Forecast accuracy after pretesting with an application to the stock market

In econometrics, as a rule, the same data set is used to select the model and, conditional on the selected model, to forecast. However, one typically reports the properties of the (conditional) forecast, ignoring the fact that its properties are affected by the model selection (pretesting). This is wrong, and in this paper we show that the error can be substantial. We obtain explicit expressions for this error. To illustrate the theory we consider a regression approach to stock market forecasting, and show that the standard predictions ignoring pretesting are much less robust than naive econometrics might suggest. We also propose a forecast procedure based on the ‘neutral Laplace estimator’, which leads to an improvement over standard model selection procedures. Copyright © 2004 John Wiley & Sons, Ltd.     

Vernier templating and synthesis of a 12-porphyrin nano-ring

Templates are widely used to arrange molecular components so they can be covalently linked into complex molecules that are not readily accessible by classical synthetic methods. Nature uses sophisticated templates such as the ribosome, whereas chemists use simple ions or small molecules. But as we tackle the synthesis of larger targets, we require larger templates-which themselves become synthetically challenging. Here we show that Vernier complexes can solve this problem: if the number of binding sites on the template, n(T), is not a multiple of the number of binding sites on the molecular building blocks, n(B), then small templates can direct the assembly of relatively large Vernier complexes where the number of binding sites in the product, n(P), is the lowest common multiple of n(B) and n(T) (refs 8, 9). We illustrate the value of this concept for the covalent synthesis of challenging targets by using a simple six-site template to direct the synthesis of a 12-porphyrin nano-ring with a diameter of 4.7?nm, thus establishing Vernier templating as a powerful new strategy for the synthesis of large monodisperse macromolecules.     

Robins have a magnetic compass in both eyes

Arising from W. Wiltschko et al. 419, 467-470 (2002); Wiltschko et al. replyThe magnetic compass of migratory birds is embedded in the visual system and it has been reported by Wiltschko et al. that European Robins, Erithacus rubecula, cannot show magnetic compass orientation using their left eye only. This has led to the notion that the magnetic compass should be located only in the right eye of birds. However, a complete right lateralization of the magnetic compass would be very surprising, and functional neuroanatomical data have questioned this notion. Here we show that the results of Wiltschko et al. could not be independently confirmed using double-blind protocols. European Robins can perform magnetic compass orientation with both eyes open, with the left eye open only, and with the right eye open only. No clear lateralization is observed.     

Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity

Expression of oncogenic Ras in primary human cells activates p53, thereby protecting cells from transformation. We show that in Ras-expressing IMR-90 cells, p53 is phosphorylated at Ser33 and Ser46 by the p38 mitogen-activated protein kinase (MAPK). Activity of p38 MAPK is regulated by the p53-inducible phosphatase PPM1D, creating a potential feedback loop. Expression of oncogenic Ras suppresses PPM1D mRNA induction, leaving p53 phosphorylated at Ser33 and Ser46 and in an active state. Retrovirus-mediated overexpression of PPM1D reduced p53 phosphorylation at these sites, abrogated Ras-induced apoptosis and partially rescued cells from cell-cycle arrest. Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice. The gene encoding PPM1D (PPM1D, at 17q22/q23) is amplified in human breast-tumor cell lines and in approximately 11% of primary breast tumors, most of which harbor wildtype p53. These findings suggest that inactivation of the p38 MAPK through PPM1D overexpression resulting from PPM1D amplification contributes to the development of human cancers by suppressing p53 activation.     

Cadmium is a mutagen that acts by inhibiting mismatch repair

Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.     

A young source for the Hawaiian plume

Recycling of oceanic crust through subduction, mantle upwelling, and remelting in mantle plumes is a widely accepted mechanism to explain ocean island volcanism. The timescale of this recycling is important to our understanding of mantle circulation rates. Correlations of uranogenic lead isotopes in lavas from ocean islands such as Hawaii or Iceland, when interpreted as model isochrons, have yielded source differentiation ages between 1 and 2.5?billion years (Gyr). However, if such correlations are produced by mixing of unrelated mantle components they will have no direct age significance. Re-Os decay model ages take into account the mixing of sources with different histories, but they depend on the assumed initial Re/Os ratio of the subducted crust, which is poorly constrained because of the high mobility of rhenium during subduction. Here we report the first data on (87)Sr/(86)Sr ratios for 138 melt inclusions in olivine phenocrysts from lavas of Mauna Loa shield volcano, Hawaii, indicating enormous mantle source heterogeneity. We show that highly radiogenic strontium in severely rubidium-depleted melt inclusions matches the isotopic composition of 200-650-Myr-old sea water. We infer that such sea water must have contaminated the Mauna Loa source rock, before subduction, imparting a unique 'time stamp' on this source. Small amounts of seawater-derived strontium in plume sources may be common but can be identified clearly only in ultra-depleted melts originating from generally highly (incompatible-element) depleted source components. The presence of 200-650-Myr-old oceanic crust in the source of Hawaiian lavas implies a timescale of general mantle circulation with an average rate of about 2 (±1)?cm?yr(-1), much faster than previously thought.     

Linking mantle plumes, large igneous provinces and environmental catastrophes

Large igneous provinces (LIPs) are known for their rapid production of enormous volumes of magma (up to several million cubic kilometres in less than a million years), for marked thinning of the lithosphere, often ending with a continental break-up, and for their links to global environmental catastrophes. Despite the importance of LIPs, controversy surrounds even the basic idea that they form through melting in the heads of thermal mantle plumes. The Permo-Triassic Siberian Traps--the type example and the largest continental LIP--is located on thick cratonic lithosphere and was synchronous with the largest known mass-extinction event. However, there is no evidence of pre-magmatic uplift or of a large lithospheric stretching, as predicted above a plume head. Moreover, estimates of magmatic CO(2) degassing from the Siberian Traps are considered insufficient to trigger climatic crises, leading to the hypothesis that the release of thermogenic gases from the sediment pile caused the mass extinction. Here we present petrological evidence for a large amount (15?wt%) of dense recycled oceanic crust in the head of the plume and develop a thermomechanical model that predicts no pre-magmatic uplift and requires no lithospheric extension. The model implies extensive plume melting and heterogeneous erosion of the thick cratonic lithosphere over the course of a few hundred thousand years. The model suggests that massive degassing of CO(2) and HCl, mostly from the recycled crust in the plume head, could alone trigger a mass extinction and predicts it happening before the main volcanic phase, in agreement with stratigraphic and geochronological data for the Siberian Traps and other LIPs.