The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E1*5B) located in the 5′-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

Optimal HMM processing of differentially phase modulated communication systems

This paper investigates demodulation of differentially phase modulated signals DPMS using optimal HMM filters. The optimal HMM filter presented in the paper is computationally of order N3 per time instant, where N is the number of message symbols. Previously, optimal HMM filters have been of computational order N4 per time instant. Also, suboptimal HMM filters have be proposed of computation order N2 per time instant. The approach presented in this paper uses two coupled HMM filters and exploits knowledge of ...

Design after design to bridge between people living with cognitive or sensory impairments, their friends and proxies

A carer or teacher often plays the role of proxy or spokesperson for a person living with an intellectual disability or form of cognitive or sensory impairment. Our research undertook co-design with people living with cognitive and sensory impairments and their proxies in order to explore new ways of facilitating communication. We developed simple functioning interactive prototypes to support people with a diverse range of competencies to communicate and explore their use. Deployment of the prototypes enabled use, appropriation and design after design by our two participant groups; adults living with cognitive or sensory impairments and children identified with language delays and autism spectrum disorder. The prototypes supported concrete expression of likes, dislikes, capabilities, emotional wants and needs and forms of expression that hitherto had not been fostered, further informing design. Carers and designers were surprised at the ways in which the technology was used and how it fostered new forms of social interaction and expression. We elaborate on how design after design can be an effective approach for engaging people living with intellectual disabilities, giving them greater capacity for expression and power in design and offering the potential to expand and deepen their social relationships.

Design for creative activity : a framework for analyzing the creative potential of computer games

This paper describes a design framework intended to conceptually map the influence that game design has on the creative activity people engage in during gameplay. The framework builds on behavioral and verbal analysis of people playing puzzle games. The analysis was designed to better understand the extent to which gameplay activities within different games facilitate creative problem solving. We have used an expert review process to evaluate these games in terms of their game design elements and have taken a cognitive action approach to this process to investigate how particular elements produce the potential for creative activity. This paper proposes guidelines that build upon our understanding of the relationship between the creative processes that players undertake during a game and the components of the game that allow these processes to occur. These guidelines may be used in the game design process to better facilitate creative gameplay activity.

Simulated hyperopic anisometropia and reading, visual information processing, and reading-related eye movement performance in children

Purpose: This study investigated the impact of simulated hyperopic anisometropia and sustained near work on performance of academic-related measures in children. Methods: Participants included 16 children (mean age: 11.1 ± 0.8 years) with minimal refractive error. Academic-related outcome measures included a reading test (Neale Analysis of Reading Ability), visual information processing tests (Coding and Symbol Search subtests from the Wechsler Intelligence Scale for Children) and a reading-related eye movement test (Developmental Eye Movement test). Performance was assessed with and without 0.75 D of imposed monocular hyperopic defocus (administered in a randomised order), before and after 20 minutes of sustained near work. Unilateral hyperopic defocus was systematically assigned to either the dominant or non-dominant sighting eye to evaluate the impact of ocular dominance on any performance decrements. Results: Simulated hyperopic anisometropia and sustained near work both independently reduced performance on all of the outcome measures (p<0.001). A significant interaction was also observed between simulated anisometropia and near work (p<0.05), with the greatest decrement in performance observed during simulated anisometropia in combination with sustained near work. Laterality of the refractive error simulation (ocular dominance) did not significantly influence the outcome measures (p>0.05). A reduction of up to 12% in performance was observed across the range of academic-related measures following sustained near work undertaken during the anisometropic simulation. Conclusion: Simulated hyperopic anisometropia significantly impaired academic–related performance, particularly in combination with sustained near work. The impact of uncorrected habitual anisometropia on academic-related performance in children requires further investigation.

Symptom correlates of static and dynamic facial affect processing in schizophrenia : evidence of a double dissociation?

Schizophrenia patients have been shown to be compromised in their ability to recognize facial emotion. This deficit has been shown to be related to negative symptoms severity. However, to date, most studies have used static rather than dynamic depictions of faces. Nineteen patients with schizophrenia were compared with seventeen controls on 2 tasks; the first involving the discrimination of facial identity, emotion, and butterfly wings; the second testing emotion recognition using both static and dynamic stimuli. In the first task, the patients performed more poorly than controls for emotion discrimination only, confirming a specific deficit in facial emotion recognition. In the second task, patients performed more poorly in both static and dynamic facial emotion processing. An interesting pattern of associations suggestive of a possible double dissociation emerged in relation to correlations with symptom ratings: high negative symptom ratings were associated with poorer recognition of static displays of emotion, whereas high positive symptom ratings were associated with poorer recognition of dynamic displays of emotion. However, while the strength of associations between negative symptom ratings and accuracy during static and dynamic facial emotion processing was significantly different, those between positive symptom ratings and task performance were not. The results confirm a facial emotion-processing deficit in schizophrenia using more ecologically valid dynamic expressions of emotion. The pattern of findings may reflect differential patterns of cortical dysfunction associated with negative and positive symptoms of schizophrenia in the context of differential neural mechanisms for the processing of static and dynamic displays of facial emotion.

Exploring cognitive style and task-specific preferences for process representations

Process models describe someone’s understanding of processes. Processes can be described using unstructured, semi-formal or diagrammatic representation forms. These representations are used in a variety of task settings, ranging from understanding processes to executing or improving processes, with the implicit assumption that the chosen representation form will be appropriate for all task settings. We explore the validity of this assumption by examining empirically the preference for different process representation forms depending on the task setting and cognitive style of the user. Based on data collected from 120 business school students, we show that preferences for process representation formats vary dependent on application purpose and cognitive styles of the participants. However, users consistently prefer diagrams over other representation formats. Our research informs a broader research agenda on task-specific applications of process modeling. We offer several recommendations for further research in this area.

Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching

Cerebellar dysfunction has been proposed to lead to “cognitive dysmetria” in schizophrenia via the cortico-cerebellar-thalamic-cortical circuit, contributing to a range of cognitive and clinical symptoms of the disorder. Here we investigated total cerebellar grey and white matter volumes and cerebellar regional grey matter abnormalities in 13 remitted first-episode schizophrenia patients with less than 2 years’ duration of illness. Patient data were compared to 13 pair-wise age, gender, and handedness-matched healthy volunteers using cortical pattern averaging on high-resolution magnetic resonance images. Total cerebellar volume and total grey matter volumes in first-episode schizophrenia patients did not differ from healthy control subjects, but total cerebellar white matter was increased and total grey to white matter ratios were reduced in patients. Four clusters of cerebellar grey matter reduction were identified: (i) in superior vermis; (ii) in the left lobuli VI; (iii) in right-inferior lobule IX, extending into left lobule IX; and (iv) bilaterally in the areas of lobuli III, peduncle and left flocculus. Grey matter deficits were particularly prominent in right lobuli III and IX, left flocculus and bilateral pedunculi. These cerebellar areas have been implicated in attention control, emotional regulation, social functioning, initiation of smooth pursuit eye movements, eye-blink conditioning, language processing, verbal memory, executive function and the processing of spatial and emotional information. Consistent with common clinical, cognitive, and pathophysiological signs of established illness, our findings demonstrate cerebellar pathology as early as in first-episode schizophrenia.

Steady state visually evoked potential correlates of static and dynamic emotional face processing

While the neural regions associated with facial identity recognition are considered to be well defined, the neural correlates of non-moving and moving images of facial emotion processing are less clear. This study examined the brain electrical activity changes in 26 participants (14 males M = 21.64, SD = 3.99; 12 females M = 24.42, SD = 4.36), during a passive face viewing task, a scrambled face task and separate emotion and gender face discrimination tasks. The steady state visual evoked potential (SSVEP) was recorded from 64-electrode sites. Consistent with previous research, face related activity was evidenced at scalp regions over the parieto-temporal region approximately 170 ms after stimulus presentation. Results also identified different SSVEP spatio-temporal changes associated with the processing of static and dynamic facial emotions with respect to gender, with static stimuli predominately associated with an increase in inhibitory processing within the frontal region. Dynamic facial emotions were associated with changes in SSVEP response within the temporal region, which are proposed to index inhibitory processing. It is suggested that static images represent non-canonical stimuli which are processed via different mechanisms to their more ecologically valid dynamic counterparts.

The potential for new understandings of normal and abnormal cognition by integration of neuroimaging and behavioral data : Not an exercise in carrying coals to Newcastle

Discovering the means to prevent and cure schizophrenia is a vision that motivates many scientists. But in order to achieve this goal, we need to understand its neurobiological basis. The emergent metadiscipline of cognitive neuroscience fields an impressive array of tools that can be marshaled towards achieving this goal, including powerful new methods of imaging the brain (both structural and functional) as well as assessments of perceptual and cognitive capacities based on psychophysical procedures, experimental tasks and models developed by cognitive science. We believe that the integration of data from this array of tools offers the greatest possibilities and potential for advancing understanding of the neural basis of not only normal cognition but also the cognitive impairments that are fundamental to schizophrenia. Since sufficient expertise in the application of these tools and methods rarely reside in a single individual, or even a single laboratory, collaboration is a key element in this endeavor. Here, we review some of the products of our integrative efforts in collaboration with our colleagues on the East Coast of Australia and Pacific Rim. This research focuses on the neural basis of executive function deficits and impairments in early auditory processing in patients using various combinations of performance indices (from perceptual and cognitive paradigms), ERPs, fMRI and sMRI. In each case, integration of two or more sources of information provides more information than any one source alone by revealing new insights into structure-function relationships. Furthermore, the addition of other imaging methodologies (such as DTI) and approaches (such as computational models of cognition) offers new horizons in human brain imaging research and in understanding human behavior.

Mirror neuron activation is associated with facial emotion processing

Theoretical accounts suggest that mirror neurons play a crucial role in social cognition. The current study used transcranial-magnetic stimulation (TMS) to investigate the association between mirror neuron activation and facialemotion processing, a fundamental aspect of social cognition, among healthy adults (n = 20). Facial emotion processing of static (but not dynamic) images correlated significantly with an enhanced motor response, proposed to reflect mirror neuron activation. These correlations did not appear to reflect general facial processing or pattern recognition, and provide support to current theoretical accounts linking the mirror neuron system to aspects of social cognition. We discuss the mechanism by which mirror neurons might facilitate facial emotion recognition.

Can’t we all just get along? A qualitative investigation of the cognitive processes motivating driver aggression.

Although driver aggression has been identified as contributing to crashes, current understanding of the fundamental causes of the behaviour is poor. Two key reasons for this are evident. Firstly, existing research has been largely atheoretical, with no unifying conceptual framework guiding investigation. Secondly, emphasis on observable behaviours has resulted in limited knowledge of the underlying thought processes that motivate behaviour. Since driving is fundamentally a social situation, requiring drivers to interpret on-road events, insight regarding these perception and appraisal processes is paramount in advancing understanding of the underlying causes. Thus, the current study aimed to explore the cognitive appraisal processes involved in driver aggression, using a conceptual model founded on the General Aggression Model (Anderson & Bushman, 2002). The present results reflect the first of several studies testing this model. Participants completed 3 structured driving diaries to explore perceptions and cognitions. Thematic analysis of diaries identified several cognitive themes. The first, ‘driving etiquette’ concerned an implied code of awareness and consideration for other motorists, breaches of which were strongly associated with reports of anger and frustration. Such breaches were considered intentional; attributed to dispositional traits of another driver, and precipitated the second theme, ‘justified retaliation’. This theme showed that drivers view their aggressive behaviour as warranted, to convey criticism towards another motorist’s etiquette violation. However, the third theme, ‘superiority’ suggested that those refraining from an aggressive response were motivated by a desire to perceive themselves as ‘better’ than the offending motorists. Collectively, the themes indicate deep-seated and complex thought patterns underlying driver aggression, and suggest the behaviour will be challenging to modify. Implications of these themes in relation to the proposed model will be discussed, and continued research will explore these cognitive processes further, to examine their interaction with person-related factors.

Selection procedures for module discovery : exploring evolutionary algorithms for cognitive science

Evolutionary algorithms are playing an increasingly important role as search methods in cognitive science domains. In this study, methodological issues in the use of evolutionary algorithms were investigated via simulations in which procedures were systematically varied to modify the selection pressures on populations of evolving agents. Traditional roulette wheel, tournament, and variations of these selection algorithms were compared on the “needle-in-a-haystack” problem developed by Hinton and Nowlan in their 1987 study of the Baldwin effect. The task is an important one for cognitive science, as it demonstrates the power of learning as a local search technique in smoothing a fitness landscape that lacks gradient information. One aspect that has continued to foster interest in the problem is the observation of residual learning ability in simulated populations even after long periods of time. Effective evolutionary algorithms balance their search effort between broad exploration of the search space and in-depth exploitation of promising solutions already found. Issues discussed include the differential effects of rank and proportional selection, the tradeoff between migration of populations towards good solutions and maintenance of diversity, and the development of measures that illustrate how each selection algorithm affects the search process over generations. We show that both roulette wheel and tournament algorithms can be modified to appropriately balance search between exploration and exploitation, and effectively eliminate residual learning in this problem.

Pre-processing for approximate Bayesian computation in image analysis

Most of the existing algorithms for approximate Bayesian computation (ABC) assume that it is feasible to simulate pseudo-data from the model at each iteration. However, the computational cost of these simulations can be prohibitive for high dimensional data. An important example is the Potts model, which is commonly used in image analysis. Images encountered in real world applications can have millions of pixels, therefore scalability is a major concern. We apply ABC with a synthetic likelihood to the hidden Potts model with additive Gaussian noise. Using a pre-processing step, we fit a binding function to model the relationship between the model parameters and the synthetic likelihood parameters. Our numerical experiments demonstrate that the precomputed binding function dramatically improves the scalability of ABC, reducing the average runtime required for model fitting from 71 hours to only 7 minutes. We also illustrate the method by estimating the smoothing parameter for remotely sensed satellite imagery. Without precomputation, Bayesian inference is impractical for datasets of that scale.