Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication.

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects <or =40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

Nidovirales: evolving the largest RNA virus genome.

This review focuses on the monophyletic group of animal RNA viruses united in the order Nidovirales. The order includes the distantly related coronaviruses, toroviruses, and roniviruses, which possess the largest known RNA genomes (from 26 to 32 kb) and will therefore be called ‘large’ nidoviruses in this review. They are compared with their arterivirus cousins, which also belong to the Nidovirales despite having a much smaller genome (13–16 kb). Common and unique features that have been identified for either large or all nidoviruses are outlined. These include the nidovirus genetic plan and genome diversity, the composition of the replicase machinery and virus particles, virus-specific accessory genes, the mechanisms of RNA and protein synthesis, and the origin and evolution of nidoviruses with small and large genomes. Nidoviruses employ single-stranded, polycistronic RNA genomes of positive polarity that direct the synthesis of the subunits of the replicative complex, including the RNA-dependent RNA polymerase and helicase. Replicase gene expression is under the principal control of a ribosomal frameshifting signal and a chymotrypsin-like protease, which is assisted by one or more papain-like proteases. A nested set of subgenomic RNAs is synthesized to express the 3'-proximal ORFs that encode most conserved structural proteins and, in some large nidoviruses, also diverse accessory proteins that may promote virus adaptation to specific hosts. The replicase machinery includes a set of RNA-processing enzymes some of which are unique for either all or large nidoviruses. The acquisition of these enzymes may have improved the low fidelity of RNA replication to allow genome expansion and give rise to the ancestors of small and, subsequently, large nidoviruses.

Stable GeV Ion Beam Acceleration from Thin Foils by Circularly Polarized Laser Pulses

A stable relativistic ion acceleration regime for thin foils irradiated by circularly polarized laser pulses is suggested. In this regime, the "light-sail" stage of radiation pressure acceleration for ions is smoothly connected with the initial relativistic "hole-boring" stage, and a defined relationship between laser intensity I(0), foil density n(0), and thickness l(0) should be satisfied. For foils with a wide range of n(0), the required I(0) and l(0) for the regime are theoretically estimated and verified with the particle-in-cell code ILLUMINATION. It is shown for the first time by 2D simulations that high-density monoenergetic ion beams with energy above GeV/u and divergence of 10 degrees are produced by circularly polarized lasers at intensities of 10(22) W/cm(2), which are within reach of current laser systems.

Minimum Wage Regulation under Devolution in Northern Ireland

This paper assesses the development and functioning of regional minimum wage regulation in Northern Ireland in the interwar period under a federal form of devolution. Unlike current devolution arrangements in Scotland and Wales, this gave the Stormont Parliament powers over employment and minimum wage regulation. Northern Ireland Trade Boards were set up by the Ulster Unionist Government under the Trade Boards (Northern Ireland) Act 1923 and functioned along the same lines as those in Great Britain. Uniquely in the UK in this period, employer opposition resulted in the main Trade Board in the Irish Linen Industry being replaced by voluntary collective bargaining machinery. About one-quarter of employees were covered by minimum wage regulation, including two-thirds of females in Belfast, keeping a protective floor under low pay.

The redox-Bohr group associated with iron-sulfur cluster N2 of complex I

Proton pumping respiratory complex I (NADH: ubiquinone oxidoreductase) is a major component of the oxidative phosphorylation system in mitochondria and many bacteria. In mammalian cells it provides 40% of the proton motive force needed to make ATP. Defects in this giant and most complicated membrane-bound enzyme cause numerous human disorders. Yet the mechanism of complex I is still elusive. A group exhibiting redox-linked protonation that is associated with iron-sulfur cluster N2 of complex I has been proposed to act as a central component of the proton pumping machinery. Here we show that a histidine in the 49-kDa subunit that resides near iron-sulfur cluster N2 confers this redox-Bohr effect. Mutating this residue to methionine in complex I from Yarrowia lipolytica resulted in a marked shift of the redox midpoint potential of iron-sulfur cluster N2 to the negative and abolished the redox-Bohr effect. However, the mutation did not significantly affect the catalytic activity of complex I and protons were pumped with an unchanged stoichiometry of 4 H+/2e(-). This finding has significant implications on the discussion about possible proton pumping mechanism for complex I.

