Model-based parametric study of frontostriatal abnormalities in schizophrenia patients

<p>Abstract</p> <p>Background</p> <p>Several studies have suggested that the activity of the prefrontal cortex (PFC) and the dopamine (DA) release in the striatum has an inverse relationship. One would attribute this relationship primarily to the circuitry comprised of the glutamatergic projection from the PFC to the striatum and the GABAergic projection from the striatum to the midbrain DA nucleus. However, this circuitry has not characterized satisfactorily yet, so that no quantitative analysis has ever been made on the activities of the PFC and the striatum and also the DA release in the striatum.</p> <p>Methods</p> <p>In this study, a system dynamics model of the corticostriatal system with dopaminergic innervations is constructed to describe the relationships between the activities of the PFC and the striatum and the DA release in the striatum. By taking published receptor imaging data from schizophrenia patients and healthy subjects into this model, this article analyzes the effects of striatal D2 receptor activation on the balance of the activity and neurotransmission in the frontostriatal system of schizophrenic patients in comparison with healthy controls.</p> <p>Results</p> <p>The model predicts that the suppressive effect by D2 receptors at the terminals of the glutamatergic afferents to the striatum from the PFC enhances the hypofrontality-induced elevation of striatal DA release by at most 83%. The occupancy-based estimation of the 'optimum' D2 receptor occupancy by antipsychotic drugs is 52%. This study further predicts that patients with lower PFC activity tend to have greater improvement of positive symptoms following antipsychotic medication.</p> <p>Conclusion</p> <p>This model-based parametric study would be useful for system-level analysis of the brains with psychiatric diseases. It will be able to make reliable prediction of clinical outcome when sufficient data will be available.</p

The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the Prostaglandin E2 human model of headache

Using a human Prostaglandin E2 (PGE2) model of headache, we examined whether a novel potent and selective EP4 receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healthy volunteers were randomly allocated to receive 200 and 400 mg BGC20-1531 and placebo, followed by a 25-min infusion of PGE2. We recorded headache intensity on a verbal rating scale, MCA blood flow velocity and STA diameter. There was no difference in headache response or prevention of the dilation of the MCA or the STA (P > 0.05) with either dose of BGC20-1531 relative to placebo, although putative therapeutic exposures were not reached in all volunteers. In conclusion, these data suggest that the other EP receptors may be involved in PGE2 induced headache and dilatation in normal subjects

Rare Copy Number Deletions Predict Individual Variation in Intelligence

Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in “mutation load” emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent) copy number variations (CNVs), and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77) had been administered the Wechsler Abbreviated Scale of Intelligence (WASI). After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = −.30, p = .01). As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES), we also examined the impact of ethnicity (Anglo/White vs. Other), as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less) adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed

Functional gene group analysis indicates no role for heterotrimeric g proteins in cognitive ability

Peer reviewedPublisher PD

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe