Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.     

How could models possibly provide how-possibly explanations?

One puzzle concerning highly idealized models is whether they explain. Some suggest they provide so-called ‘how-possibly explanations’. However, this raises an important question about the nature of how-possibly explanations, namely what distinguishes them from ‘normal’, or how-actually, explanations? I provide an account of how-possibly explanations that clarifies their nature in the context of solving the puzzle of model-based explanation. I argue that the modal notions of actuality and possibility provide the relevant dividing lines between how-possibly and how-actually explanations. Whereas how-possibly explanations establish claims of possible explanations, how-actually explanations establish claims of actual ones. Models, in turn, simply provide evidence for these claims.     

Evidence for an unusual multifunctional protoreceptor in hormone action

Summary Contrary to the techniques of mere association, column chromatography has revealed a protoreceptor that accepts aldosterone agonists and antagonists only in the physiological target, the kidney, and is absent in non-targets, liver and serum; it is furthermore different from the aldosterone specific receptor in renal cytosol.Supported in part by grants from the CNRS AI 03 1917 and UER Broussais Hôtel Dieu.     

Astrocladistics: A Phylogenetic Analysis of Galaxy Evolution II. Formation and Diversification of Galaxies

This series of papers is intended to evaluate astrocladistics in reconstructing phylogenies of galaxies. The objective of this second paper is to formalize the concept of galaxy formation and to identify the processes of diversification. We show that galaxy diversity can be expected to organize itself in a hierarchy. In order to better understand the role of mergers, we have selected a sample of 43 galaxies from the GALICS database built from simulations with a hybrid model for galaxy formation studies. These simulated galaxies, described by 119 characters and considered as representing still undefined classes, have experienced different numbers of merger events during evolution. Our cladistic analysis yields a robust tree that proves the existence of a hierarchy. Mergers, like interactions (not taken into account in the GALICS simulations), are probably a strong driver for galaxy diversification. Our result shows that mergers participate in a branching type of evolution, but do not seem to play the role of an evolutionary clock.     

CD36 is a sensor of diacylglycerides

Toll-like receptor 2 (TLR2) is required for the recognition of numerous molecular components of bacteria, fungi and protozoa. The breadth of the ligand repertoire seems unusual, even if one considers that TLR2 may form heteromers with TLRs 1 and 6 (ref. 12), and it is likely that additional proteins serve as adapters for TLR2 activation. Here we show that an N-ethyl-N-nitrosourea-induced nonsense mutation of Cd36 (oblivious) causes a recessive immunodeficiency phenotype in which macrophages are insensitive to the R-enantiomer of MALP-2 (a diacylated bacterial lipopeptide) and to lipoteichoic acid. Homozygous mice are hypersusceptible to Staphylococcus aureus infection. Cd36(obl) macrophages readily detect S-MALP-2, PAM(2)CSK(4), PAM(3)CSK(4) and zymosan, revealing that some--but not all--TLR2 ligands are dependent on CD36. Already known as a receptor for endogenous molecules, CD36 is also a selective and nonredundant sensor of microbial diacylglycerides that signal via the TLR2/6 heterodimer.     

A complete insect from the Late Devonian period

After terrestrialization, the diversification of arthropods and vertebrates is thought to have occurred in two distinct phases, the first between the Silurian and the Frasnian stages (Late Devonian period) (425-385?million years (Myr) ago), and the second characterized by the emergence of numerous new major taxa, during the Late Carboniferous period (after 345?Myr ago). These two diversification periods bracket the depauperate vertebrate Romer's gap (360-345?Myr ago) and arthropod gap (385-325?Myr ago), which could be due to preservational artefact. Although a recent molecular dating has given an age of 390?Myr for the Holometabola, the record of hexapods during the Early-Middle Devonian (411.5-391?Myr ago, Pragian to Givetian stages) is exceptionally sparse and based on fragmentary remains, which hinders the timing of this diversification. Indeed, although Devonian Archaeognatha are problematic, the Pragian of Scotland has given some Collembola and the incomplete insect Rhyniognatha, with its diagnostic dicondylic, metapterygotan mandibles. The oldest, definitively winged insects are from the Serpukhovian stage (latest Early Carboniferous period). Here we report the first complete Late Devonian insect, which was probably a terrestrial species. Its 'orthopteroid' mandibles are of an omnivorous type, clearly not modified for a solely carnivorous diet. This discovery narrows the 45-Myr gap in the fossil record of Hexapoda, and demonstrates further a first Devonian phase of diversification for the Hexapoda, as in vertebrates, and suggests that the Pterygota diversified before and during Romer's gap.     

Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.     

Lamprey-like gills in a gnathostome-related Devonian jawless vertebrate

So far, the Palaeozoic fossil jawless vertebrates have not provided any direct evidence for the organization of the gills, apart from vague impressions--supposedly left by gill filaments--on the bony surface of the gill chamber in certain armoured forms or 'ostracoderms' (for example, osteostracans and heterostracans). The latter are currently regarded as more closely related to the living jawed vertebrates (crown gnathostomes) than to the living jawless vertebrates (hagfish and lampreys, or cyclostomes). Here we report the first direct evidence for the position of the gill filaments--possibly supported by gill rays--enclosed by gill pouches in a 370-million year (Myr)-old jawless vertebrate, Endeiolepis, from the Late Devonian fossil fish site of Miguasha, Quebec, Canada. This extinct jawless fish has much the same gill organization as living lampreys, although it possesses an unusually large number of gill pouches--a condition unlike that in any extant vertebrates and that raises questions about gill development. Endeiolepis is currently regarded as a close relative of anaspids, a group of 410-430-Myr-old 'ostracoderms'. Assuming that current vertebrate phylogeny is correct, this discovery demonstrates that pouches enclosing the gills are primitive for vertebrates, but have been subsequently lost in jawed vertebrates.