Hydroxyproline production in chick fibroblast cultures

Zusammenfassung Kulturen von Hühnerherzfibroblasten wurden nach 10, 21 und 28 Tagenin vitro auf ihren Gehaltan Hydroxyprolin — einer wichtigen Aminosäure des Kollagens — untersucht. Nach 10, bzw. 21 Tagen ist eine signifikante, durch Prolinzugaben nicht beeinflussbare Vermehrung des zu 50% löslichen Hydroxyprolins feststellbar.

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Kantonsspital, Chur.     

Evaluating volatility and interval forecasts

A widely used approach to evaluating volatility forecasts uses a regression framework which measures the bias and variance of the forecast. We show that the associated test for bias is inappropriate before introducing a more suitable procedure which is based on the test for bias in a conditional mean forecast. Although volatility has been the most common measure of the variability in a financial time series, in many situations confidence interval forecasts are required. We consider the evaluation of interval forecasts and present a regression‐based procedure which uses quantile regression to assess quantile estimator bias and variance. We use exchange rate data to illustrate the proposal by evaluating seven quantile estimators, one of which is a new non‐parametric autoregressive conditional heteroscedasticity quantile estimator. The empirical analysis shows that the new evaluation procedure provides useful insight into the quality of quantile estimators. Copyright © 1999 John Wiley & Sons, Ltd.     

Reweighting the general household survey 1979-2007

We have calculated two new sets of weights applicable to the General Household Survey (GHS) from 1979 to 2007. One of these is for use with any general analysis of GHS topics and the second is designed for analyses of data collected in the Family Information section. The methods used follow closely those employed by ONS from 1996 onwards. The performance of the weights is assessed in estimating the Total Fertility Rate (TFR) from 1971-2007, an aggregate measure of fertility for which reliable figures are available at national level from vital registration statistics. Our weights improve the GHS estimates, reducing bias both in the TFR and in age-specific fertility rates.     

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.     

To Attract or to Inform: What Are Titles For?

This paper critiques some titles in journal articles for being misleading and it argues that titles need to be informative. Examples are given of work on measuring the effectiveness of titles in two areas-sentence structure and reader comprehension - and the paper concludes with brief comments on the effectiveness of book titles.……     

Intercepting the first rat ashore

A single Norway rat released on to a rat-free island was not caught for more than four months, despite intensive efforts to trap it. The rat first explored the 9.5-hectare island and then swam 400 metres across open water to another rat-free island, evading capture for 18 weeks until an aggressive combination of detection and trapping methods were deployed simultaneously. The exceptional difficulty of this capture indicates that methods normally used to eradicate rats in dense populations are unlikely to be effective on small numbers, a finding that could have global implications for conservation on protected islands.     

Changing Arctic Ocean freshwater pathways

Freshening in the Canada basin of the Arctic Ocean began in the 1990s and continued to at least the end of 2008. By then, the Arctic Ocean might have gained four times as much fresh water as comprised the Great Salinity Anomaly of the 1970s, raising the spectre of slowing global ocean circulation. Freshening has been attributed to increased sea ice melting and contributions from runoff, but a leading explanation has been a strengthening of the Beaufort High--a characteristic peak in sea level atmospheric pressure--which tends to accelerate an anticyclonic (clockwise) wind pattern causing convergence of fresh surface water. Limited observations have made this explanation difficult to verify, and observations of increasing freshwater content under a weakened Beaufort High suggest that other factors must be affecting freshwater content. Here we use observations to show that during a time of record reductions in ice extent from 2005 to 2008, the dominant freshwater content changes were an increase in the Canada basin balanced by a decrease in the Eurasian basin. Observations are drawn from satellite data (sea surface height and ocean-bottom pressure) and in situ data. The freshwater changes were due to a cyclonic (anticlockwise) shift in the ocean pathway of Eurasian runoff forced by strengthening of the west-to-east Northern Hemisphere atmospheric circulation characterized by an increased Arctic Oscillation index. Our results confirm that runoff is an important influence on the Arctic Ocean and establish that the spatial and temporal manifestations of the runoff pathways are modulated by the Arctic Oscillation, rather than the strength of the wind-driven Beaufort Gyre circulation.     

Event-horizon-scale structure in the supermassive black hole candidate at the Galactic Centre

The cores of most galaxies are thought to harbour supermassive black holes, which power galactic nuclei by converting the gravitational energy of accreting matter into radiation. Sagittarius A* (Sgr A*), the compact source of radio, infrared and X-ray emission at the centre of the Milky Way, is the closest example of this phenomenon, with an estimated black hole mass that is 4,000,000 times that of the Sun. A long-standing astronomical goal is to resolve structures in the innermost accretion flow surrounding Sgr A*, where strong gravitational fields will distort the appearance of radiation emitted near the black hole. Radio observations at wavelengths of 3.5 mm and 7 mm have detected intrinsic structure in Sgr A*, but the spatial resolution of observations at these wavelengths is limited by interstellar scattering. Here we report observations at a wavelength of 1.3 mm that set a size of 37(+16)(-10) microarcseconds on the intrinsic diameter of Sgr A*. This is less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow.     

Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-Kit(mid)CD3(+)Lin(-) compartment, where unphosphorylated beta-catenin is significantly increased. Conditional ablation of one allele of the beta-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the beta-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit(mid)CD3(+)Lin(-) LSCs and CD3(+) leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation.