The knockout mouse project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.     

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.     

Carbon turnover times shape topsoil carbon difference between Tibetan Plateau and Arctic tundra

The Tibetan Plateau(TP)and Arctic permafrost constitute two large reservoirs of organic carbon,but pro-cesses which control carbon accumulation within the surfa...     

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.     

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.     

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.     

Generation of optical 'Schrödinger cats' from photon number states

Schr?dinger's cat is a Gedankenexperiment in quantum physics, in which an atomic decay triggers the death of the cat. Because quantum physics allow atoms to remain in superpositions of states, the classical cat would then be simultaneously dead and alive. By analogy, a 'cat' state of freely propagating light can be defined as a quantum superposition of well separated quasi-classical states-it is a classical light wave that simultaneously possesses two opposite phases. Such states play an important role in fundamental tests of quantum theory and in many quantum information processing tasks, including quantum computation, quantum teleportation and precision measurements. Recently, optical Schr?dinger 'kittens' were prepared; however, they are too small for most of the aforementioned applications and increasing their size is experimentally challenging. Here we demonstrate, theoretically and experimentally, a protocol that allows the generation of arbitrarily large squeezed Schr?dinger cat states, using homodyne detection and photon number states as resources. We implemented this protocol with light pulses containing two photons, producing a squeezed Schr?dinger cat state with a negative Wigner function. This state clearly exhibits several quantum phase-space interference fringes between the 'dead' and 'alive' components, and is large enough to become useful for quantum information processing and experimental tests of quantum theory.