168 research outputs found
p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest
No full textmicroRNAs provide a novel layer of regulation for gene expression by interfering with the stability and/or translation of specific target mRNAs. Overall levels of microRNTAs are frequently down-regulated in cancer cells, and reducing general microRNA processing increases cancerogenesis in transgenic models, suggesting that at least some microRNAs might act as effectors in tumor suppression. Accordingly, the tumor suppressor p53 up-regulates miR-34a, a microR-NtA that contributes to apoptosis and acute senescence. Here, we used array hybridization to rind that p53 induces two additional, mutually related clusters of microRNAs, leading to the up-regulation of miR-192, miR-194, and miR-215. The same microRNAs were detected at high levels in normal colon tissue but were severely reduced in many colon cancer samples. On the other hand, miR-192 and its cousin miR-215 can each contribute to enhanced CDKN1A/p21 levels, colony suppression, cell cycle arrest, and cell detachment from a solid support. These effects were partially dependent on the presence of wild-type p53. Antagonizing endogenous miR-192 attenuated 5-fluorouracil-induced accumulation of p21. Hence, miR-192 and miR-215 can act as effectors as well as regulators of p53; they seem to suppress cancerogenesis through p21 accumulation and cell cycle arrest. [Cancer Res 2008;68(24):10094-104]NCI NIH HHS [R01 CA060664, R01 CA060664-13
The case for a symmetric reaction function of the European Central Bank
No full textIn a macro-economic framework where the European Central Bank targets individual country data, the nature of strategic interactions between fiscal authorities in the euro-zone can be described as a stag hunt game with (at least) two equilibria that can be pareto-ranked. In fact we show that, because of the indiscriminate nature of its monetary response, an ECB strategy of monetary retaliation to any individual countrys over-expenditure affects all eleven countries to the same extent. This collective effect is similar to the teachers old favorite all children stay behind in the class if one misbehaves. This mechanism, we show, makes the game between fiscal authorities a multiple equilibria co-ordination game. We subsequently address the problem of equilibrium selection that is of particular importance to co-ordination games. Following Kandori et al. (1993), we apply Harsanyi and Seltens (1988) riskdominance criterion to single out the conditions for fiscal restraint to emerge as the equilibrium selected by interacting actors. Our main conclusions are that the ECB can ensure convergence of fiscal authorities upon the pareto-optimal equilibrium (that is, fiscal restraint) by adopting a reward-oriented, counter-cyclical strategy that compensates fiscal authorities at the output level both for giving up fiscal discretion and for incurring the risk of being hit by a monetary tightening in response to developments elsewhere in the euro-economy. This means that interest rates' movements should smoothen economic fluctuations in order to give economic actors sufficient incentives to maintain restraint. -- In einem makroökonomischen Kontext, in dem die Europäische Zentralbank die wirtschaftlichen Daten einzelner Länder anvisiert, können die strategischen Interaktionen zwischen den Finanzbehörden der Euro-Zone als ein stag hunt- Spiel mit (mindestens) zwei pareto-Equilibrien beschrieben werden. Wir zeigen daß, aufgrund der ungezielten Art der monetären Reaktion, eine EZB-Strategie der monetären Vergeltung für zu hohe Ausgaben eines einzelnen Landes alle elf Länder gleichermaßen betrifft. Dieser Kollektiveffekt erinnert an die alte Lehrermethode: Alle Kinder müssen nachsitzen, wenn eins aus der Reihe tanzt. Dieser Mechanismus macht das Spiel zwischen den Finanzbehörden zu einem Koordinationsspiel mit mehreren Equilibrien. Anschließend befassen wir uns mit dem in Koordinationsspielen besonders bedeutsamen Problem der Wahl zwischen Equilibrien. In Anlehnung an Kandori et al. (1993) wenden wir Harsanyi und Selten's (1988) Risikodominanzkriterium an, um die Bedingungen herauszufiltern, unter denen fiskale Zurückhaltung das Equilibrium bildet, das von den beteiligten Akteuren gewählt wird. Unsere wesentlichen Schlußfolgerungen sind, daß die EZB eine Konvergenz der Finanzbehörden auf das pareto-optimale Equilibrium (d.h. fiskale Zurückhaltung) sicherstellen kann, indem sie eine auf Belohnung ausgerichte, antizyklische Strategie verfolgt, bei der die Finanzbehörden auf der Output-Ebene entschädigt werden -sowohl für die Abgabe fiskaler Entscheidungsfreiheit als auch für das Risiko, einer monetären Kontraktion ausgesetzt zu werden, die auf Entwicklungen anderswo in der Euro-Wirtschaft abzielt. Das bedeutet, daß Zinsentwicklungen wirtschaftliche Fluktuationen ausgleichen sollten, um den relevanten Akteuren ausreichende Anreize für fiskale Zurückhaltung zu bieten.
Author Correction: Insights from serial cardiovascular magnetic resonance imaging show early progress in diastolic dysfunction relates to impaired right ventricular deformation
No full textGerman production networks in Central, Eastern Europe: between dependency and globalisation
No full textThis paper offers a first assessment of the contribution of international production to the dynamics of regional integration in Europe. After very high expectations, there is increasing scepticism concerning the role of foreign direct investment as an engine of growth in the region. On the basis of often implicit cross regional comparisons, it is argued that the level of foreign direct investment in Central and Eastern Europe (CEE) is low, that it does not lead to significant technology transfers and backward linkages, and that the prospects for Cross national productions networks to develop continent-wide are at best uncertain. The paper argues that generalisations based on foreign direct investment figures hide more than reveal and looks at the development of Outward Processing Traffic between the European Union (EU) and CEE as an alternative source of evidence to characterise some of the transformations that the European model of integration is undergoing. It finds that EU firms, mainly medium sized German companies, make an important use of non equity forms of international production when expanding eastwards. The resulting patterns of cooperation are fluid, but not necessarily precarious. In fact, they are an ideal vehicle for implementing new flexible methods of production which have greater potentials for spillovers and multiplier effects. Overall, these patterns of cooperation give rise to different market linkages that hardly fit into static categories, a process in which policy makers have only little say. -- Die vorliegende Studie bietet eine erste Bewertung der Auswirkungen internationaler Produktion auf die Dynamik regionaler Integration in Europa. Was die Rolle ausländischer Direktinvestitionen angeht, so sind die anfänglich sehr hohen Erwartungen mittlerweile der Skepsis gewichen. Auf der Grundlage oftmals impliziter regionsübergreifender Vergleiche wird hier festgestellt, daß Direktinvestitionen in Zentral- und Osteuropa niedrig sind, daß sie keine nennenswerten Technologietransfers und backward linkages mit sich bringen, und daß die Aussichten für die europaweite Entwicklung transnationaler Produktionsnetzwerke bestenfalls unsicher sind. Es wird argumentiert, daß Verallgemeinerungen auf der Basis von Direktinvestitionsziffern mehr verschleiern als enthüllen. Daher wird hier die Entwicklung von Outward-Processing-Verkehr zwischen der Europäischen Union und Zentral- und Osteuropa als alternative Quelle herangezogen, um einige der Transformationen zu kennzeichnen, welche das europäische Integrationsmodell im Augenblick durchmacht. Eine Feststellung ist, daß EU-Firmen, insbesondere mittelständische deutsche Unternehmen, bei der Ausdehnung in Richtung Osten starken Gebrauch von internationalen Produktionsnetzen zwischen unabhängigen Firmen (non-equity forms of production) machen. Die daraus resultierenden Kooperationsmuster sind fließend, aber nicht unbedingt unsicher. Sie könnten sich im Gegenteil als ideales Vehikel für die Einführung neuer flexibler Produktionsmethoden erweisen, die größeres Potential für Spillovers und Multiplikationseffekte bieten. Insgesamt führen solche Produktionsnetze zwischen unabhängigen Unternehmen zu neuen Marktverbindungen, die sich kaum in feststehende Kategorien einordnen lassen. Auf diesen Prozeß haben Politiker nur wenig Einfluß.
