Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.     

Reduced North Atlantic Deep Water flux to the glacial Southern Ocean inferred from neodymium isotope ratios

The global circulation of the oceans and the atmosphere transports heat around the Earth. Broecker and Denton suggested that changes in the global ocean circulation might have triggered or enhanced the glacial-interglacial cycles. But proxy data for past circulation taken from sediment cores in the South Atlantic Ocean have yielded conflicting interpretations of ocean circulation in glacial times--delta13C variations in benthic foraminifera support the idea of a glacial weakening or shutdown of North Atlantic Deep Water production, whereas other proxies, such as Cd/Ca, Ba/Ca and 231Pa/230Th ratios, show little change from the Last Glacial Maximum to the Holocene epoch. Here we report neodymium isotope ratios from the dispersed Fe-Mn oxide component of two southeast Atlantic sediment cores. Both cores show variations that tend towards North Atlantic signatures during the warm marine isotope stages 1 and 3, whereas for the full glacial stages 2 and 4 they are closer to Pacific Ocean signatures. We conclude that the export of North Atlantic Deep Water to the Southern Ocean has resembled present-day conditions during the warm climate intervals, but was reduced during the cold stages. An increase in biological productivity may explain the various proxy data during the times of reduced North Atlantic Deep Water export.     

Geminus and the concept of mean motion in Greco-Latin astronomy

Conclusion Geminus account of lunar motion in chapter 18 of hisIntroductio astronomiae is, in our view, an important contribution to Greco-Latin astronomy because, in attempting to reconstruct arithmetically (the parameters of) the Moon's motion in longitude, he undermines the task astronomers had hitherto set for themselves. This undermining of a commonly acknowledged view of the purpose of astronomy is articulated in a whole new set of questions concerning the nature and place of both observation and mathematical reasoning in the science of the heavens. Yet, one must not overlook the fact thatGeminus reconstruction also indicates resources for addressing these questions. Of these resources, the most powerful proved to be the idea that irregular motion could be quantified as a systematic departure from a mean motion, and the idea that observational data could be organized and structured by means of genetic arithmetical reconstructions.But, since we limit our attention to extant treatises and decline to speculate about works or parts of works that have not survived, we must say that it would takePtolemy to discern the new direction for astronomy thatGeminus opened up and to pursue it. In part, this involved straightening out the conflated conception of mean motion in chapter 18 — the qua arithmetic mean daily displacement can only be anapparent lunar motion in longitude and not one the Moonreally makes, but the same need not be true of the qua periodic mean daily displacement — and determining its proper relation to real and apparent planetary motion. Indeed,Ptolemy's genius lay, we think, in seeing that even though, in assimilating Babylonian astronomy, earlier and contemporary Greco-Latin writers betrayed a confused, inconsistent, and unsophisticated grasp of the proper role of arithmetic, geometry, and observation in astronomical argument [seeBowen 1994], the solution lay in a mathematical reconstruction of the observed celestial motions, in which mean motion played an essential role.     

A single-nucleotide polymorphism tagging set for human drug metabolism and transport

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.     

Maxwell’s contrived analogy: An early version of the methodology of modeling

The term “analogy” stands for a variety of methodological practices all related in one way or another to the idea of proportionality. We claim that in his first substantial contribution to electromagnetism James Clerk Maxwell developed a methodology of analogy which was completely new at the time or, to borrow John North’s expression, Maxwell’s methodology was a “newly contrived analogue”. In his initial response to Michael Faraday’s experimental researches in electromagnetism, Maxwell did not seek an analogy with some physical system in a domain different from electromagnetism as advocated by William Thomson; rather, he constructed an entirely artificial one to suit his needs. Following North, we claim that the modification which Maxwell introduced to the methodology of analogy has not been properly appreciated. In view of our examination of the evidence, we argue that Maxwell gave a new meaning to analogy; in fact, it comes close to modeling in current usage.     

Symmetry and asymmetry in electrodynamics from Rowland to Einstein

Halfway through the paper in which he laid down the foundations for the theory of special relativity, Einstein concludes that “the asymmetry mentioned in the Introduction … disappears.” Making asymmetry disappear has proved to be one of Einstein's many significant moves in his annus mirabilis of 1905. This elimination of asymmetry has led many commentators to claim that Einstein was motivated by either an aesthetic or an epistemic argument which gives priority to symmetry over asymmetry. Following closely the development of electrodynamics in the period from 1880 to 1905 and the usage of the related terms reciprocity and symmetry, we suggest a different way of understanding Einstein's motivation and the path he took. In contrast to the received view, we argue that Einstein responded to a debate in the literature on electrodynamics and that he was concerned neither with an aesthetic nor with an epistemic argument; rather, his reasoning was physical in the best sense, and most original. We will show that by providing a new perspective on the relation between electricity and magnetism, Einstein succeeded in bringing the discussion of symmetry in electrodynamics to an end.