1,720,958 research outputs found
Localization and expression of two human b-defensins (HBD-1 and HBD-2) in intestinal biopsies of celiac patients
No full textPrimate beta-defensins--structure, function and evolution.
No full textHost defense peptides (HDPs) are endogenous antibiotics that play a multifunctional role in the innate immunity of mammals. Among these, β-defensins contribute to mucosal and epithelial defense, also acting as signal molecules for cellular components of innate and adaptive immunity. Numerous members of this family have been identified in mammalian and avian species, and genomic studies in human and mouse indicate a considerable complexity in their gene organization. Recent reports on the evolution of primate and rodent members of this family indicate quite a complex pattern of variation. In this review we briefly discuss the evolution of mammalian β-defensins in relation to other types of defensins, and then concentrate on the evolution of β-defensins 1 to 4 in primates. In particular, the surprisingly varied patterns of evolution, which range from neutral or weakly purifying, to positive selection to a high level of conservation are analyzed in terms of possible genetics, structural or functional implications, as well as to observed variations on the antimicrobial activity in vitro. The role of polymorphisms in the genes encoding for these host defense peptides in determining susceptibility to human diseases are also briefly considered. © 2005 Bentham Science Publishers Ltd
Inhibition of DNA repair by the small molecule Chk1/Chk2 inhibitor PF-0477736 (Pfizer) in B-acute lymphoblastic leukemia (ALL)
No full textSINGLE-AGENT INHIBITION OF CHECKPOINT KINASE 1 (CHK1) AND 2 (CHK2) BY PF-0477736 (PFIZER) AS A NEW PROMISING THERAPY IN B-ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
No full textIntroduction. Chk1 and Chk2 are serine/threonine kinases that play a critical role in determining cellular responses to DNA damage both by halting the cell cycle through checkpoint activation and by actively repairing DNA. We explored the cellular effects of single-agent inhibition of Chk1/2 by PF-0477736 and its potential use as a therapeutic strategy for the treatment of B-ALL. Methods. Cellular viability was assessed by using a colorimetric assay based on mitochondrial dehydrogenase cleavage of WST-1 reagent (Roche); apoptosis was assessed by use of Annexin V/Propidium Iodide (PI); gene expression profile was performed using Affymetrix GeneChip Human Gene 1.0 ST platform (Affymetrix). Results. BCR-ABL1-positive (BV-173, SUPB-15) and negative cell lines (NALM6, NALM19, REH) were incubated with increasing concentrations of PF-0477736 (0.005-2 M) for 24, 48 and 72 hours. Inhibition of Chk1 resulted in dose and time-dependent
cytotoxicity with IC50 at 24 hours of 0.1-1.5 μM, with BV-173 being the most sensitive, while NALM6 the most resistant. All cell lines were TP53 wild-type, CDKN2A deleted. Consistent with the viability results, Annexin V/Propidium Iodide staining analysis showed a significant increase of apoptosis at 24 and 48 hours in all cell lines. Functionally, PF-0477736 decreased the inhibitory phosphorylation of Cdc25c Ser216 which is inactivated by Chk1 to prevent mitotic entry and increased the number of H2AX foci, a markers of DNA damage, that culminated in a proportion of cells developing intense staining for H2AX together with nuclear morphological characteristics of apoptosis as demonstrated by immunofluorescence analysis. The efficacy of PF-0477736 was thereafter confirmed in primary blasts from 11 B-ALL patients. Based on the viability results, three groups of patients were identified: very good responders, 46% (IC50: 0.1-0.5 μM at 24 hours); good responders, 36% (IC50: 0.6-1 μM at 24 hours); poor responders, 18% (IC50 > 1 μM at 24 hours). Finally, in order to elucidate the mechanisms of action of PF-0477736 and to determine biomarkers of response, gene expression profiling analysis was performed on treated cell lines and their untreated counterparts (DMSO 0.1%) after 24 hours. Consistent with a specific Chk1- mechanism of action, treatment resulted in differential expression (p < 0.05) of genes involved in apoptosis and cell cycle (e.g. CEBPB, CUL1, Histone H1-H2A, 2B family clusters) and DNA damage (DDIT3, GADD34 and GADD45a), suggesting that PF-0477736 contributes to accumulation of DNA damage and subsequent apoptosis in B-ALL cells. Conclusions. For the first time we demonstrated the efficacy of PF-0477736 in vitro models of B- ALL, suggesting that single-agent Chk1/2 inhibition may be further evaluated in clinical trials. Supported by European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna-Ravenna, FIRB2006, PRIN2009, PIO program, Programma Ricerca Regione-Università 2007–2009. PF-0477736 provided by Pfizer
Going 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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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