1,721,101 research outputs found
Function of Nucleophosmin in Zebrafish Hematopoiesis
No full textNucleophosmin (NPM1) is a multi-functional ubiquitous phosphoprotein that shuttles between the nucleolus and cytoplasm. Located on chromosome 5q35 NPM1 is involved in the development of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) both as a chimeric fusion partner and as a putative key haploinsufficient tumor suppressor. Heterozygous NPMc+ mutations have been identified in 30% of AML, usually with normal karyotype. Such mutations create new nuclear export signals and disrupt the normal nucleolar localization signal, resulting in re-localization of both mutant and heterodimeric wild-type (WT) NPM protein from the nucleolus to the cytoplasm. The zebrafish is a model organism ideally suited to genotypic and phenotypic analysis of myelopoiesis and leukemogenesis, with a proven track record for facilitating the discovery of novel pathogenetic pathways. Using in silico analysis we identified two homologues (a common finding in zebrafish due to genome duplication during piscine evolution) of the human nucleophosmin gene in zebrafish. These two genes have been designated znpm1a and znpm1b. znpm1a is annotated by the National Center for Biotechnology (NCBI) while znpm1b is a known protein-coding region located via blast search of the human NPM1 amino acid sequence at www.ensembl.org/Danio_rerio/index.html. Whilst znpm1b exhibits slightly less identity to human NPM1 (47%) than znpm1a (64%) it demonstrates clear synteny with human chromosome 5q35 and mouse chromosome 11 (Figure 1). We confirmed expression of both znpm1a and znpm1b in embryonic tissue and adult hematopoietic tissue of the major lineages by RT-PCR of Green Fluorescent Protein (GFP)-sorted cells in pu.1-GFP transgenic zebrafish embryos and in adult zebrafish kidney cells (sorted by forward and side scatter charactersistics). Morpholinos (stable, synthesized antisense oligonucleotides that specifically block gene expression when injected into embryos at the one-cell stage) were designed to inhibit znpm1a or 1b and injected into zebrafish embryos at the 1–4 cells stage to assess the effect of knockdown of znpm1a and 1b alone and in combination on hematopoiesis. Whole-mount in situ hybridization of 48 hours post-fertilization(hpf) injected embryos demonstrated a 50% reduction in the expression of myeloperoxidase (mpo) and a similar reduction in alpha globin (-globin) expression as markers of myelo- and erythropoiesis. To investigate the mechanism of the reduction in hematopoietic cells we injected the znpm1a and 1b morpholinos into zebrafish carrying mutated p53 and observed partial rescue of the hematopoietic phenotype suggesting that loss of npm1 in zebrafish activates p53 dependent cell cycle arrest, senescence or cell death. Thus zebrafish npm1 proteins are required for normal hematopoiesis consistent with the role for NPM1 as a tumor suppressor in AML/MDS with loss of all or part of chromosome 5. Future studies using this model will address which pathways are disrupted by the loss of npm1 and thus may contribute to the pathogenesis of human AML/MDS and facilitate identification of potential therapeutic targets
Acute Myeloid Leukemia with Mutated Nucleophosmin (NPM1): Molecular, Pathological, and Clinical Features
No full text
NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia.
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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