications were investigated. The authors had previously reported the effects of prenatal medication exposure in this same cohort when they were newborns and infants at 3 and 8 months of age.

Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure

In this prospective study, we examined biobehavioral responses to acute procedural pain at 2 months of age in infants with prenatal and postnatal selective serotonin reuptake inhibitor (SSRI) medication exposure. Based on previous findings showing reduced pain responses in newborns after prenatal exposure, we hypothesized that altered pain reactivity would also be found at 2 months of age.

The developmental character of cardiac autonomic responses to an acute noxious event in 4- and 8-month-old healthy infants

Heart rate (HR) has been widely studied as a measure of an individual's response to painful stimuli. It remains unclear whether changes in mean HR or the variability of HR are specifically related to the noxious stimulus (i.e. pain). Neither is it well understood how such changes reflect underlying neurologic control mechanisms that produce these responses, or how these mechanisms change during the first year of life. To study the changes in cardiac autonomic modulation that occur with acute pain and with age during early infancy, the relationship between respiratory activity and short-term variations of HR (i.e. respiratory sinus arrhythmia) was quantified in a longitudinal study of term born healthy infants who underwent a finger lance blood collection at 4 months of age (n = 24) and again at 8 months of age (n = 20). Quantitative respiratory activity and HR were obtained during baseline, lance, and recovery periods. Time and frequency domain analyses from 2.2-min epochs of data yielded mean values, spectral measures of low (0.04-0.15 Hz) and high (0.15-0.80 Hz) frequency power (LF and HF), and the LF/HF ratio. To determine sympathetic and parasympathetic cardiac activity, the transfer relation between respiration and HR was used. At both 4 and 8 months, mean HR increased significantly with the noxious event (p > 0.01). There were age-related differences in the pattern of LF, HF, and LF/HF ratio changes. Although these parameters all decreased (p > 0.01) at 4 months, LF and LF/HF increased at 8 months and at 8 months HF remained stable in response to the noxious stimulus. Transfer gain changes with the lance demonstrated a change from predominant vagal baseline to a sympathetic condition at both ages. The primary finding of this study is that a response to an acute noxious stimulus appears to produce an increase in respiratory-related sympathetic HR control and a significant decrease in respiratory-related parasympathetic control at both 4 and 8 months. Furthermore, with increasing age, the sympathetic and parasympathetic changes appear to be less intense, but more sustained.

Developmental changes in pain expression in premature, full-term, two- and four-month-old infants

The purpose of this study was to examine the behavioural responses of infants to pain stimuli across different developmental ages. Eighty infants were included in this cross-sectional design. Four subsamples of 20 infants each included: (1) premature infants between 32 and 34 weeks gestational age undergoing heel-stick procedure; (2) full-term infants receiving intramuscular vitamin K injection; (3) 2-month-old infants receiving subcutaneous injection for immunisation against DPT; and (4) 4-month-old infants receiving subcutaneous injection for immunisation against DPT. Audio and video recordings were made for 15 sec from stimulus. Cry analysis was conducted on the first full expiratory cry by FFT with time and frequency measures. Facial action was coded using the Neonatal Facial Action Coding System (NFCS). Results from multivariate analysis showed that premature infants were different from older infants, that full-term newborns were different from others, but that 2- and 4-month-olds were similar. The specific variables contributing to the significance were higher pitched cries and more horizontal mouth stretch in the premature group and more taut tongue in the full-term newborns. The results imply that the premature infant has the basis for communicating pain via facial actions but that these are not well developed. The full-term newborn is better equipped to interact with his caretakers and express his distress through specific facial actions. The cries of the premature infant, however, have more of the characteristics that are arousing to the listener which serve to alert the caregiver of the state of distress from pain.

Examination of the physical and psychosocial determinants of health behaviour in 4-5-year-old children with congenital cardiac disease

To assess the general health and activity levels of 4- and 5-year-old children after intervention for congenital cardiac disease.

'All Good Things Must Come to an End': Terminating Co-Ownership Under the 'Old' Partition and Sale Rules

Despite its benefits, co-ownership of land creates problems where relations between the parties
have soured, or one person simply wants to extricate themselves from this arrangement. The
remedies of compulsory partition and sale allow one joint tenant or tenant in common to terminate
co-ownership against the wishes of the others, by seeking a court order to this effect. Throughout
parts of the common law world, this has be en based on nineteenth century English legislation namely
the Partition Act 1868, the key elements of which remain in force in Western Australia,
South Australia, Tasmania and the Australian Capital Territory. This article provides an up-to-date
analysis of the law on compulsory partition and sale as derived from the 1868 Act and analogous
provisions, drawing not only on Australian cases, but on frequently overlooked decisions from
courts in both parts of Ireland and in parts of Canada, as well as ‘old’ English judgments on the
1868 Act.