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

The synthetic psychology of the self

Synthetic psychology describes the approach of “understanding through building” applied to the human condition. In this chapter, we consider the specific challenge of synthesizing a robot “sense of self”. Our starting hypothesis is that the human self is brought into being by the activity of a set of transient self-processes instantiated by the brain and body. We propose that we can synthesize a robot self by developing equivalent sub-systems within an integrated biomimetic cognitive architecture for a humanoid robot. We begin the chapter by motivating this work in the context of the criteria for recognizing other minds, and the challenge of benchmarking artificial intelligence against human, and conclude by describing efforts to create a sense of self for the iCub humanoid robot that has ecological, temporally-extended, interpersonal and narrative components set within a multi-layered model of mind

Evidence against dopamine D1/D2 receptor heteromers

Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKIIα that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies

Arsenic uptake and toxicity in plants: integrating mycorrhizal influences

Arsenic (As) contamination of soil and water is a global problem that impacts on many areas of biology. This review firstly covers aspects of soil chemistry and soil-plant interactions relevant to the ways plants take up As (particularly arsenate (As(V)) from aerobic soils, with especial attention to As-phosphorus (P) interactions. It then assesses the extent to which studies of plant As tolerance based on short-term uptake of As(V) from nutrient solutions can be extrapolated to longer-term growth in contaminated soil. Mycorrhizal symbioses are then highlighted, because they are formed by ~ 90% of higher plants, often with increased uptake of phosphate (Pi) compared with non-mycorrhizal (NM) counterparts. It is therefore likely that mycorrhizas influence As(V) uptake. Published work shows that arbuscular mycorrhizal (AM) plants (the most common mycorrhizal type) have higher P/As ratios than NM plants, and this would be expected to affect sensitivity to soil As. We discuss ways in which higher P/As selectivity might result from differential operation of P and As uptake pathways in AM compared with NM plants, taking into account new understanding of P uptake mechanisms. We also give suggestions for future research required to increase understanding of mechanisms of As(V) uptake, and its interactions with plant P. © Springer Science + Business Media B.V. 2009.Sally E. Smith, Helle M. Christophersen, Suzanne Pope and F. Andrew Smit