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.

Second-to-Fourth Digit Ratio and Impulsivity: A Comparison between Offenders and Nonoffenders

Personality characteristics, particularly impulsive tendencies, have long been conceived as the primary culprit in delinquent behavior. One crucial question to emerge from this line of work is whether impulsivity has a biological basis. To test this possibility, 44 male offenders and 46 nonoffenders completed the Eysenck Impulsivity Questionnaire, and had their 2D:4D ratio measured. Offenders exhibited smaller right hand digit ratio measurements compared to non-offenders, but higher impulsivity scores. Both impulsivity and 2D:4D ratio measurements significantly predicted criminality (offenders vs. nonoffenders). Controlling for education level, the 2D:4D ratio measurements had remained a significant predictor of criminality, while impulsivity scores no longer predicted criminality significantly. Our data, thus, indicates that impulsivity but not 2D:4D ratio measurements relate to educational attainment. As offenders varied in their number of previous convictions and the nature of their individual crimes, we also tested for differences in 2D:4D ratio and impulsivity among offenders. Number of previous convictions did not correlate significantly with the 2D:4D ratio measurements or impulsivity scores. Our study established a link between a biological marker and impulsivity among offenders (and lack thereof among non-offenders), which emphasise the importance of studying the relationship between biological markers, impulsivity and criminal behavior.

Can we meet targets for biofuels and renewable energy in transport given the constraints imposed by policy in agriculture and energy?

The deployment of biofuels is significantly affected by policy in energy and agriculture. In the energy arena, concerns regarding the sustainability of biofuel systems and their impact on food prices led to a set of sustainability criteria in EU Directive 2009/28/EC on Renewable Energy. In addition, the 10% biofuels target by 2020 was replaced with a 10% renewable energy in transport target. This allows the share of renewable electricity used by electric vehicles to contribute to the mix in achieving the 2020 target. Furthermore, only biofuel systems that effect a 60% reduction in greenhouse gas emissions by 2020 compared with the fuel they replace are allowed to contribute to meeting the target. In the agricultural arena, cross-compliance (which is part of EU Common Agricultural Policy) dictates the allowable ratio of grassland to total agricultural land, and has a significant impact on which biofuels may be supported. This paper outlines the impact of these policy areas and their implications for the production and use of biofuels in terms of the 2020 target for 10% renewable transport energy, focusing on Ireland. The policies effectively impose constraints on many conventional energy crop biofuels and reinforce the merits of using biomethane, a gaseous biofuel. The analysis shows that Ireland can potentially satisfy 15% of renewable energy in transport by 2020 (allowing for double credit for biofuels from residues and ligno-cellulosic materials, as per Directive 2009/28/EC) through the use of indigenous biofuels: grass biomethane, waste and residue derived biofuels, electric vehicles and rapeseed biodiesel. © 2010 Elsevier Ltd. All rights reserved.

Economic Vulnerability and the Severity of Debt Problems::An Analysis of the Irish EU-SILC 2008

In this article, using Ireland where debt issues are of particular salience, as a test case, we seek to locate over-indebtedness and the severity of debt problems in the context of the broader economic circumstances of households. In doing so, we first identify an economically vulnerable segment of households and then explore the debt experience of vulnerable and non-vulnerable households. Our analysis reveals a striking contrast between the debt experiences of less than one in five households defined as economically vulnerable and all others. Financial exclusion, relating to access to a bank account and a credit card, was found to increase debt levels. However, such effects were modest. The impact of economic vulnerability seems to be largely a consequence of its relationship to a wide
range of socio-economic attributes and circumstances. The manner in which a potential debt crisis
unfolds will be shaped by the broader socio-economic structuring of life-chances. Any attempt to
respond to such problems by concentrating on financial exclusion or household behaviour or, indeed,
triggering factors without taking the wider social structuring of economic vulnerability is likely to be
both seriously misguided and largely ineffective.

Prospective, Randomized Assessment of Transfer of Training (ToT) and Transfer Effectiveness Ratio (TER) of Virtual Reality Simulation Training for Laparoscopic Skill Acquisition

OBJECTIVES:: We assessed the effectiveness of ToT from VR laparoscopic simulation training in 2 studies. In a second study, we also assessed the TER. ToT is a detectable performance improvement between equivalent groups, and TER is the observed percentage performance differences between 2 matched groups carrying out the same task but with 1 group pretrained on VR simulation. Concordance between simulated and in-vivo procedure performance was also assessed. DESIGN:: Prospective, randomized, and blinded. PARTICIPANTS:: In Study 1, experienced laparoscopic surgeons (n = 195) and in Study 2 laparoscopic novices (n = 30) were randomized to either train on VR simulation before completing an equivalent real-world task or complete the real-world task only. RESULTS:: Experienced laparoscopic surgeons and novices who trained on the simulator performed significantly better than their controls, thus demonstrating ToT. Their performance showed a TER between 7% and 42% from the virtual to the real tasks. Simulation training impacted most on procedural error reduction in both studies (32- 42%). The correlation observed between the VR and real-world task performance was r > 0·96 (Study 2). CONCLUSIONS:: VR simulation training offers a powerful and effective platform for training safer skills.

Genetic association suggests that SMOC1 mediates between prenatal sex hormones and digit ratio

Men and women differ statistically in the relative lengths of their index and ring fingers; and the ratio of these lengths has been used as a biomarker for prenatal testosterone. The ratio has been correlated with a wide range of traits and conditions including prostate cancer, obesity, autism, ADHD, and sexual orientation. In a genome-wide association study of 979 healthy adults, we find that digit ratio is strongly associated with variation upstream of SMOC1 (rs4902759: P = 1.41 × 10(-8)) and a meta-analysis of this and an independent study shows a probability of P = 1.5 × 10(-11). The protein encoded by SMOC1 has recently been shown to play a critical role in limb development; its expression in prostate tissue is dependent on sex hormones, and it has been implicated in the sexually dimorphic development of the gonads. We put forward the hypothesis that SMOC1 provides a link between prenatal hormone exposure and digit ratio.

CCN2/CTGF increases expression of miR-302 microRNAs, which target the TGF beta type II receptor with implications for nephropathic cell phenotypes

Signalling interplay between transforming growth factor-beta (TGF beta) and CCN2 [also called connective tissue growth factor (CTGF)] plays a crucial role in the progression of diabetic nephropathy and has been implicated in cellular differentiation. To investigate the potential role of microRNAs (miRNAs) in the mediation of this signalling network, we performed miRNA screening in mesangial cells treated with recombinant human CCN2. Analysis revealed a cohort of 22 miRNAs differentially expressed by twofold or more, including members of the miR-302 family. Target analysis of miRNA to 3'-untranslated regions (3'-UTRs) identified TGF beta receptor II (T beta RII) as a potential miR-302 target. In mesangial cells, decreased T beta RII expression was confirmed in response to CCN2 together with increased expression of miR-302d. T beta RII was confirmed as an miR-302 target, and inhibition of miR-302d was sufficient to attenuate the effect of CCN2 on T beta RII. Data from the European Renal cDNA Biopsy Bank revealed decreased T beta RII in diabetic patients, suggesting pathophysiological significance. In a mouse model of fibrosis (UUO), miR-302d was increased, with decreased T beta RII expression and aberrant signalling, suggesting relevance in chronic fibrosis. miR-302d decreased TGF beta-induced epithelial mesenchymal transition (EMT) in renal HKC8 epithelial cells and attenuated TGF beta-induced mesangial production of fibronectin and thrombospondin. In summary, we demonstrate a new mode of regulation of TGF beta by CCN2, and conclude that the miR-302 family has a role in regulating growth factor signalling pathways, with implications for nephropathic cell fate transitions.

Population enumeration and assessing conservation status in a widespread amphibian: A case study of Rana temporaria in Ireland

Global amphibian declines are a major element of the current biodiversity crisis. Monitoring changes in the distribution and abundance of target species is a basic component in conservation decision making and requires robust and repeatable sampling. For EU member states, surveillance of designated species, including the common frog Rana temporaria, is a formal requirement of the 'EC Habitats & Species Directive'. We deployed established methods for estimating frog population density at local water bodies and extrapolated these to the national and ecoregion scale. Spawn occurred at 49.4% of water bodies and 70.1% of independent 500-m survey squares. Using spawn mat area, we estimated the number of adult breeding females and subsequently the total population assuming a sex ratio of 1:1. A negative binomial model suggested that mean frog density was 23.5 frogsha [95% confidence interval (CI) 14.9-44.0] equating to 196M frogs (95%CI 124M-367M) throughout Ireland. A total of 86% of frogs bred in drainage ditches, which were a notably common feature of the landscape. The recorded distribution of the species did not change significantly between the last Article 17 reporting period (1993-2006) and the current period (2007-2011) throughout the Republic of Ireland. Recording effort was markedly lower in Northern Ireland, which led to an apparent decline in the recorded distribution. We highlight the need to coordinate biological surveys between adjacent political jurisdictions that share a common ecoregion to avoid apparent disparities in the quality of distributional information. Power analysis suggested that a reduced sample of 40-50 survey squares is sufficient to detect a 30% decline (consistent with the International Union for Conservation of Nature Category of 'Vulnerable') at 80% power providing guidance for minimizing future survey effort. Our results provin assessments for R. temporaria and other clump-spawning amphibians. 2013 The Zoological Society of London.

Export Cartels: Is it Legal to Target your Neighbour? Analysis in Light of Recent Case Law

Despite the growing sophistication of antitrust regimes around the world, export cartels benefit from special treatment: they are almost universally tolerated, if not encouraged in the countries of origin. Economists do not offer an unambiguous policy recommendation on how to deal with them in part due to the lack of empirical data. This article discusses arguments for and against export cartels and it identifies the existing gaps in the present regulatory framework. The theoretical part is followed by an analysis of the recent case law: a US cartel challenged with different outcomes in India and South Africa, as well as Chinese export cartels pursued in the USA. The Chinese cases are particularly topical as the conduct at stake, apart from being subject to private antitrust actions before US courts, was also challenged within the WTO dispute settlement framework, pointing out to the existing interface between trade and competition. While the recent developments prove that unaddressed issues tend not to vanish, the new South-North dimension has the potential of placing export cartels again on the international agenda. Pragmatic thinking suggests looking for the solution within the WTO framework.

Law, Politics and Financial Development: The Great Reversal of the U.K. Corporate Debt Market

This article examines the role of creditor protection in the development of the U.K. corporate bond market. This market grew rapidly in the late nineteenth century, but in the twentieth century it experienced a reversal, albeit with a short-lived post-1945 renaissance. Such was the extent of the reversal that the market from the 1970s onwards was smaller than it had been in 1870. We find that law does not explain the variation in the size of this market over time. Alternatively, our evidence suggests that inflation and taxation policies were major drivers of this market in the post-1945 era. Copyright © The Economic History Association 2013

Informational masking in young and elderly listeners for speech masked by simultaneous speech and noise

Three experiments measured the effects of age on informational masking of speech by competing speech. The experiments were designed to minimize the energetic contributions of the competing speech so that informational masking could be measured with no large corrections for energetic masking. Experiment 1 used a "speech-in-speech-in-noise" design, in which the competing speech was presented in noise at a signal-to-noise ratio (SNR) of -4 dB. This ensured that the noise primarily contributed the energetic masking but the competing speech contributed the informational masking. Equal amounts of informational masking (3 dB) were observed for young and elderly listeners, although less was found for hearing-impaired listeners. Experiment 2 tested a range of SNRs in this design and showed that informational masking increased with SNR up to about an SNR of -4 dB, but decreased thereafter. Experiment 3 further reduced the energetic contribution of the competing speech by filtering it into different frequency bands from the target speech. The elderly listeners again showed approximately the same amount of informational masking (4-5 dB), although some elderly listeners had particular difficulty understanding these stimuli in any condition. On the whole, these results suggest that young and elderly listeners were equally susceptible to informational masking. © 2009 Acoustical Society of America.