115 research outputs found

    Student and teacher co-navigation of a course: following the natural lines of academic enquiry.

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    Using the mountaineering metaphor of ‘natural lines’ this article describes the co-navigation of an honours course by students and teachers. It suggests the benefits and possibilities of going beyond the confines of conventional teaching and learning wisdom (as canonised in the notion of constructive alignment) and offering just and joyful ways for students to explore disciplinary knowledge. We openly explore issues of power between students and teachers in the construction of so-called partnerships, recognising the inherent challenges in moving beyond the prevailing mainstream. We suggest that a natural lines approach enables students to act as genuine co-navigators and to experience disciplinary knowledge in authentic ways and provides rich opportunities for personal reflection and development

    The relationship between moral development, distorted cognitions and social problem solving amongst men with intellectual disabilities who have a history of criminal offending

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    Aim: Little is known about the self-rated health status of people with co-morbid autism and intellectual disabilities (ID) in whole country populations. This paper will present analysis of: self-rated general health status, demographic factors, and prevalence of other disabilities for people with co-morbid autism and ID, as well as people with autism only. Method: We analysed data from Scotland’s Census 2011, and generated descriptive statistics. Results: People with co-morbid autism and ID (n=5,709)comprised 0.1% of the total population of Scotland (n=5,295,403) and 18 .0% of the whole population of people with autism in Scotland(n=31,712) across all ages. Only 2,863 (50.1%) people with co-morbid autism and ID rated their health as good or very good, compared with 19,97 1 (76.8%) of all people with autism only. Conclusions: Health is poorer for people with c o-morbid autism and ID than for people with autism only. Further analysis will explore the impact of individual and household characteristics on the health o f people with co-morbid autism and ID

    Management and prevalence of long-term conditions in primary health care for adults with intellectual disabilities compared with the general population: a population-based cohort study

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    Background: In the UK, general practitioners/family physicians receive pay for performance on management of long-term conditions, according to best-practice indicators. Method: Management of long-term conditions was compared between 721 adults with intellectual disabilities and the general population (n = 764,672). Prevalence of long-term conditions was determined, and associated factors were investigated via logistic regression analyses. Results: Adults with intellectual disabilities received significantly poorer management of all long-term conditions on 38/57 (66.7%) indicators. Achievement was high (75.1%–100%) for only 19.6% of adults with intellectual disabilities, compared with 76.8% of the general population. Adults with intellectual disabilities had higher rates of epilepsy, psychosis, hypothyroidism, asthma, diabetes and heart failure. There were no clear associations with neighbourhood deprivation. Conclusions: Adults with intellectual disabilities receive poorer care, despite conditions being more prevalent. The imperative now is to find practical, implementable means of supporting the challenges that general practices face in delivering equitable care

    Seawater redox variations during the deposition of the Kimmeridge Clay Formation, United Kingdom (Upper Jurassic): evidence from molybdenum isotopes and trace metal ratios

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    The Kimmeridge Clay Formation (KCF) and its equivalents worldwide represent one of the most prolonged periods of organic carbon accumulation of the Mesozoic. In this study, we use the molybdenum (Mo) stable isotope system in conjunction with a range of trace metal paleoredox proxies to assess how seawater redox varied both locally and globally during the deposition of the KCF. Facies with lower organic carbon contents (TOC 1–7 wt %) were deposited under mildly reducing (suboxic) conditions, while organic-rich facies (TOC >7 wt %) accumulated under more strongly reducing (anoxic or euxinic) local conditions. Trace metal abundances are closely linked to TOC content, suggesting that the intensity of reducing conditions varied repeatedly during the deposition of the KCF and may have been related to orbitally controlled climate changes. Long-term variations in ?98/95Mo are associated with the formation of organic-rich intervals and are related to third-order fluctuations in relative sea level. Differences in the mean ?98/95Mo composition of the organic-rich intervals suggest that the global distribution of reducing conditions was more extensive during the deposition of the Pectinatites wheatleyensis and lower Pectinatites hudlestoni zones than during the deposition of the upper Pectinatites hudlestoni and Pectinatites pectinatus zones. The global extent of reducing conditions during the Kimmerigidan was greater than today but was less widespread than during the Toarcian (Early Jurassic) oceanic anoxic event. This study also demonstrates that the Mo isotope system in Jurassic seawater responded to changes in redox conditions in a manner consistent with its behavior in present-day sedimentary environment

    Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

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    SummaryBRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors

    Clinical presentation and proteomic signature of patients with TANGO2 mutations

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    Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C&gt;T/p.Arg88*; c.220A&gt;C/p.Thr74Pro; c.380+1G&gt;A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10 ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.</p

    Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling

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    Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naĂŻve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression
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