What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit.

The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms

Synthesis of a protected keto-lysidine analogue via improved preparation of arabino-isocytosine nucleosides

Anhydrouridines react with aliphatic amines to give N-alkyl isocytosines, but reported procedures often demand very long reaction times and can be low yielding, with narrow scope. A modified procedure for such reactions has been developed, using microwave irradiation, significantly reducing reaction time and allowing facile access to a diverse range of novel nucleosides on the gram scale. The method has been used to prepare a precursor to a novel analogue of lysidine, a naturally occurring iminonucleoside found in (t)RNA

Partially fluidized shear granular flows: Continuum theory and MD simulations

The continuum theory of partially fluidized shear granular flows is tested and calibrated using two dimensional soft particle molecular dynamics simulations. The theory is based on the relaxational dynamics of the order parameter that describes the transition between static and flowing regimes of granular material. We define the order parameter as a fraction of static contacts among all contacts between particles. We also propose and verify by direct simulations the constitutive relation based on the splitting of the shear stress tensor into a``fluid part'' proportional to the strain rate tensor, and a remaining ``solid part''. The ratio of these two parts is a function of the order parameter. The rheology of the fluid component agrees well with the kinetic theory of granular fluids even in the dense regime. Based on the hysteretic bifurcation diagram for a thin shear granular layer obtained in simulations, we construct the ``free energy'' for the order parameter. The theory calibrated using numerical experiments with the thin granular layer is applied to the surface-driven stationary two dimensional granular flows in a thick granular layer under gravity.Comment: 20 pages, 19 figures, submitted to Phys. Rev.

Continuous synthesis of dispersant-coated hydroxyapatite plates

A continuous flow hydrothermal synthetic route which allows the direct “in situ” capping/coating of hydroxyapatite nanoplates with functional dispersants in a single stage is reported. The methodology induced crystallisation by rapid mixing of streams of preheated water and solutions of reagents in water, whilst the hydrophobic surface modification of the HA platelets was achieved without morphological disruption. The effect of adding the hydrocarbon either before or after the HA platelet formation point has also been assessed, proving that the presence of surfactant at the reaction site does not interfere with the formation of HA and allows for a more efficient binding and extraction of the inorganic materials. The coupling mechanisms between the surfactant and the HA surface have been proposed to be a mixture of covalent and electrostatic interactions (i.e. all forms of chemisorption). This synthesis route is fully scalable to pilot (10 tons per year) and industrial (1000 tons per year) scales

Statistics of the contact network in frictional and frictionless granular packings

Simulated granular packings with different particle friction coefficient mu are examined. The distribution of the particle-particle and particle-wall normal and tangential contact forces P(f) are computed and compared with existing experimental data. Here f equivalent to F/F-bar is the contact force F normalized by the average value F-bar. P(f) exhibits exponential-like decay at large forces, a plateau/peak near f = 1, with additional features at forces smaller than the average that depend on mu. Computations of the force-force spatial distribution function and the contact point radial distribution function indicate that correlations between forces are only weakly dependent on friction and decay rapidly beyond approximately three particle diameters. Distributions of the particle-particle contact angles show that the contact network is not isotropic and only weakly dependent on friction. High force-bearing structures, or force chains, do not play a dominant role in these three dimensional, unloaded packings.Comment: 11 pages, 13 figures, submitted to PR

An Overview of Systematic Reviews on Prognostic Factors in Neck Pain

Given the challenges of chronic musculoskeletal pain and disability, establishing a clear prognosis in the acute stage has become increasingly recognized as a valuable approach to mitigate chronic problems. Neck pain represents a condition that is common, potentially disabling, and has a high rate of transition to chronic or persistent problems. As a field of research, prognosis in neck pain has stimulated several empirical primary research papers, and a number of systematic reviews. As part of the International Consensus on Neck (ICON) project, we sought to establish the general state of knowl

NuSTAR unveils a Compton-thick type 2 quasar in MrK 34

We present Nuclear Spectroscopic Telescope Array (NuSTAR) 3-40 keV observations of the optically selected Type 2 quasar (QSO2) SDSS J1034+6001 or Mrk 34. The high-quality hard X-ray spectrum and archival XMM-Newton data can be fitted self-consistently with a reflection-dominated continuum and a strong Fe K? fluorescence line with equivalent width >1 keV. Prior X-ray spectral fitting below 10 keV showed the source to be consistent with being obscured by Compton-thin column densities of gas along the line of sight, despite evidence for much higher columns from multiwavelength data. NuSTAR now enables a direct measurement of this column and shows that N H lies in the Compton-thick (CT) regime. The new data also show a high intrinsic 2-10 keV luminosity of L 2-10 ~ 1044 erg s–1, in contrast to previous low-energy X-ray measurements where L 2-10 lesssim 1043 erg s–1 (i.e., X-ray selection below 10 keV does not pick up this source as an intrinsically luminous obscured quasar). Both the obscuring column and the intrinsic power are about an order of magnitude (or more) larger than inferred from pre-NuSTAR X-ray spectral fitting. Mrk 34 is thus a "gold standard" CT QSO2 and is the nearest non-merging system in this class, in contrast to the other local CT quasar NGC 6240, which is currently undergoing a major merger coupled with strong star formation. For typical X-ray bolometric correction factors, the accretion luminosity of Mrk 34 is high enough to potentially power the total infrared luminosity. X-ray spectral fitting also shows that thermal emission related to star formation is unlikely to drive the observed bright soft component below ~3 keV, favoring photoionization instead