1,721,145 research outputs found
NAMPT: A critical driver and therapeutic target for cancer
Get PDFNicotinamide phosphoribosyltransferase (NAMPT) possesses a vital role in mammalian cells due to its activity as a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. NAD is an essential redox cofactor, but it also functions as a substrate for NAD-consuming enzymes, regulating multiple cellular processes such as DNA repair and gene expression, fundamental to sustain tumor growth and survival and energetic needs. A common strategy that several tumor types adopt to sustain NAD synthesis is to over-express NAMPT. However, beside its intracellular functions, this enzyme has a second life outside of cells exerting cytokine-like functions and mediating pro-inflammatory conditions activating signaling pathways. While the effects of NAMPT/NAD axis on energetic metabolism in tumors has been well-established, increasing evidence demonstrated the impact of NAMPT over-expression (intra-/extra-cellular) on several tumor cellular processes, including DNA repair, gene expression, signaling pathways, proliferation, invasion, stemness, phenotype plasticity, metastatization, angiogenesis, immune regulation, and drug resistance. For all these reasons, NAMPT targeting has emerged as promising anti-cancer strategy to deplete NAD and impair cellular metabolism, but also to counteract the other NAMPT-related functions. In this review, we summarize the key role of NAMPT in multiple biological processes implicated in cancer biology and the impact of NAMPT inhibition as therapeutic strategy for cancer treatment
Enzymology of extracellular NAD metabolism
Get PDFExtracellular NAD represents a key signaling molecule in different physiological and pathological conditions. It exerts such function both directly, through the activation of specific purinergic receptors, or indirectly, serving as substrate of ectoenzymes, such as CD73, nucleotide pyrophosphatase/phosphodiesterase 1, CD38 and its paralog CD157, and ecto ADP ribosyltransferases. By hydrolyzing NAD, these enzymes dictate extracellular NAD availability, thus regulating its direct signaling role. In addition, they can generate from NAD smaller signaling molecules, like the immunomodulator adenosine, or they can use NAD to ADP-ribosylate various extracellular proteins and membrane receptors, with significant impact on the control of immunity, inflammatory response, tumorigenesis, and other diseases. Besides, they release from NAD several pyridine metabolites that can be taken up by the cell for the intracellular regeneration of NAD itself. The extracellular environment also hosts nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase, which inside the cell catalyze key reactions in NAD salvaging pathways. The extracellular forms of these enzymes behave as cytokines, with pro-inflammatory functions. This review summarizes the current knowledge on the extracellular NAD metabolome and describes the major biochemical properties of the enzymes involved in extracellular NAD metabolism, focusing on the contribution of their catalytic activities to the biological function. By uncovering the controversies and gaps in their characterization, further research directions are suggested, also to better exploit the great potential of these enzymes as therapeutic targets in various human diseases
Massive hydrothermal dolomitization in the Southwestern Cantabrian Zone (Spain) and its relation to the Late Variscan Evolution.
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
Multiple Dolomitization Episodes In Deep-Water Limestones of the Triassic Lagonegro Basin (Southern Italy): From Early Reflux To Tectonically Driven Fluid Flow
Get PDFMassive dolomitization does not commonly occur in deep-water carbonates. However, this regional study on outcrops and subsurface samples of Triassic Lagonegro basinal carbonates from the southern Apennines fold and thrust belt (Italy) shows that the evolution of the Lagonegro basin was punctuated by two events of massive dolomitization. These processes resulted in two distinct dolomite types, displaying different petrographic and geochemical features. A medium-crystalline and fabric-preservative dolomite in the northern area (Molise, Campagna, and San Fele–Mount Pierno) contrasts with a medium- to coarse-crystalline and fabric-destructive dolomite in the southern area (from Pignola to the high Val d'Agri).
Geochemical data (increase in δ18O with respect to typical Late Triassic seawater values, high Sr and low Mn and Fe content, Sr isotopes consistent with Late Triassic seawater) indicate that the dolomite in the northern area is the result of an early replacement caused by a marine and possibly oxidizing fluid during shallow burial. Dolomitizing fluids likely were expelled through reflux from the Norian Apenninic carbonate platform towards the proximal Lagonegro basin. This reflux was promoted by the Norian peculiar paleoceanographic and climatic conditions in the Tethyan region, and affected only the proximal basinal facies.
Dolomites in the southern area display a decrease in δ18O compared to Late Triassic seawater values and show lower Sr, higher Mn and Fe contents, and higher Sr isotope ratios compared to the early dolomites of the northern area. Fluid-inclusion microthermometry reveals homogenization temperatures between 70 and 120°C and salinities of 1.9 to 6.4 wt % NaCl eq. for saddle dolomites. These geochemical signatures indicate that the southern area was affected by late diagenetic burial dolomitization, interpreted to be the result of large scale tectonically driven fluid flow during the second compressional phase characterizing the southern Apennines fold and thrust belt emplacement.
The dolomite distribution across the Lagonegro basin (northern and southern) is possibly controlled by the paleogeographic distribution of the facies (proximal vs. distal) as well as by their proximity to thrust faults. The Lagonegro case study demonstrates that basinal successions may undergo multiple dolomitization episodes in a manner similar to carbonate platform successions, from early shallow to deep-burial diagenesis. One of the relevant implications is that in areas of restricted oceanographic circulation, during periods of aridity, reflux dolomitization may extend beyond the platform margin, into deep-water carbonates, having the potential to alter their reservoir quality
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