No transfer of calibration between action and perception in learning a golf putting task

We assessed calibration of perception and action in the context of a golf putting task. Previous research has shown that right-handed novice golfers make rightward errors both in the perception of the perfect aiming line from the ball to the hole and in the putting action. Right-handed experts, however, produce accurate putting actions but tend to make leftward errors in perception. In two experiments, we examined whether these skill-related differences in directional error reflect transfer of calibration from action to perception. In the main experiment, three groups of right-handed novice participants followed a pretest, practice, posttest, retention test design. During the tests, directional error for the putting action and the perception of the perfect aiming line were determined. During practice, participants were provided only with verbal outcome feedback about directional error; one group trained perception and the second trained action, whereas the third group did not practice. Practice led to a relatively permanent annihilation of directional error, but these improvements in accuracy were specific to the trained task. Hence, no transfer of calibration occurred between perception and action. The findings are discussed within the two-visual-system model for perception and action, and implications for perceptual learning in action are raised

Prion pathogenesis is unaltered following down-regulation of SIGN-R1

AbstractPrion diseases are infectious neurodegenerative disorders characterised by accumulations of abnormal prion glycoprotein in affected tissues. Following peripheral exposure, many prion strains replicate upon follicular dendritic cells (FDC) in lymphoid tissues before infecting the brain. An intact splenic marginal zone is important for the efficient delivery of prions to FDC. The marginal zone contains a ring of specific intercellular adhesion molecule-3-grabbing non-integrin related 1 (SIGN-R1)-expressing macrophages. This lectin binds dextran and capsular pneumococcal polysaccharides, and also enhances the clearance of apoptotic cells via interactions with complement components. Since prions are acquired as complement-opsonized complexes we determined the role of SIGN-R1 in disease pathogenesis. We show that transient down-regulation of SIGN-R1 prior to intravenous prion exposure had no effect on the early accumulation of prions upon splenic FDC or their subsequent spread to the brain. Thus, SIGN-R1 expression by marginal zone macrophages is not rate-limiting for peripheral prion disease pathogenesis

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

Expression of selected genes isolated from whole blood, liver and obex in lambs with experimental classical scrapie and healthy controls, showing a systemic innate immune response at the clinical end-stage

Abstract Background Incubation period, disease progression, pathology and clinical presentation of classical scrapie in sheep are highly dependent on PRNP genotype, time and route of inoculation and prion strain. Our experimental model with pre-colostrum inoculation of homozygous VRQ lambs has shown to be an effective model with extensive PrPSc dissemination in lymphatic tissue and a short incubation period with severe clinical disease. Serum protein analysis has shown an elevation of acute phase proteins in the clinical stages of this experimental model, and here, we investigate changes in gene expression in whole blood, liver and brain. Results The animals in the scrapie group showed severe signs of illness 22 weeks post inoculation necessitating euthanasia at 23 weeks post inoculation. This severe clinical presentation was accompanied by changes in expression of several genes. The following genes were differentially expressed in whole blood: TLR2, TLR4, C3, IL1B, LF and SAA, in liver tissue, the following genes differentially expressed: TNF-α, SAA, HP, CP, AAT, TTR and TF, and in the brain tissue, the following genes were differentially expressed: HP, CP, ALB and TTR. Conclusions We report a strong and evident transcriptional innate immune response in the terminal stage of classical scrapie in these animals. The PRNP genotype and time of inoculation are believed to contribute to the clinical presentation, including the extensive dissemination of PrPSc throughout the lymphatic tissue

Increased Abundance of M cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases