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

Spatial variability of the Purbeck–Wight Fault Zone—a long-lived tectonic element in the southern UK

New seamless onshore to offshore bedrock (1:10 k scale) mapping for the Lyme Bay area is used to resolve the westward termination of the Purbeck–Wight Fault Zone (PWFZ) structure, comprising one of the most prominent, long-lived (Variscan–Cimmerian–Alpine) structural lineaments in the southern UK. The study area lies south of the Variscan Frontal Thrust and overlays the basement Variscide Rhenohercynian Zone, in a region of dominant E-W tectonic fabric and a secondary conjugate NW-SE/NE-SW fabric. The PWFZ comprises one of the E-W major structures, with a typical history including Permian to early Cretaceous growth movement (relating to basement Variscan Thrust reactivation) followed by significant Alpine (Helvetic) inversion. Previous interpretations of the PWFZ have been limited by the low resolution (1:250 k scale) of the available offshore BGS mapping, and our study fills this gap. We describe a significant change in structural style of the fault zone from east to west. In the Weymouth Bay area, previous studies demonstrate the development of focussed strain associated with the PWFZ, accompanied by distributed strain, N-S fault development, and potential basement uplift in its hangingwall. In the Lyme Bay area to the west, faulting is dominantly E-W, with N-S faulting absent. Comparison of the newly mapped faulting networks to gravity data suggests a spatial relationship between this faulting variation and basement variability and uplift

Dissociations within short-term memory in GluA1 AMPA receptor subunit knockout mice

GluA1 AMPA receptor subunit knockout mice display a selective impairment on short-term recognition memory tasks. In this study we tested whether GluA1 is important for short-term memory that is necessary for bridging the discontiguity between cues in trace conditioning. GluA1 knockout mice were not impaired at using short-term memory traces of T-maze floor inserts, made of different materials, to bridge the temporal gap between conditioned stimuli and reinforcement during appetitive discrimination tasks. Thus, different aspects of short-term memory are differentially sensitive to GluA1 deletion. This dissociation may reflect processing of qualitatively different short-term memory traces. Memory that results in performance of short-term recognition (e.g. for objects or places) may be different from the memory required for associative learning in trace conditioning

Lift, Drag and Thrust Measurement in a Hypersonic Impulse Facility

This paper reports the extension of the stress wave force balance to the measurement of forces on models which are non-axisymmetric or which have non-axisymmetric load distributions. Recent results are presented which demonstrate the performance of the stress wave force balance for drag measurement, for three-component force measurement and preliminary results for thrust measurement on a two-dimensional scramjet nozzle. In all cases, the balances respond within a few hundred microseconds

Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease

The effects of respiratory viral infection on the time course of chronic obstructive pulmonary disease (COPD) exacerbation were examined by monitoring changes in systemic inflammatory markers in stable COPD and at exacerbation. Eighty-three patients with COPD (mean [SD] age, 66.6 [7.1] yr, FEV1, 1.06 [0.61] L) recorded daily peak expiratory flow rate and any increases in respiratory symptoms. Nasal samples and blood were taken for respiratory virus detection by culture, polymerase chain reaction, and serology, and plasma fibrinogen and serum interleukin-6 (IL-6) were determined at stable baseline and exacerbation. Sixty-four percent of exacerbations were associated with a cold occurring up to 18 d before exacerbation. Seventy-seven viruses (39 [58.2%] rhinoviruses) were detected in 66 (39.2%) of 168 COPD exacerbations in 53 (64%) patients. Viral exacerbations were associated with frequent exacerbators, colds with increased dyspnea, a higher total symptom count at presentation, a longer median symptom recovery period of 13 d, and a tendency toward higher plasma fibrinogen and serum IL-6 levels. Non-respiratory syncytial virus (RSV) respiratory viruses were detected in 11 (16%), and RSV in 16 (23.5%), of 68 stable COPD patients, with RSV detection associated with higher inflammatory marker levels. Respiratory virus infections are associated with more severe and frequent exacerbations, and may cause chronic infection in COPD. Prevention and early treatment of viral infections may lead to a decreased exacerbation frequency and morbidity associated with COPD

The politics of innovation: why innovations need a godfather

Innovation is closely linked to the development of technology. Hence it is often assumed that when an innovation fails it is the technology that is at fault. While this may be true in many instances, there are occasions when it is not the technology that is at fault, rather, it is managerial and organisational aspects that cause problems and lead to failure. Studies have shown that individuals who take on specific roles can play an important part in avoiding these problems. These roles include the technological gatekeeper, the product champion and the sponsor/coach. In addition to these roles, this paper argues that there is another, namely that of godfather. With this role a highly respected, senior figure within an organisation provides support that is critical in ensuring the project overcomes the hurdles that lie in the path of any major new development. The nature of the godfather role is explored through three case studies. These provide examples of the role and show how it can facilitate the innovation process

Crossover between ionic/covalent and pure ionic bonding in magnesium oxyde clusters

An empirical potential with fluctuating charges is proposed for modelling (MgO)_n clusters in both the molecular (small n) and bulk (n->infty) regimes. Vectorial polarization forces are explicitely taken into account in the self-consistent determination of the charges. Our model predicts cuboid cluster structures, in agreement with previous experimental and theoretical results. The effective charge transferred between magnesium and oxygen smoothly increases from 1 to 2, with an estimated crossover size above 300 MgO molecules

Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium

Background: Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk. Methods: Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 μg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry. Results: In the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology. Conclusions: A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology

Modelling mucociliary clearance

Mathematical modelling of the fluid mechanics of mucociliary clearance (MCC) is reviewed and future challenges for researchers are discussed. The morphology of the bronchial and tracheal airway surface liquid (ASL) and ciliated epithelium are briefly introduced. The cilia beat cycle, beat frequency and metachronal coordination are described, along with the rheology of the mucous layer. Theoretical modelling of MCC from the late 1960s onwards is reviewed, and distinctions between ‘phenomenological’, ‘slender body theory’ and recent ‘fluid–structure interaction’ models are explained.\ud \ud The ASL consists of two layers, an overlying mucous layer and underlying watery periciliary layer (PCL) which bathes the cilia. Previous models have predicted very little transport of fluid in the PCL compared with the mucous layer. Fluorescent tracer transport experiments on human airway cultures conducted by Matsui et al. [Matsui, H., Randell, S.H., Peretti, S.W., Davis, C.W., Boucher, R.C., 1998. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J. Clin. Invest. 102 (6), 1125–1131] apparently showed equal transport in both the PCL and mucous layer. Recent attempts to resolve this discrepancy by the present authors are reviewed, along with associated modelling findings. These findings have suggested new insights into the interaction of cilia with mucus due to pressure gradients associated with the flat PCL/mucus interface. This phenomenon complements previously known mechanisms for ciliary propulsion. Modelling results are related to clinical findings, in particular the increased MCC observed in patients with pseudohypoaldosteronism. Recent important advances by several groups in modelling the fluid–structure interaction by which the cilia movement and fluid transport emerge from specification of internal mechanics, viscous and elastic forces are reviewed. Finally, we discuss the limitations of existing work, and the challenges for the next generation of models, which may provide further insight into this complex and vital system