Localisation and obfuscation techniques for enhanced multi-factor authentification in mcommerce applications
No full textAbstract The focus of this thesis is to investigate solutions that shall enhance the security of remote client authentication for mCommerce applications on phones such as Smartphones or Tablet-PCs. This thesis details three innovative authentication schemes developed during the course of this study. These schemes are based on the use of localisation and obfuscation techniques in combination with multi-factor authentication to enforce the knowledge of "who, when, where and how" necessary for any remote client authentication attempt. Thus, assuring the mCommerce service provider about the genuine client as well as ensuring correct capturing and processing of the client's authentication data on the remote phone. The author of this thesis believes that these schemes, when developed on commercial mCommerce applications, shall enhance the service provider's trust into the received client data and therefore shall encourage more service providers to offer their mCommerce services via phone applications to their clients. The first proposed scheme, called MORE-BAILS, combines multiple authentication factors into a One-Time Multi-Factor Biometric Representation (OTMFBR) of a client, so to achieve robust, secure, and privacy-preserving client authentication. Tests and trials of this scheme proved that it is viable for use in the authentication process of any type of mCommerce phone applications. The second and third schemes, called oBiometrics and LocAuth respectively, use a new obfuscated-interpretation approach to protect the mComrnerce application against misuse by attackers as well as to ensure the real-time and one-time properties of the client's authentication attempt. The novelty of combining biornetric-based keys with obfuscated-interpretation tightly binds the correct mCommerce application execution to the genuine client. Furthermore, integration of the client's current location and real-time in the LocAuth challenge / response scheme eliminates the risk that an attacker can illegitimately re-use previously gathered genuine client authentication data in a replay attack. f Based on appropriate criteria, the MORE-BAILS, oBiometrics and LocAuth levels of security, user-friendliness and algorithms' ease-of-implementation are proven m experiments and trials on state-of-the-art Android-based Smartphones.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
A nuclear export block triggers the decay of newly synthesized polyadenylated RNA
No full textA nuclear export block triggers the decay of newly synthesized polyadenylated RNA
Agnieszka Tudek1, Manfred Schmid1, Marius Makaras1, J. David Barrass2, Jean D. Beggs2, Torben Heick Jensen1*
1Department of Molecular Biology and Genetics, Aarhus University, C. F. Møllers Allé 3, building 1130, 8000 Aarhus C, Denmark, 2Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK
*corresponding author and lead contact: [email protected]
Keywords: nuclear export of pA+ RNA, nuclear degradation of pA+ RNA, Mex67p, Nab2p, transcription.
ABSTRACT
Genomes are promiscuously transcribed necessitating mechanisms that facilitate the sorting of RNA for function or destruction. The polyA (pA) tail is one such distinguishing feature, which in the Saccharomyces cerevisiae nucleus is bound by the Nab2p protein, yielding transcript protection. As Nab2p also contacts the main nuclear export factor Mex67p, we asked whether transport kinetics contributes to RNA sorting. Indeed, 3’end sequencing of newly transcribed pA+ RNAs demonstrates that nuclear depletion of Mex67p elicits their instant and global decay. A similar phenotype is evident upon inactivation of other export factors and proportional to the amount of nuclear pA+ RNA. As RNA expression is partially rescued by Nab2p over-expression, we propose that an export-block out-titrates Nab2p onto nuclear retained pA+ RNA, reducing the pool of Nab2p available to protect new transcripts. More generally, we suggest that nuclear RNA decay, negotiated by Nab2p availability, aids in balancing cellular transcript supply with demand
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
No full textObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation
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