A myogenic differentiation checkpoint activated by genotoxic stress

Cell-cycle checkpoints help to protect the genomes of proliferating cells under genotoxic stress. In multicellular organisms, cell proliferation is often directed toward differentiation during development and throughout adult homeostasis. To prevent the formation of differentiated cells with genetic instability, we hypothesized that genotoxic stress may trigger a differentiation checkpoint. Here we show that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression is suppressed by DNA-damaging agents if applied prior to differentiation induction but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded by the oncogene Jun). These results support the idea that genotoxic stress can regulate differentiation, and identify a new biological function for DNA damage-activated signaling network.     

A correlation between mid-ocean-ridge basalt chemistry and distance to continents

To fully understand the structure and dynamics of the Earth's convecting mantle, the origins of temperature variations within the mantle need to be resolved. Different hypotheses have been proposed to account for these temperature variations: for example, heat coming from the decay of radioactive elements or heat flowing out of the Earth's core. In addition, theoretical studies suggest that the thermal properties of continental masses can affect mantle convection, but quantitative data that could allow us to test these models are scarce. To address this latter problem, we have examined the chemistry of mid-ocean-ridge basalt--which reflects the temperature of the source mantle--as a function of the distance of the ridge from the closest continental margin. No correlation is observed for oceanic ridges close to subduction zones or hotspots; subduction zones probably inhibit thermal transfer between the mantle beneath continents and ocean, whereas hotspots influence the major-element chemistry of ridge basalts, which makes their interpretation with respect to mantle temperature more difficult. However, we do observe a significant correlation for mid-oceanic basalts from the Atlantic and Indian oceans. From this, we conclude that the location of continental masses relative to active ridges influences the large-scale thermal structure of the mantle and we estimate that the mantle cools by 0.05 to 0.1 degrees C per kilometre from the continental margins.     

Investigations on the toxic action ofAmanita phalloides Fr. on the hepatic cell

Riassunto Nel ratto intossicato con estratto diAmanita phalloide le prime alterazioni strutturali dell'epatocita si realizzano a livello del nucleo e del nucleolo con formazioni di «nucleolar caps». Da queste stesse strutture iniziano i fenomeni di regressione delle alterazioni. Le manifestazioni sia del danno che della sua regressione a livello citoplasmatico risultano essere successive a quelle nucleari. Il comportamento del DNA e di alcuni enzimi del tessuto epatico è risultato nel complesso coerente con le alterazioni morfologiche. In rapporto con la dose usata queste alterazioni risultano reversibili poichè nelle cellule colpite entro 12 h cominciano i fenomeni di ristrutturazione.     

DNA sequence and analysis of human chromosome 18

Chromosome 18 appears to have the lowest gene density of any human chromosome and is one of only three chromosomes for which trisomic individuals survive to term. There are also a number of genetic disorders stemming from chromosome 18 trisomy and aneuploidy. Here we report the finished sequence and gene annotation of human chromosome 18, which will allow a better understanding of the normal and disease biology of this chromosome. Despite the low density of protein-coding genes on chromosome 18, we find that the proportion of non-protein-coding sequences evolutionarily conserved among mammals is close to the genome-wide average. Extending this analysis to the entire human genome, we find that the density of conserved non-protein-coding sequences is largely uncorrelated with gene density. This has important implications for the nature and roles of non-protein-coding sequence elements.     

Genome sequence, comparative analysis and haplotype structure of the domestic dog

Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.     

Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2

Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.     

A new class of homoserine lactone quorum-sensing signals

Quorum sensing is a term used to describe cell-to-cell communication that allows cell-density-dependent gene expression. Many bacteria use acyl-homoserine lactone (acyl-HSL) synthases to generate fatty acyl-HSL quorum-sensing signals, which function with signal receptors to control expression of specific genes. The fatty acyl group is derived from fatty acid biosynthesis and provides signal specificity, but the variety of signals is limited. Here we show that the photosynthetic bacterium Rhodopseudomonas palustris uses an acyl-HSL synthase to produce p-coumaroyl-HSL by using environmental p-coumaric acid rather than fatty acids from cellular pools. The bacterium has a signal receptor with homology to fatty acyl-HSL receptors that responds to p-coumaroyl-HSL to regulate global gene expression. We also found that p-coumaroyl-HSL is made by other bacteria including Bradyrhizobium sp. and Silicibacter pomeroyi. This discovery extends the range of possibilities for acyl-HSL quorum sensing and raises fundamental questions about quorum sensing within the context of environmental signalling.     

Automatic removal of eye movement artifacts from the EEG using ICA and the dipole model

In this study, we proposed and evaluated the use of Independent Component Analysis (ICA) combining the EEG dipole model to automatically remove eye movement artifacts from the EEG without needing EOG as a reference. We separated the EEG data into independent components using the ICA method, and determined the source localization of these independent components with a single dipole model. The EEG signal was reconstructed by automatically excluding those components localized within a preset eye model. EEGs from 12 patients were analyzed. The experimental results indicate that ICA with the dipole model is very efficient at automatically subtracting the eye movement artifacts, while retaining the EEG slow waves and making their interpretation easier.     

Forecasting Mixed‐Frequency Time Series with ECM‐MIDAS Models

This paper proposes a mixed‐frequency error correction model for possibly cointegrated non‐stationary time series sampled at different frequencies. We highlight the impact, in terms of model specification, of the choice of the particular high‐frequency explanatory variable to be included in the cointegrating relationship, which we call a dynamic mixed‐frequency cointegrating relationship. The forecasting performance of aggregated models and several mixed‐frequency regressions are compared in a set of Monte Carlo experiments. In particular, we look at both the unrestricted mixed‐frequency model and at a more parsimonious MIDAS regression. Whereas the existing literature has only investigated the potential improvements of the MIDAS framework for stationary time series, our study emphasizes the need to include the relevant cointegrating vectors in the non‐stationary case. Furthermore, it is illustrated that the choice of dynamic mixed‐frequency cointegrating relationship does not matter as long as the short‐run dynamics are adapted accordingly. Finally, the unrestricted model is shown to suffer from parameter proliferation for samples of relatively small size, whereas MIDAS forecasts are robust to over‐parameterization. We illustrate our results for the US inflation rate. Copyright © 2014 John Wiley & Sons, Ltd.