6,096 research outputs found

    Exome sequencing in classic hairy cell leukaemia reveals widespread variation in acquired somatic mutations between individual tumours apart from the signature BRAF V(600)E lesion

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    In classic Hairy cell leukaemia (HCLc), a single case has thus far been interrogated by whole exome sequencing (WES) in a treatment naive patient, in which BRAF V(600)E was identified as an acquired somatic mutation and confirmed as occurring near-universally in this form of disease by conventional PCR-based cohort screens. It left open however the question whether other genome-wide mutations may also commonly occur at high frequency in presentation HCLc disease. To address this, we have carried out WES of 5 such typical HCLc cases, using highly purified splenic tumour cells paired with autologous T cells for germline. Apart from BRAF V(600)E, no other recurrent somatic mutation was identified in these HCLc exomes, thereby excluding additional acquired mutations as also prevalent at a near-universal frequency in this form of the disease. These data then place mutant BRAF at the centre of the neoplastic drive in HCLc. A comparison of our exome data with emerging genetic findings in HCL indicates that additional somatic mutations may however occur recurrently in smaller subsets of disease. As mutant BRAF alone is insufficient to drive malignant transformation in other histological cancers, it suggests that individual tumours utilise largely differing patterns of genetic somatic mutations to coalesce with BRAF V(600)E to drive pathogenesis of malignant HCLc disease

    Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

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    Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype

    Run 2 Upgrades to the CMS Level-1 Calorimeter Trigger

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    The CMS Level-1 calorimeter trigger is being upgraded in two stages to maintain performance as the LHC increases pile-up and instantaneous luminosity in its second run. In the first stage, improved algorithms including event-by-event pile-up corrections are used. New algorithms for heavy ion running have also been developed. In the second stage, higher granularity inputs and a time-multiplexed approach allow for improved position and energy resolution. Data processing in both stages of the upgrade is performed with new, Xilinx Virtex-7 based AMC cards.Comment: 10 pages, 7 figure

    Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States.

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    From October 4 to November 2, 2001, the first 10 confirmed cases of inhalational anthrax caused by intentional release of Bacillus anthracis were identified in the United States. Epidemiologic investigation indicated that the outbreak, in the District of Columbia, Florida, New Jersey, and New York, resulted from intentional delivery of B. anthracis spores through mailed letters or packages. We describe the clinical presentation and course of these cases of bioterrorism-related inhalational anthrax. The median age of patients was 56 years (range 43 to 73 years), 70% were male, and except for one, all were known or believed to have processed, handled, or received letters containing B. anthracis spores. The median incubation period from the time of exposure to onset of symptoms, when known (n=6), was 4 days (range 4 to 6 days). Symptoms at initial presentation included fever or chills (n=10), sweats (n=7), fatigue or malaise (n=10), minimal or nonproductive cough (n=9), dyspnea (n=8), and nausea or vomiting (n=9). The median white blood cell count was 9.8 X 10(3)/mm(3) (range 7.5 to 13.3), often with increased neutrophils and band forms. Nine patients had elevated serum transaminase levels, and six were hypoxic. All 10 patients had abnormal chest X-rays; abnormalities included infiltrates (n=7), pleural effusion (n=8), and mediastinal widening (seven patients). Computed tomography of the chest was performed on eight patients, and mediastinal lymphadenopathy was present in seven. With multidrug antibiotic regimens and supportive care, survival of patients (60%) was markedly higher (<15%) than previously reported

    Commercial chicken breeds exhibit highly divergent patterns of linkage disequilibrium

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    The analysis of linkage disequilibrium (LD) underpins the development of effective genotyping technologies, trait mapping and understanding of biological mechanisms such as those driving recombination and the impact of selection. We apply the Malécot-Morton model of LD to create additive LD maps that describe the high-resolution LD landscape of commercial chickens. We investigated LD in chickens (Gallus gallus) at the highest resolution to date for broiler, white egg and brown egg layer commercial lines. There is minimal concordance between breeds of fine-scale LD patterns (correlation coefficient &lt;0.21), and even between discrete broiler lines. Regions of LD breakdown, which may align with recombination hot spots, are enriched near CpG islands and transcription start sites (P&lt;2.2 × 10?16), consistent with recent evidence described in finches, but concordance in hot spot locations between commercial breeds is only marginally greater than random. As in other birds, functional elements in the chicken genome are associated with recombination but, unlike evidence from other bird species, the LD landscape is not stable in the populations studied. The development of optimal genotyping panels for genome-led selection programmes will depend on careful analysis of the LD structure of each line of interest. Further study is required to fully elucidate the mechanisms underlying highly divergent LD patterns found in commercial chickens

    Turning collegial governance on its head : symbolic violence, hegemony and the academic board

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    This article draws on Bourdieu&rsquo;s theorisation of domination and Gramsci&rsquo;s notions of hegemony within the context of a larger empirical study of Australian university academic governance, and of academic boards (also known as academic senates or faculty senates) in particular. Reporting data that suggest a continued but radically altered form of collegial governance in which hegemony is exercised by management rather than by the professor, it theorises the domination of academic boards within western democratic universities. However, traditional collegial governance is also dependent upon a community of scholars, a role historically played by the academic board. In view of the suggested transition in collegial governance and the resultant convergence of academic work and management, the article concludes with questions about whether academic boards can continue to serve as communities of scholars in future
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