Astrophysics: is a doomsday catastrophe likely?

The risk of a doomsday scenario in which high-energy physics experiments trigger the destruction of the Earth has been estimated to be minuscule. But this may give a false sense of security: the fact that the Earth has survived for so long does not necessarily mean that such disasters are unlikely, because observers are, by definition, in places that have avoided destruction. Here we derive a new upper bound of one per billion years (99.9% confidence level) for the exogenous terminal-catastrophe rate that is free of such selection bias, using calculations based on the relatively late formation time of Earth.     

If the cap fits,wear it: an overview of telomeric structures over evolution

Genome organization into linear chromosomes likely represents an important evolutionary innovation that has permitted the development of the sexual life cycle; this process has consequently advanced nuclear expansion and increased complexity of eukaryotic genomes. Chromosome linearity, however, poses a major challenge to the internal cellular machinery. The need to efficiently recognize and repair DNA double-strand breaks that occur as a consequence of DNA damage presents a constant threat to native chromosome ends known as telomeres. In this review, we present a comparative survey of various solutions to the end protection problem, maintaining an emphasis on DNA structure. This begins with telomeric structures derived from a subset of prokaryotes, mitochondria, and viruses, and will progress into the typical telomere structure exhibited by higher organisms containing TTAGG-like tandem sequences. We next examine non-canonical telomeres from Drosophila melanogaster, which comprise arrays of retrotransposons. Finally, we discuss telomeric structures in evolution and possible switches between canonical and non-canonical solutions to chromosome end protection.     

Robust evaluation of fixed‐event forecast rationality

In this paper we introduce a new testing procedure for evaluating the rationality of fixed‐event forecasts based on a pseudo‐maximum likelihood estimator. The procedure is designed to be robust to departures in the normality assumption. A model is introduced to show that such departures are likely when forecasters experience a credibility loss when they make large changes to their forecasts. The test is illustrated using monthly fixed‐event forecasts produced by four UK institutions. Use of the robust test leads to the conclusion that certain forecasts are rational while use of the Gaussian‐based test implies that certain forecasts are irrational. The difference in the results is due to the nature of the underlying data. Copyright © 2001 John Wiley & Sons, Ltd.     

A transient placental source of serotonin for the fetal forebrain

Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1(-/-) (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.     

The energetics of genome complexity

All complex life is composed of eukaryotic (nucleated) cells. The eukaryotic cell arose from prokaryotes just once in four billion years, and otherwise prokaryotes show no tendency to evolve greater complexity. Why not? Prokaryotic genome size is constrained by bioenergetics. The endosymbiosis that gave rise to mitochondria restructured the distribution of DNA in relation to bioenergetic membranes, permitting a remarkable 200,000-fold expansion in the number of genes expressed. This vast leap in genomic capacity was strictly dependent on mitochondrial power, and prerequisite to eukaryote complexity: the key innovation en route to multicellular life.     

Genetic history of an archaic hominin group from Denisova Cave in Siberia

Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.     

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.     

Evidence for recycled Archaean oceanic mantle lithosphere in the Azores plume

The compositional differences between mid-ocean-ridge and ocean-island basalts place important constraints on the form of mantle convection. Also, it is thought that the scale and nature of heterogeneities within plumes and the degree to which heterogeneous material endures within the mantle might be reflected in spatial variations of basalt composition observed at the Earth's surface. Here we report osmium isotope data on lavas from a transect across the Azores archipelago which vary in a symmetrical pattern across what is thought to be a mantle plume. Many of the lavas from the centre of the plume have lower 187Os/188Os ratios than most ocean-island basalts and some extend to subchondritic 187Os/188Os ratios-lower than any yet reported from ocean-island basalts. These low ratios require derivation from a depleted, harzburgitic mantle, consistent with the low-iron signature of the Azores plume. Rhenium-depletion model ages extend to 2.5 Gyr, and we infer that the osmium isotope signature is unlikely to be derived from Iberian subcontinental lithospheric mantle. Instead, we interpret the osmium isotope signature as having a deep origin and infer that it may be recycled, Archaean oceanic mantle lithosphere that has delaminated from its overlying oceanic crust. If correct, our data provide evidence for deep mantle subduction and storage of oceanic mantle lithosphere during the Archaean era.     

The European dimension for the mouse genome mutagenesis program

The European Mouse Mutagenesis Consortium is the European initiative contributing to the international effort on functional annotation of the mouse genome. Its objectives are to establish and integrate mutagenesis platforms, gene expression resources, phenotyping units, storage and distribution centers and bioinformatics resources. The combined efforts will accelerate our understanding of gene function and of human health and disease.