Paying attention to emotional images with impact.

Emotional stimuli receive high processing priority in attention and memory. This processing "advantage" is generally thought to be predominantly mediated by arousal. However, recent data suggest that ratings of an image's affective "impact" may be a better predictor of recollection than arousal or valence. One interpretation of these findings is that high-impact images may draw an individual's attention, thus facilitating subsequent processing. We investigated the allocation of visual attention to negative emotional images that differed in impact but were matched for valence, arousal, and other characteristics. Participants viewed a central image flanked by 2 neutral indoor or outdoor scenes and made speeded judgments about whether the neutral scenes matched. In Experiment 1, responses were slower on high-impact relative to low-impact or neutral trials. In Experiment 2, responses on high-arousal relative to low-arousal trials did not differ significantly. These data provide evidence for differential allocation of attention to distinct sets of negative, equally arousing images, and argue against the prevailing view that heightened attention to and processing of emotional stimuli relate simply to arousal or valence.

Cognitive processing in bipolar disorder conceptualized using the Interactive Cognitive Subsystems (ICS) model.

BACKGROUND: There are few theoretical proposals that attempt to account for the variation in affective processing across different affective states of bipolar disorder (BD). The Interacting Cognitive Subsystems (ICS) framework has been recently extended to account for manic states. Within the framework, positive mood state is hypothesized to tap into an implicational level of processing, which is proposed to be more extreme in states of mania. METHOD: Thirty individuals with BD and 30 individuals with no history of affective disorder were tested in euthymic mood state and then in induced positive mood state using the Question-Answer task to examine the mode of processing of schemas. The task was designed to test whether individuals would detect discrepancies within the prevailing schemas of the sentences. RESULTS: Although the present study did not support the hypothesis that the groups differ in their ability to detect discrepancies within schemas, we did find that the BD group was significantly more likely than the control group to answer questions that were consistent with the prevailing schemas, both before and after mood induction. CONCLUSIONS: These results may reflect a general cognitive bias, that individuals with BD have a tendency to operate at a more abstract level of representation. This may leave an individual prone to affective disturbance, although further research is required to replicate this finding.

In vitro assays for assessing the potential for copper complexes to function as radiopharmaceutical agents.

A series of chemical in vitro assays are described to provide a rapid initial assessment of the in vivo stability and biological behaviour of potential new copper(II) based radiopharmaceutical agents. Chemical challenges using an excess of cysteine, glutathione (GSH) and histidine, which are models of S- and N-donor molecules found in vivo, are used to provide a measure of the potential for loss of the copper(II) ion from the radiopharmaceutical as a result of ligand dissociation. In addition, thiol containing molecules such as cysteine and GSH provide a redox challenge, whereby the copper(II) complex may be reduced to give a copper(I) species. The stability of the copper(I) species toward oxidation, protonation, and ligand dissociation may be crucial in determining the biodistribution, the biological half-life and excretion mechanisms of a potential radiopharmaceutical. Further evaluation of the redox stability is assessed using the ubiquitous biological reductant ascorbic acid. The relative stability of a complex with respect to ligand dissociation in human serum provides one of the most important experiments assessing the potential of a complex to be used in vivo. Further challenge experiments with serum proteins such as thioredoxin and serum albumin can be used to provide more detailed information on the probable fate of the complex in serum. Evaluation of complex stability and speciation over a range of pH values may also be used to obtain information on potential biodistribution.

Paying attention to meaning.

Several paradigms show that responses to one event compromise responses to a second event for around 500 ms. Such effects are generally attributed to attentional capacity limitations associated with processing information in the first event. In a task in which targets could be distinguished only by their meaning, we varied the semantic relationship between distractors and targets following at different lags. Semantic relatedness alone produced a classic attentional blink. We conclude by discussing how attention theory might best accommodate these new effects.

When the central executive lets us down: Schemas, attention, and load in a generative working memory task.

Participants were asked to generate a single sequence of numbers in between two bounds. By varying the requested sequence length and way in which the question is posed, this paradigm enables assessment of the contributions to central executive functioning of schema, focus of attention, and load. With sequences of three or four numbers, a quarter of the sample failed fully to comply with the instructions. They generated an incorrect number of numbers or went outside the specified bounds. With sequences of six numbers, more than half of the sample infringed one or more of the constraints. Participants consistently generated sequences with particular generic properties. The overall frequency and patterns of infringements suggest that a substantial proportion of participants focused their conceptual attention on sequence content and often neglected the problem of how the length and boundary constraints were going to be evaluated either before or during response delivery.

When the central executive lets us down: schemas, attention, and load in a generative working memory task.

Participants were asked to generate a single sequence of numbers in between two bounds. By varying the requested sequence length and way in which the question is posed, this paradigm enables assessment of the contributions to central executive functioning of schema, focus of attention, and load. With sequences of three or four numbers, a quarter of the sample failed fully to comply with the instructions. They generated an incorrect number of numbers or went outside the specified bounds. With sequences of six numbers, more than half of the sample infringed one or more of the constraints. Participants consistently generated sequences with particular generic properties. The overall frequency and patterns of infringements suggest that a substantial proportion of participants focused their conceptual attention on sequence content and often neglected the problem of how thelength and boundary constraints were going to be evaluated either before or during response delivery.

Specifying executive representations and processes in number generation tasks.

The Interacting Cognitive Subsystems framework, ICS (Barnard, 1985) proposes that central executive phenomena can be accounted for by two autonomous subsystems, which process different forms of meaning: propositional and schematic (implicational) meanings. The apparent supervisory role of the executive arises from limitations on the exchange of information between these and other cognitive subsystems. This general proposal is elaborated in four experiments in which a total of 1,293 participants are asked to spontaneously generate a large verbal number to varying task constraints, with the intention of specifying the representations of number and task that underlie responses. Responses change systematically according to participants' use of explicit propositional information provided by the instructions, and inferred implicational information about what the experimenter is requesting. There was a high error rate (between 6% and 24%), participants producing responses that did not fall within the large range indicated by the instructions. The studies support the distinction between propositional and implicational processing in executive function, and provide a framework for understanding normal executive representations and processes.

Autobiographical memory and daily schemas at work.

This exploratory study examines how daily schemas for work activities influence retrospective memory. Twelve subjects were asked to describe their 'typical day' at work, and to recall their work activities of yesterday and of the same day a week ago. The number of basic activities occurring in each description was counted, and the number of basic activities occurring in the typical day description was viewed as an index of the degree of elaboration of the schema. There were three major findings. First, people recalled fewer activities from last week than they did from yesterday, and those activities that were recalled from last week tended to be those that were in the daily schema. Second, there was a tendency for people with highly elaborated daily schemas to recall more activities from last week than people with poorly elaborated schemas. And third, there were more schematic references in the recalls from last week than in those from yesterday. Taken together, these findings indicate that there are strong schematic influences on the recall of activities from last week, but not on those from yesterday. The discussion points to a number of research issues, both applied and theoretical, which arise from this preliminary investigation of daily work schemas.

Mapping of a liver phosphorylase kinase alpha-subunit gene on the mouse X chromosome.

Phosphorylase kinase (PHK) is a regulatory enzyme of the glycogenolytic pathway composed of a complex of four subunits. We recently mapped the muscle alpha-subunit gene (Phka) to the mouse X chromosome in a region syntenic with the proximal long arm of the human X chromosome and containing the human homologue of this gene, PHKA. We now report the mapping of the liver alpha-subunit gene to the telomeric end of the mouse X chromosome. This mapping position would suggest a location for the human liver alpha-subunit gene on the proximal short arm of the X chromosome, a region recently implicated in X-linked liver glycogenosis (XLG).

Expression of four alternative dystrophin transcripts in brain regions regulated by different promoters.

Cognitive impairment occurs in one-third of patients with Duchenne muscular dystrophy, a lethal X-linked, recessive disease caused by mutations in the dystrophin gene which is expressed in both brain and muscle, the two transcripts having alternative first exons. Previous reports have indicated that the 'brain-type' dystrophin transcript predominates in brain. Using in situ hybridisation with antisense oligonucleotides, expression of four distinct mRNAs in specific brain areas is demonstrated here; the 14 kb muscle-type and brain-type transcripts were found to coexist in cortical and hippocampal neurons and two new transcripts have been identified in dentate gyrus and cerebellar Purkinje neurons, respectively. The latter has a novel first exon which was isolated and sequenced from mouse and human, and which would encode a protein with a different amino-terminus from the known muscle- and brain-type isoforms. Mapping in human located this exon in a large intron between the muscle-type promoter and second exon of the dystrophin gene. This finding of four alternative transcripts regulated by different promoters in brain reveals a new complexity to dystrophin expression that may have important insights for mental retardation mechanisms.

Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes.

Genes encoding the neuron-specific phosphoprotein synapsin I (SYN1), the glycoprotein tissue inhibitor of metalloproteinases (TIMP), the proto-oncogene A-raf-1 (ARAF1), and properdin (PFC), a positive regulator of the alternative pathway of human complement, lie within a conserved synteny encompassing the proximal short arm of the human X chromosome (Xp21.1-p11) and the centromeric end of the mouse X chromosome (A1-A5). We have used a mouse interspecific cross to demonstrate genetic linkage of Syn-1, Timp, and Araf and also show physical linkage, with Timp lying only 10 kb from Araf, within an intron of the Syn-1 gene. Detailed restriction mapping shows that Timp is transcribed in the same direction as Araf but in the opposite direction to the Syn-1 gene. Analysis of the corresponding region of the human X chromosome indicates a similar arrangement and in addition shows that the properdin gene lies within 5 kb of the 5' end of the synapsin I gene.

Expression of the dystrophin gene in mouse and rat brain.

Duchenne muscular dystrophy is due to mutations in the dystrophin gene which is predominantly expressed in muscle and brain. Since the disease is associated with cognitive impairment, we sought to localize dystrophin mRNA in brain using in situ hybridization with oligonucleotide probes. We find the gene strongly expressed in the hippocampus and cerebral cortex, areas with an established cognitive function, and also in the Purkinje cells of the cerebellum, an area associated with motor coordination.

Mapping of the glycine receptor alpha 2-subunit gene and the GABAA alpha 3-subunit gene on the mouse X chromosome.

We have mapped the gene for the alpha 2-subunit of the inhibitory glycine receptor (Glra2) to the telomeric end of the mouse X chromosome by backcross analysis of a Mus musculus/Mus spretus interspecific cross. In addition, we have extended the mapping of the GABAA alpha 3-subunit receptor gene (Gabra3). A deduced gene order of cen-Cybb-Hprt-DXPas6-Gabra3-Rsvp-Gdx/Cf-8- Dmd-Pgk-1-DXPas2-Plp-DXPas1-Glra2-tel places Gabra3 proximal to the visual pigment gene Rsvp and Glra2 in the region of loci for hypophosphatemia (Hyp), steroid sulfatase (Sts), and the E1 alpha-subunit of pyruvate dehydrogenase (Pdha1). This establishes the XF region of the mouse X chromosome as homologous with the Xp22.1-p22.3 region of the human X chromosome and indicates the presence of an evolutionary breakpoint in the region of Xp21.3.

Developmental and tissue-specific regulation of mouse dystrophin: the embryonic isoform in muscular dystrophy.

Dystrophin, the protein product of the Duchenne muscular dystrophy locus, is encoded by a 14 kb transcript of over 65 exons. A point mutation in the homologous mouse gene causes muscular dystrophy in mdx mice. We have examined the developmental regulation of transcription of this gene in skeletal mouse muscle and also the tissue specificity of the transcript in muscle and brain, by using the polymerase chain reaction to amplify overlapping segments of dystrophin mRNA spanning the entire coding sequence and 5'-untranslated region. We have characterised a specific embryonic transcript that would encode dystrophin with a different C-terminus and have shown that this persists from the earliest stages to the adult in mdx skeletal muscle. The brain transcript shows striking sequence homology to rat and human, being highly conserved at the 5'-untranslated region and is present in both wild-type and mdx mice.

Mapping of the phosphorylase kinase alpha subunit gene on the mouse X chromosome.

Phosphorylase kinase is a glycogenolytic enzyme in several animal tissues. Within the last few years all four subunits of the enzyme have been cloned. The beta, gamma, and delta subunits are known to be autosomal. We have mapped the alpha subunit of phosphorylase kinase, recently cloned by Zander et al. (1988), in an interspecific mouse pedigree and localized it on the X chromosome, where it maps between the X-linked zinc finger protein and phosphoglycerate kinase genes, close to the latter. In man and mouse several X-linked disorders of this enzyme have been described. Although the X-linked phosphorylase kinase deficiency in mice may be caused by a mutation in the structural gene for the alpha subunit, mapped here, the existence of a separate regulatory locus, important in the normal expression or function of the enzyme in muscle, still remains a possibility.

Chromosomal localization of GABAA receptor subunit genes: relationship to human genetic disease.

Hybridization of GABAA receptor probes to human chromosomes in situ and to DNA from sorted human chromosomes has localized the genes encoding a beta subunit and three isoforms of the alpha subunit. The alpha 2 and beta genes are both located on chromosome 4 in bands p12-p13 and may be adjacent. The alpha 1 gene is on chromosome 5 (bands q34-q35) and the alpha 3 gene is on the X chromosome. The alpha 3 locus was mapped also on the mouse X chromosome using genetic break-point analysis in an interspecies pedigree. The combined results locate the human alpha 3 gene within band Xq28, in a location that makes it a candidate gene for the X-linked form of manic depression.

The molecular basis of muscular dystrophy in the mdx mouse: a point mutation.

The mdx mouse is an X-linked myopathic mutant, an animal model for human Duchenne muscular dystrophy. In both mouse and man the mutations lie within the dystrophin gene, but the phenotypic differences of the disease in the two species confer much interest on the molecular basis of the mdx mutation. The complementary DNA for mouse dystrophin has been cloned, and the sequence has been used in the polymerase chain reaction to amplify normal and mdx dystrophin transcripts in the area of the mdx mutation. Sequence analysis of the amplification products showed that the mdx mouse has a single base substitution within an exon, which causes premature termination of the polypeptide chain.

Localization of the mdx mutation within the mouse dystrophin gene.

We have mapped human and mouse X chromosome-specific genomic and cDNA probes through an interspecies Mus musculus/spretus pedigree which contains the mdx mutation. The positions of these markers relative to one another and to the mdx mutation were delineated. Using probes corresponding to segments of the human Duchenne muscular dystrophy (DMD) gene transcript, the position of a cross-hybridizing mouse equivalent gene (mDMD) was located. In more than 200 animals mapped, three were identified which show recombination within this mDMD gene. Analysis of these three animals shows that the mDMD gene is oriented with its 5' end centromeric and its 3' end telomeric on the mouse X chromosome. Furthermore, their recombinational breakpoints are on either side of the mdx mutation, thus providing the first unequivocal demonstration that the mdx mutation is located within the mDMD gene and defining limits within that gene between which the mutation must lie. Within that segment the evidence indicates that there is no major deletion of an exon as detectable by Southern blot analysis in mdx animals. The mdx mouse becomes important as an animal model for the study of the expression of the DMD gene and its developmental consequences, for transgenic and other corrective manipulations.