Fostering clinical reasoning in physiotherapy: Comparing the effects of concept map study and concept map completion after example study in novice and advanced learners

Background: Health profession learners can foster clinical reasoning by studying worked examples presenting fully worked out solutions to a clinical problem. It is possible to improve the learning effect of these worked examples by combining them with other learning activities based on con

Immunoseq: the identification of functionally relevant variants through targeted capture and sequencing of active regulatory regions in human immune cells

$\textbf{BACKGROUND}$: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq". $\textbf{RESULTS}$: We performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells. We identified a large number of novel non-coding variants in these samples. Relying on allele specific expression measurements, we also showed that our selected capture regions are enriched for functional variants that have an impact on differential allelic gene expression. The results from a replication set with 180 samples confirmed our observations. $\textbf{CONCLUSIONS}$: We show that Immunoseq is a powerful approach to detect novel rare variants in regulatory regions. We also demonstrate that these novel variants have a potential functional role in immune cells.This work was supported by grants from the Canadian Institute of Health Research (CIHR), the UK Medical Research Council (G1100125), the Swedish Research Council (DO283001) and Knut and Alice Wallenberg Foundation (KAW). We also acknowledge the use of subjects from the Cambridge BioResource and the support of the Cambridge NIHR Biomedical Research Centre. AM was supported by the Fond de Recherche Santé Québec Doctoral training award. TP and CL holds a Canada Research Chair

Learning in the European Union: Theoretical Lenses and Meta-Theory

notes: This paper is based on research carried out with the support of the European Research Council grant on Analysis of Learning in Regulatory Governance, ALREG http://centres.exeter.ac.uk/ceg/research/ALREG/index.php. The authors wish to express their gratitude to the other authors in this special edition and in particular its editor, Nikos Zaharaidis and X anonymous referees.publication-status: AcceptedThe European Union may well be a learning organization, yet there is still confusion about the nature of learning, its causal structure and the normative implications. In this article we select four perspectives that address complexity, governance, the agency-structure nexus, and how learning occurs or may be blocked by institutional features. They are transactional theory, purposeful opportunism, experimental governance, and the joint decision trap. We use the four cases to investigate how history and disciplinary traditions inform theory; the core causal arguments about learning; the normative implications of the analysis; the types of learning that are theoretically predicted; the meta-theoretical aspects and the lessons for better theories of the policy process and political scientists more generally

Ybp2 Associates with the Central Kinetochore of Saccharomyces cerevisiae and Mediates Proper Mitotic Progression

The spindle checkpoint ensures the accurate segregation of chromosomes by monitoring the status of kinetochore attachment to microtubules. Simultaneous mutations in one of several kinetochore and cohesion genes and a spindle checkpoint gene cause a synthetic-lethal or synthetic-sick phenotype. A synthetic genetic array (SGA) analysis using a mad2Δ query mutant strain of yeast identified YBP2, a gene whose product shares sequence similarity with the product of YBP1, which is required for H2O2-induced oxidation of the transcription factor Yap1. ybp2Δ was sensitive to benomyl and accumulated at the mitotic stage of the cell cycle. Ybp2 physically associates with proteins of the COMA complex (Ctf19, Okp1, Mcm21, and Ame1) and 3 components of the Ndc80 complex (Ndc80, Nuf2, and Spc25 but not Spc24) in the central kinetochore and with Cse4 (the centromeric histone and CENP-A homolog). Chromatin-immunoprecipitation analyses revealed that Ybp2 associates specifically with CEN DNA. Furthermore, ybp2Δ showed synthetic-sick interactions with mutants of the genes that encode the COMA complex components. Ybp2 seems to be part of a macromolecular kinetochore complex and appears to contribute to the proper associations among the central kinetochore subcomplexes and the kinetochore-specific nucleosome

High-intensity interval training improves VO2peak, maximal lactate accumulation, time trial and competition performance in 9–11-year-old swimmers

Training volume in swimming is usually very high when compared to the relatively short competition time. High-intensity interval training (HIIT) has been demonstrated to improve performance in a relatively short training period. The main purpose of the present study was to examine the effects of a 5-week HIIT versus high-volume training (HVT) in 9–11-year-old swimmers on competition performance, 100 and 2,000 m time (T100 m and T2,000 m), VO2peak and rate of maximal lactate accumulation (Lacmax). In a 5-week crossover study, 26 competitive swimmers with a mean (SD) age of 11.5 ± 1.4 years performed a training period of HIIT and HVT. Competition (P < 0.01; effect size = 0.48) and T2,000 m (P = 0.04; effect size = 0.21) performance increased following HIIT. No changes were found in T100 m (P = 0.20). Lacmax increased following HIIT (P < 0.01; effect size = 0.43) and decreased after HVT (P < 0.01; effect size = 0.51). VO2peak increased following both interventions (P < 0.05; effect sizes = 0.46–0.57). The increases in competition performance, T2,000 m, Lacmax and VO2peak following HIIT were achieved in significantly less training time (~2 h/week)

