Five minutes with Peter Kellner: “History could repeat itself in a British referendum on EU membership”

If there were to be a referendum held on the UK’s membership of the European Union, how would British citizens vote? EUROPP’s Managing Editor Stuart Brown spoke to Peter Kellner, President of YouGov, about current polling trends, the lessons from previous UK referendums, and the factors, such as David Cameron’s plan to renegotiate the UK’s membership, which might have a significant impact on the result

Microstructural analysis and high temperature creep of Mo-9Si-8B alloys with Al and Ge additions

Refractory metals and their alloys show potential for high temperature applications, due to the increased melting point and creep resistance. Spark plasma sintering technology as well as argon arc melting is used to prepare quaternary and quinternary Mo-9Si-8B-xAl-yGe (x is 0 or 2; y is 0 or 2) samples. Compositions are stated in at.%. All the compositions consist of a Mo solid solution (α-Mo) and two intermetallic phases: Mo3Si (A15) and Mo5SiB2 (T2). On the one hand, no zirconium is added to the alloys to avoid evaporation of MoO3 due to the phase transformation from a monoclinic to a tetragonal crystallographic structure of ZrO2 at 1150°C. On the other hand, fractions of Al and Ge are alloyed to reduce the melting point of the intermetallic phases. The specimens are homogenized and coarsened by a subsequent heat treatment in a vacuum radiation furnace at 1850°C for 24 h. Both the reduction of the melting point and the heat treatment at a temperature of 1850°C result in an increase in diffusion rate. This procedure is expected to generate an α-Mo interpenetrating network. The resulting microstructures are investigated using SEM, EDX and XRD analyses. A creep testing device for a very short specimen heated in a radiation furnance up to 1400°C usable in air or vacuum is presented. Creep tests are performed at elevated temperatures in vacuum to investigate the influence of different fabrication techniques. Please click Additional Files below to see the full abstract

Mentale Rotation bei Grundschulkindern: Zusammenhang mit motorischen Fähigkeiten und Einfluss motorischer Prozesse

In dieser Arbeit wird der Zusammenhang zwischen den motorischen Fähigkeiten und der kognitiven Fähigkeit der mentalen Rotation, der Fähigkeit sich einen Gegenstand beliebig gedreht vorstellen zu können, bei Kindern im Grundschulalter untersucht. Zusätzlich wird mittels eines Interferenzparadigmas überprüft, ob motorische Prozesse, wie sie z. B. zum Drehen eines Knopfes mit der Hand benötigt werden, an der mentalen Rotation beteiligt sind. Außerdem wurde untersucht, ob die motorischen Fähigkeiten einen Einfluss auf die Beteiligung solcher motorischer Prozesse an der mentalen Rotation haben. Anhand der Ergebnisse kann festgehalten werden, dass der Zusammenhang zwischen den motorischen Fähigkeiten und der mentalen Rotationsfähigkeit von mehreren Faktoren moduliert wird. Werden durch das Stimulusmaterial oder durch motorische Aufgaben mit Bezug zur mentalen Rotation die Verwendung motorischer Prozesse bei der mentalen Rotation implizit angeregt, lässt sich ein signifikanter Zusammenhang zwischen den motorischen Fähigkeiten der Kinder und der mentalen Rotationsfähigkeit nachweisen. Kinder mit ausgeprägteren motorischen Fähigkeiten machen weniger Fehler im mentalen Rotationstest als Kinder mit weniger ausgeprägten motorischen Fähigkeiten. Außerdem konnte bei 7-8 jährigen Jungen eine Interferenz zwischen dem Drehen eines Knopfes in die eine Richtung und der gleichzeitigen mentalen Rotation in die entgegengesetzte Richtung festgestellt werden. Stimmen mentale und manuelle Drehrichtung überein, sind die mittleren Reaktionszeiten um 300ms schneller als wenn die Drehrichtungen inkompatibel sind. In einem weiteren Experiment konnte eine Interferenz allein durch einen der mentalen Rotation entgegengesetzten Bewegungsplan nachgewiesen werden. 7-8 Jährige Mädchen und Jungen hatten um 430ms längere Reaktionszeiten wenn sie während der mentalen Rotation den Bewegungsplan für eine inkompatible Handbewegung aufrechterhalten mussten, als wenn mentale Rotation und Bewegungsplan für eine Handbewegung die gleiche Richtung hatten. Ein Zusammenhang zwischen den motorischen Fähigkeiten und den Interferenzerscheinungen konnte nicht nachgewiesen werden

Disentangling trophic interactions inside a Caribbean marine reserve

Author Posting. © Ecological Society of America, 2010. This article is posted here by permission of Ecological Society of America for personal use, not for redistribution. The definitive version was published in Ecological Applications 20 (2010): 1979–1992, doi:10.1890/09-1217.1.Recent empirical studies have demonstrated that human activities such as fishing can strongly affect the natural capital and services provided by tropical seascapes. However, policies to mitigate anthropogenic impacts can also alter food web structure and interactions, regardless of whether the regulations are aimed at single or multiple species, with possible unexpected consequences for the ecosystems and their associated services. Complex community response to management interventions have been highlighted in the Caribbean, where, contrary to predictions from linear food chain models, a reduction in fishing intensity through the establishment of a marine reserve has led to greater biomass of herbivorous fish inside the reserve, despite an increased abundance of large predatory piscivores. This positive multi-trophic response, where both predators and prey benefit from protection, highlights the need to take an integrated approach that considers how numerous factors control species coexistence in both fished and unfished systems. In order to understand these complex relationships, we developed a general model to examine the trade-offs between fishing pressure and trophic control on reef fish communities, including an exploration of top-down and bottom-up effects. We then validated the general model predictions by parameterizing the model for a reef system in the Bahamas in order to tease apart the wide range of species responses to reserves in the Caribbean. Combining the development of general theory and site-specific models parameterized with field data reveals the underlying driving forces in these communities and enables us to make better predictions about possible population and community responses to different management schemes.This work was supported by funding from the Bahamas Biocomplexity Project (U.S. NSF Biocomplexity grant OCE-0119976) and U.S. EPA Science to Achieve Results (R832223)

Synthesis of Galactosyl‐Queuosine and Distribution of Hypermodified Q‐Nucleosides in Mouse Tissues

Queuosine (Q) is a hypermodified RNA nucleoside that is found in tRNAHis, tRNAAsn, tRNATyr, and tRNAAsp. It is located at the wobble position of the tRNA anticodon loop, where it can interact with U as well as C bases located at the respective position of the corresponding mRNA codons. In tRNATyr and tRNAAsp of higher eukaryotes, including humans, the Q base is for yet unknown reasons further modified by the addition of a galactose and a mannose sugar, respectively. The reason for this additional modification, and how the sugar modification is orchestrated with Q formation and insertion, is unknown. Here, we report a total synthesis of the hypermodified nucleoside galactosyl‐queuosine (galQ). The availability of the compound enabled us to study the absolute levels of the Q‐family nucleosides in six different organs of newborn and adult mice, and also in human cytosolic tRNA. Our synthesis now paves the way to a more detailed analysis of the biological function of the Q‐nucleoside family

The replisome-coupled E3 ubiquitin ligase Rtt101Mms22 counteracts Mrc1 function to tolerate genotoxic stress

Faithful DNA replication and repair requires the activity of cullin 4-based E3 ubiquitin ligases (CRL4), but the underlying mechanisms remain poorly understood. The budding yeast Cul4 homologue, Rtt101, in complex with the linker Mms1 and the putative substrate adaptor Mms22 promotes progression of replication forks through damaged DNA. Here we characterized the interactome of Mms22 and found that the Rtt101Mms22 ligase associates with the replisome progression complex during S-phase via the amino-terminal WD40 domain of Ctf4. Moreover, genetic screening for suppressors of the genotoxic sensitivity of rtt101Δ cells identified a cluster of replication proteins, among them a component of the fork protection complex, Mrc1. In contrast to rtt101Δ and mms22Δ cells, mrc1Δ rtt101Δ and mrc1Δ mms22Δ double mutants complete DNA replication upon replication stress by facilitating the repair/restart of stalled replication forks using a Rad52-dependent mechanism. Our results suggest that the Rtt101Mms22 E3 ligase does not induce Mrc1 degradation, but specifically counteracts Mrc1's replicative function, possibly by modulating its interaction with the CMG (Cdc45-MCM-GINS) complex at stalled forks.</p

Novel genomic island modifies DNA with 7-deazaguanine derivatives

The discovery of ∼20-kb gene clusters containing a family of paralogs of tRNA guanosine transglycosylase genes, called tgtA5, alongside 7-cyano-7-deazaguanine (preQ[subscript 0]) synthesis and DNA metabolism genes, led to the hypothesis that 7-deazaguanine derivatives are inserted in DNA. This was established by detecting 2’-deoxy-preQ[subscript 0] and 2’-deoxy-7-amido-7-deazaguanosine in enzymatic hydrolysates of DNA extracted from the pathogenic, Gram-negative bacteria Salmonella enterica serovar Montevideo. These modifications were absent in the closely related S. enterica serovar Typhimurium LT2 and from a mutant of S. Montevideo, each lacking the gene cluster. This led us to rename the genes of the S. Montevideo cluster as dpdA-K for 7-deazapurine in DNA. Similar gene clusters were analyzed in ∼150 phylogenetically diverse bacteria, and the modifications were detected in DNA from other organisms containing these clusters, including Kineococcus radiotolerans, Comamonas testosteroni, and Sphingopyxis alaskensis. Comparative genomic analysis shows that, in Enterobacteriaceae, the cluster is a genomic island integrated at the leuX locus, and the phylogenetic analysis of the TgtA5 family is consistent with widespread horizontal gene transfer. Comparison of transformation efficiencies of modified or unmodified plasmids into isogenic S. Montevideo strains containing or lacking the cluster strongly suggests a restriction–modification role for the cluster in Enterobacteriaceae. Another preQ[subscript 0] derivative, 2’-deoxy-7-formamidino-7-deazaguanosine, was found in the Escherichia coli bacteriophage 9g, as predicted from the presence of homologs of genes involved in the synthesis of the archaeosine tRNA modification. These results illustrate a deep and unexpected evolutionary connection between DNA and tRNA metabolism.Deutsche ForschungsgemeinschaftSingapore-MIT Alliance in Research and Technology (SMART

A mathematical model of the mevalonate cholesterol biosynthesis pathway

We formulate, parameterise and analyse a mathematical model of the mevalonate pathway, a key pathway in the synthesis of cholesterol. Of high clinical importance, the pathway incorporates rate limiting enzymatic reactions with multiple negative feedbacks. In this work we investigate the pathway dynamics and demonstrate that rate limiting steps and negative feedbacks within it act in concert to tightly regulate intracellular cholesterol levels. Formulated using the theory of nonlinear ordinary differential equations and parameterised in the context of a hepatocyte, the governing equations are analysed numerically and analytically. Sensitivity and mathematical analysis demonstrate the importance of the two rate limiting enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and squalene synthase in controlling the concentration of substrates within the pathway as well as that of cholesterol. The role of individual feedbacks, both global (between that of cholesterol and sterol regulatory element-binding protein 2; SREBP-2) and local internal (between substrates in the pathway) are investigated. We find that whilst the cholesterol SREBP-2 feedback regulates the overall system dynamics, local feedbacks activate within the pathway to tightly regulate the overall cellular cholesterol concentration. The network stability is analysed by constructing a reduced model of the fall pathway and is shown to exhibit one real, stable steady-state. We close by addressing the biological question as to how farnesyl-PP levels are affected by CYP51 inhibition, and demonstrate that the regulatory mechanisms within the network work in unison to ensure they remain bounded

Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.

Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage