SNP and haplotype mapping for genetic analysis in the rat

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.     

The Effect of Nonlinearity between Credit Conditions and Economic Activity on Density Forecasts

This paper examines the effect of nonlinearities on density forecasting. It focuses on the relationship between credit markets and the rest of the economy. The possible nonlinearity of this relationship is captured by a threshold vector autoregressive model estimated on US data using Bayesian methods. Density forecasts thus account for the uncertainty in all model parameters and possible future regime changes. It is shown that considering nonlinearity can improve the probabilistic assessment of the economic outlook. Moreover, three illustrative examples are discussed to shed some light on the possible practical applicability of density forecasts derived from non‐linear models. Copyright © 2015 John Wiley & Sons, Ltd.     

Neuropsin cleaves EphB2 in the amygdala to control anxiety

A minority of individuals experiencing traumatic events develop anxiety disorders. The reason for the lack of correspondence between the prevalence of exposure to psychological trauma and the development of anxiety is unknown. Extracellular proteolysis contributes to fear-associated responses by facilitating neuronal plasticity at the neuron-matrix interface. Here we show in mice that the serine protease neuropsin is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2-NMDA-receptor interaction, the expression of Fkbp5 and anxiety-like behaviour. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala causing dissociation of EphB2 from the NR1 subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1 interaction enhances NMDA receptor current, induces Fkbp5 gene expression and enhances behavioural signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1 resulting in a static EphB2-NR1 interaction, attenuated induction of the Fkbp5 gene and low anxiety. The behavioural response to stress can be restored by intra-amygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wild-type mice. Our findings establish a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.     

Metabolic trade-offs and the maintenance of the fittest and the flattest

How is diversity maintained? Environmental heterogeneity is considered to be important, yet diversity in seemingly homogeneous environments is nonetheless observed. This, it is assumed, must either be owing to weak selection, mutational input or a fitness advantage to genotypes when rare. Here we demonstrate the possibility of a new general mechanism of stable diversity maintenance, one that stems from metabolic and physiological trade-offs. The model requires that such trade-offs translate into a fitness landscape in which the most fit has unfit near-mutational neighbours, and a lower fitness peak also exists that is more mutationally robust. The 'survival of the fittest' applies at low mutation rates, giving way to 'survival of the flattest' at high mutation rates. However, as a consequence of quasispecies-level negative frequency-dependent selection and differences in mutational robustness we observe a transition zone in which both fittest and flattest coexist. Although diversity maintenance is possible for simple organisms in simple environments, the more trade-offs there are, the wider the maintenance zone becomes. The principle may be applied to lineages within a species or species within a community, potentially explaining why competitive exclusion need not be observed in homogeneous environments. This principle predicts the enigmatic richness of metabolic strategies in clonal bacteria and questions the safety of lethal mutagenesis as an antimicrobial treatment.     

Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion

Autophagy defends the mammalian cytosol against bacterial infection. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment of NDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.     

Resolving the time when an electron exits a tunnelling barrier

The tunnelling of a particle through a barrier is one of the most fundamental and ubiquitous quantum processes. When induced by an intense laser field, electron tunnelling from atoms and molecules initiates a broad range of phenomena such as the generation of attosecond pulses, laser-induced electron diffraction and holography. These processes evolve on the attosecond timescale (1?attosecond?≡?1?as = 10(-18)?seconds) and are well suited to the investigation of a general issue much debated since the early days of quantum mechanics--the link between the tunnelling of an electron through a barrier and its dynamics outside the barrier. Previous experiments have measured tunnelling rates with attosecond time resolution and tunnelling delay times. Here we study laser-induced tunnelling by using a weak probe field to steer the tunnelled electron in the lateral direction and then monitor the effect on the attosecond light bursts emitted when the liberated electron re-encounters the parent ion. We show that this approach allows us to measure the time at which the electron exits from the tunnelling barrier. We demonstrate the high sensitivity of the measurement by detecting subtle delays in ionization times from two orbitals of a carbon dioxide molecule. Measurement of the tunnelling process is essential for all attosecond experiments where strong-field ionization initiates ultrafast dynamics. Our approach provides a general tool for time-resolving multi-electron rearrangements in atoms and molecules--one of the key challenges in ultrafast science.     

A recent disruption of the main-belt asteroid P/2010 A2

Most inner main-belt asteroids are primitive rock and metal bodies in orbit about the Sun between Mars and Jupiter. Disruption, through high-velocity collisions or rotational spin-up, is believed to be the primary mechanism for the production and destruction of small asteroids and a contributor to dust in the Sun's zodiacal cloud, while analogous collisions around other stars feed dust to their debris disks. Unfortunately, direct evidence about the mechanism or rate of disruption is lacking, owing to the rarity of the events. Here we report observations of P/2010?A2, a previously unknown inner-belt asteroid with a peculiar, comet-like morphology. The data reveal a nucleus of diameter approximately 120?metres with an associated tail of millimetre-sized dust particles. We conclude that it is most probably the remnant of a recent asteroidal disruption in February/March 2009, evolving slowly under the action of solar radiation pressure, in agreement with independent work.