On the derived category of a regular toric scheme

Let X be a quasi-compact scheme, equipped with an open covering by affine schemes U s = Spec A s . A quasi-coherent sheaf on X gives rise, by taking sections over the U s , to a diagram of modules over the coordinate rings A s , indexed by the intersection poset S of the covering. If X is a regular toric scheme over an arbitrary commutative ring, we prove that the unbounded derived category of quasi-coherent sheaves on X can be obtained from a category of Sop-diagrams of chain complexes of modules by inverting maps which induce homology isomorphisms on hyper-derived inverse limits. Moreover, we show that there is a finite set of weak generators, one for each cone in the fan S. The approach taken uses the machinery of Bousfield–Hirschhorn colocalisation of model categories. The first step is to characterise colocal objects; these turn out to be homotopy sheaves in the sense that chain complexes over different open sets U s agree on intersections up to quasi-isomorphism. In a second step it is shown that the homotopy category of homotopy sheaves is equivalent to the derived category of X.

GERMAN WORKS COUNCILS AND THE ANATOMY OF WAGES

Using matched employer-employee data from the German LIAB for 2001, the authors found that German works councils are in general associated with higher earnings, even after accounting for establishment- and worker heterogeneity. Works Council wage premia exceed those of collective bargaining and are higher, in fact, where both institutions are present in the workplace. The authors also found evidence indicating that works councils benefit women relative to men and appear to favor foreign, east-German, and service-sector workers as well. Separate evidence from quantile regressions suggests that the conjunction of works council presence and collective bargaining is important to the narrowing process. In smaller plants even the presence of a works council markup depends on the coexistence of the works council entity With the machinery of collective bargaining.

A Framework for the Evaluation of Digital Musical Instruments

At the outset of a discussion of evaluating digital musical instruments, that is to say instruments whose sound generators are digital and separable though not necessarily separate from their control interfaces (Malloch, 2006), it is reasonable to ask what the term evaluation in this context really means. After all, there may be many perspectives from which to view the effectiveness or otherwise of the instruments we build. For most performers, performance on an instrument becomes a means of evaluating how well it functions in the context of live music making, and their measure of success is the response of the audience to their performance. Audiences evaluate performances on the basis of how engaged they feel they have been by what they have seen and heard. When questioned, they are likely to describe good performances as “exciting,” “skillful,” “musical.” Bad performances are “boring,” and those which are marred by technical malfunction are often dismissed out of hand. If performance is considered to be a valid means of evaluating a musical instrument, then it follows that, for the field of DMI design, a much broader definition of the term “evaluation” than that typically used in human-computer interaction (HCI) is required to reflect the fact that there are a number of stakeholders involved in the design and evaluation of DMIs. In addition to players and audiences, there are also composers, instrument builders, component manufacturers, and perhaps even customers, each of whom will have a different concept of what is meant by “evaluation.”

HTS Motors in Aircraft Propulsion: Design Considerations

Current high temperature superconducting (HTS) wires exhibit high current densities enabling their use in electrical rotating machinery. The possibility of designing high power density superconducting motors operating at reasonable temperatures allows for new applications in mobile systems in which size and weight represent key design parameters. Thus, all-electric aircrafts represent a promising application for HTS motors. The design of such a complex system as an aircraft consists of a multi-variable optimization that requires computer models and advanced design procedures. This paper presents a specific sizing model of superconducting propulsion motors to be used in aircraft design. The model also takes into account the cooling system. The requirements for this application are presented in terms of power and dynamics as well as a load profile corresponding to a typical mission. We discuss the design implications of using a superconducting motor on an aircraft as well as the integration of the electrical propulsion in the aircraft, and the scaling laws derived from physics-based modeling of HTS motors.

Cold-induced silencing by long antisense transcripts of an Arabidopsis Polycomb target.

Transcription in eukaryotic genomes generates an extensive array of non-protein-coding RNA, the functional significance of which is mostly unknown. We are investigating the link between non-coding RNA and chromatin regulation through analysis of FLC - a regulator of flowering time in Arabidopsis and a target of several chromatin pathways. Here we use an unbiased strategy to characterize non-coding transcripts of FLC and show that sense/antisense transcript levels correlate in a range of mutants and treatments, but change independently in cold-treated plants. Prolonged cold epigenetically silences FLC in a Polycomb-mediated process called vernalization. Our data indicate that upregulation of long non-coding antisense transcripts covering the entire FLC locus may be part of the cold-sensing mechanism. Induction of these antisense transcripts occurs earlier than, and is independent of, other vernalization markers and coincides with a reduction in sense transcription. We show that addition of the FLC antisense promoter sequences to a reporter gene is sufficient to confer cold-induced silencing of the reporter. Our data indicate that cold-induced FLC antisense transcripts have an early role in the epigenetic silencing of FLC, acting to silence FLC transcription transiently. Recruitment of the Polycomb machinery then confers the epigenetic memory. Antisense transcription events originating from 3' ends of genes might be a general mechanism to regulate the corresponding sense transcription in a condition/stage-dependent manner.

Altered interactions within FY/AtCPSF complexes required for Arabidopsis FCA-mediated chromatin silencing.

The role of RNA metabolism in chromatin silencing is now widely recognized. We have studied the Arabidopsis RNA-binding protein FCA that down-regulates an endogenous floral repressor gene through a chromatin mechanism involving histone demethylase activity. This mechanism needs FCA to interact with an RNA 3' processing/polyadenylation factor (FY/Pfs2p), but the subsequent events leading to chromatin changes are unknown. Here, we show that this FCA-FY interaction is required for general chromatin silencing roles where hairpin transgenes induce DNA methylation of an endogenous gene. We also show 2 conserved RNA processing factors, AtCPSF100 and AtCPSF160, but not FCA, are stably associated with FY in vivo and form a range of different-sized complexes. A hypomorphic fy allele producing a shorter protein, able to provide some FY functions but unable to interact with FCA, reduces abundance of some of the larger MW complexes. Suppressor mutants, which specifically disrupt the FY motif through which FCA interacts, also lacked these larger complexes. Our data support a model whereby FCA, perhaps after recognition of a specific RNA feature, transiently interacts with FY, an integral component of the canonical RNA 3' processing machinery, changing the interactions of the different RNA processing components. These altered interactions would appear to be a necessary step in this RNA-mediated chromatin silencing.

Protein arginine-methyltransferase-dependent oncogenesis

Enzymes that mediate reversible epigenetic modifications have not only been recognized as key in regulating gene expression(1) and oncogenesis(2,3), but also provide potential targets for molecular therapy(4). Although the methylation of arginine 3 of histone 4 ( H4R3) by protein arginine methyltransferase 1 ( PRMT1) is a critical modification for active chromatin(5,6) and prevention of heterochromatin spread(7), there has been no direct evidence of any role of PRMTs in cancer. Here, we show that PRMT1 is an essential component of a novel Mixed Lineage Leukaemia ( MLL) oncogenic transcriptional complex with both histone acetylation and H4R3 methylation activities, which also correlate with the expression of critical MLL downstream targets. Direct fusion of MLL with PRMT1 or Sam68, a bridging molecule in the complex for PRMT1 interaction, could enhance self-renewal of primary haematopoietic cells. Conversely, specific knockdown of PRMT1 or Sam68 expression suppressed MLL-mediated transformation. This study not only functionally dissects the oncogenic transcriptional machinery associated with an MLL fusion complex, but also uncovers-for the first time-an essential function of PRMTs in oncogenesis and reveals their potential as novel therapeutic targets in human cancer.

Dominance of Radiation Pressure in Ion Acceleration with Linearly Polarized Pulses at Intensities of 10(21) W cm(-2)

A novel regime is proposed where, by employing linearly polarized laser pulses at intensities 10(21) W cm(-2) (2 orders of magnitude lower than discussed in previous work [T. Esirkepov et al., Phys. Rev. Lett. 92, 175003 (2004)]), ions are dominantly accelerated from ultrathin foils by the radiation pressure and have monoenergetic spectra. In this regime, ions accelerated from the hole-boring process quickly catch up with the ions accelerated by target normal sheath acceleration, and they then join in a single bunch, undergoing a hybrid light-sail-target normal sheath acceleration. Under an appropriate coupling condition between foil thickness, laser intensity, and pulse duration, laser radiation pressure can be dominant in this hybrid acceleration. Two-dimensional particle-in-cell simulations show that 1.26 GeV quasimonoenergetic C6+ beams are obtained by linearly polarized laser pulses at intensities of 10(21) W cm(-2).