Germline EPHB2 Receptor Variants in Familial Colorectal Cancer

Familial clustering of colorectal cancer occurs in 15–20% of cases, however recognized cancer syndromes explain only a small fraction of this disease. Thus, the genetic basis for the majority of hereditary colorectal cancer remains unknown. EPHB2 has recently been implicated as a candidate tumor suppressor gene in colorectal cancer. The aim of this study was to evaluate the contribution of EPHB2 to hereditary colorectal cancer. We screened for germline EPHB2 sequence variants in 116 population-based familial colorectal cancer cases by DNA sequencing. We then estimated the population frequencies and characterized the biological activities of the EPHB2 variants identified. Three novel nonsynonymous missense alterations were detected. Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I). The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases. Genotyping of additional patients with colorectal cancer and control subjects revealed that A438T and G787R represent rare EPHB2 alleles. In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism. Tumor tissue from the G787R variant case manifested loss of heterozygosity, with loss of the wild-type allele, supporting a tumor suppressor role for EPHB2 in rare colorectal cancer cases. Rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer

Bub1-Mediated Adaptation of the Spindle Checkpoint

During cell division, the spindle checkpoint ensures accurate chromosome segregation by monitoring the kinetochore–microtubule interaction and delaying the onset of anaphase until each pair of sister chromosomes is properly attached to microtubules. The spindle checkpoint is deactivated as chromosomes start moving toward the spindles in anaphase, but the mechanisms by which this deactivation and adaptation to prolonged mitotic arrest occur remain obscure. Our results strongly suggest that Cdc28-mediated phosphorylation of Bub1 at T566 plays an important role for the degradation of Bub1 in anaphase, and the phosphorylation is required for adaptation of the spindle checkpoint to prolonged mitotic arrest

Spatial patterns of the tau pathology in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is characterized neuropathologically by neuronal loss, gliosis, and the presence of tau-immunoreactive neuronal and glial cell inclusions affecting subcortical and some cortical regions. The objectives of this study were to determine (1) the spatial patterns of the tau-immunoreactive pathology, viz., neurofibrillary tangles (NFT), oligodendroglial inclusions (GI), tufted astrocytes (TA), and Alzheimer's disease-type neuritic plaques (NP) in PSP and (2) to investigate the spatial correlations between the histological features. Post-mortem material of cortical and subcortical regions of eight PSP cases was studied. Spatial pattern analysis was applied to the NFT, GI, TA, NP, abnormally enlarged neurons (EN), surviving neurons, and glial cells. NFT, GI, and TA were distributed either at random or in regularly distributed clusters. The EN and NP were mainly randomly distributed. Clustering of NFT and EN was more frequent in the cortex and subcortical regions, respectively. Variations in NFT density were not spatially correlated with the densities of either GI or TA, but were positively correlated with the densities of EN and surviving neurons in some regions. (1) NFT were the most widespread tau-immunoreactive pathology in PSP being distributed randomly in subcortical regions and in regular clusters in cortical regions, (2) GI and TA were more localized and exhibited a regular pattern of clustering in subcortical regions, and (3) neuronal and glial cell pathologies were not spatially correlated. © 2012 Springer-Verlag

Credibility in Policy Expertise: The Function of Boundaries Between Research and Policy

As science becomes an increasingly crucial resource for addressing complex challenges in society, extensive demands are placed upon the researchers who produce it. Creating valuable expert knowledge that intervenes in policy or practice requires knowledge brokers to facilitate interactions at the boundary between research and policy. Yet, existing research lacks a compelling account of the ways in which brokerage is performed to gain credibility. Drawing on mixed-method analysis of twelve policy research settings, I outline a novel set of strategies for attaining symbolic power, whereby policy experts position themselves and others via conceptual distances drawn between the ‘world of ideas’ and the ‘world of policy and practice’. Disciplinary distance works to situate research as either disciplinary or undisciplinary, epistemic distance creates a boundary between complex specialist research and direct digestible outputs, temporal distance represents the separation of slow rigorous research and agile responsive analysis, and economic distance situates research as either pure and intrinsic or marketable and fundable. I develop a theoretical account that unpacks the boundaries between research communities and shows how these boundaries permit policy research actors to achieve various strategic aims.ESRC Future Research Leaders ES/N016319/1 Commonwealth Scholarship Commissio