Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.     

Temporally distinct pre- and post-synaptic mechanisms maintain long-term potentiation

Long-term potentiation (LTP) in the hippocampus is widely studied as the mechanisms involved in its induction and maintenance are believed to underlie fundamental properties of learning and memory in vertebrates. Most synapses that exhibit LTP use an excitatory amino-acid neurotransmitter that acts on two types of receptor, the N-methyl-D-aspartate (NMDA) and quisqualate receptors. The quisqualate receptor mediates the fast synaptic response evoked by low-frequency stimulation, whereas the NMDA receptor system is activated transiently by tetanic stimulation, leading to the induction of LTP. The events responsible for maintaining LTP once it is established are not known. We now demonstrate that the sensitivity of CA1 neurons in hippocampal slices to ionophoretically-applied quisqualate receptor ligands slowly increases following the induction of LTP. This provides direct evidence for a functional post-synaptic change and suggests that pre-synaptic mechanisms also contribute, but in a temporally distinct manner, to the maintenance of LTP.     

The “dynamics” of Leibnizian relationism: Reference frames and force in Leibniz's plenum

This paper explores various metaphysical aspects of Leibniz's concepts of space, motion, and matter, with the intention of demonstrating how the distinctive role of force in Leibnizian physics can be used to develop a theory of relational motion using privileged reference frames. Although numerous problems will remain for a consistent Leibnizian relationist account, the version developed within our investigation will advance the work of previous commentators by more accurately reflecting the specific details of Leibniz's own natural philosophy, especially his handling of the dynamical interactions of plenum bodies.     

Secondary craters on Europa and implications for cratered surfaces

For several decades, most planetary researchers have regarded the impact crater populations on solid-surfaced planets and smaller bodies as predominantly reflecting the direct ('primary') impacts of asteroids and comets. Estimates of the relative and absolute ages of geological units on these objects have been based on this assumption. Here we present an analysis of the comparatively sparse crater population on Jupiter's icy moon Europa and suggest that this assumption is incorrect for small craters. We find that 'secondaries' (craters formed by material ejected from large primary impact craters) comprise about 95 per cent of the small craters (diameters less than 1 km) on Europa. We therefore conclude that large primary impacts into a solid surface (for example, ice or rock) produce far more secondaries than previously believed, implying that the small crater populations on the Moon, Mars and other large bodies must be dominated by secondaries. Moreover, our results indicate that there have been few small comets (less than 100 m diameter) passing through the jovian system in recent times, consistent with dynamical simulations.     

Ancient co-speciation of simian foamy viruses and primates

Although parasite-host co-speciation is a long-held hypothesis, convincing evidence for long-term co-speciation remains elusive, largely because of small numbers of hosts and parasites studied and uncertainty over rates of evolutionary change. Co-speciation is especially rare in RNA viruses, in which cross-species transfer is the dominant mode of evolution. Simian foamy viruses (SFVs) are ubiquitous, non-pathogenic retroviruses that infect all primates. Here we test the co-speciation hypothesis in SFVs and their primate hosts by comparing the phylogenies of SFV polymerase and mitochondrial cytochrome oxidase subunit II from African and Asian monkeys and apes. The phylogenetic trees were remarkably congruent in both branching order and divergence times, strongly supporting co-speciation. Molecular clock calibrations revealed an extremely low rate of SFV evolution, 1.7 x 10(-8) substitutions per site per year, making it the slowest-evolving RNA virus documented so far. These results indicate that SFVs might have co-speciated with Old World primates for at least 30 million years, making them the oldest known vertebrate RNA viruses.     

Increasing the conductivity of crystalline polymer electrolytes

Polymer electrolytes consist of salts dissolved in polymers (for example, polyethylene oxide, PEO), and represent a unique class of solid coordination compounds. They have potential applications in a diverse range of all-solid-state devices, such as rechargeable lithium batteries, flexible electrochromic displays and smart windows. For 30 years, attention was focused on amorphous polymer electrolytes in the belief that crystalline polymer:salt complexes were insulators. This view has been overturned recently by demonstrating ionic conductivity in the crystalline complexes PEO6:LiXF6 (X = P, As, Sb); however, the conductivities were relatively low. Here we demonstrate an increase of 1.5 orders of magnitude in the conductivity of these materials by replacing a small proportion of the XF6- anions in the crystal structure with isovalent N(SO2CF3)2- ions. We suggest that the larger and more irregularly shaped anions disrupt the potential around the Li+ ions, thus enhancing the ionic conductivity in a manner somewhat analogous to the AgBr(1-x)I(x) ionic conductors. The demonstration that doping strategies can enhance the conductivity of crystalline polymer electrolytes represents a significant advance towards the technological exploitation of such materials.     

Meteoritic dust from the atmospheric disintegration of a large meteoroid

Much of the mass of most meteoroids entering the Earth's atmosphere is consumed in the process of ablation. Larger meteoroids (> 10 cm), which in some cases reach the ground as meteorites, typically have survival fractions near 1-25 per cent of their initial mass. The fate of the remaining ablated material is unclear, but theory suggests that much of it should recondense through coagulation as nanometre-sized particles. No direct measurements of such meteoric 'smoke' have hitherto been made. Here we report the disintegration of one of the largest meteoroids to have entered the Earth's atmosphere during the past decade, and show that the dominant contribution to the mass of the residual atmospheric aerosol was in the form of micrometre-sized particles. This result is contrary to the usual view that most of the material in large meteoroids is efficiently converted to particles of much smaller size through ablation. Assuming that our observations are of a typical event, we suggest that large meteoroids provide the dominant source of micrometre-sized meteoritic dust at the Earth's surface over long timescales.     

Dendrite growth increased by visual activity requires NMDA receptor and Rho GTPases

Previous studies suggest that neuronal activity may guide the development of synaptic connections in the central nervous system through mechanisms involving glutamate receptors and GTPase-dependent modulation of the actin cytoskeleton. Here we demonstrate by in vivo time-lapse imaging of optic tectal cells in Xenopus laevis tadpoles that enhanced visual activity driven by a light stimulus promotes dendritic arbor growth. The stimulus-induced dendritic arbor growth requires glutamate-receptor-mediated synaptic transmission, decreased RhoA activity and increased Rac and Cdc42 activity. The results delineate a role for Rho GTPases in the structural plasticity driven by visual stimulation in vivo.