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

Assessment and Optimization of Medical Risks using the Integrated Medical Model

ObjectiveDevelop an evidence-based, probabilistic risk forecasting model that can help guide mission planning, requirements development, and align science with engineering technology development

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

NGO Legitimacy: Four Models

The aim of this paper is to examine NGOs’ legitimacy in the context of global politics. In order to yield a better understanding of NGOs’ legitimacy at the international level it is important to examine how their legitimacy claims are evaluated. This paper proposes dividing the literature into four models based on the theoretical and analytical approaches to their legitimacy claims: the market model, social change model, new institutionalism model and the critical model. The legitimacy criteria generated by the models are significantly different in their analytical scope of how one is to assess the role of NGOs operating as political actors contributing to democracy. The paper argues that the models present incomplete, and sometimes conflicting, views of NGOs’ legitimacy and that this poses a legitimacy dilemma for those assessing the political agency of NGOs in world politics. The paper concludes that only by approaching their legitimacy holistically can the democratic role of NGOs be explored and analysed in the context of world politics

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

A model to determine staff levels, cost, and productivity of hospital units

A methodology is presented with examples of the productivity, the staffing required, the resultant productivity, and costs that can be obtained for hospital units that are subject to random work demands such as laboratory, radiology, physical therapy, and nuclear medicine. The methodology assumes that the hospital has a labor productivity system that produces the RVUs or earned hours of work accomplished daily by shift. Factors considered are the distribution of the capabilities of the work force, the fatigue and delay allowances of the work standards, the quality of the work standards, the maximum amount of overtime that people will be asked to work, staffing policies such as constant or different staffing levels for each day of the week, and worker selection processes. Predicted results are compared with present practice, which indicates that substantial cost reductions can occur with the use of the methodology.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44987/1/10916_2004_Article_BF00996347.pd

Gut microbial b-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics

Bio-organic Synthesi

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors