1,720,965 research outputs found
Role of the Mitochondrial E3 Ubiquitin Ligases as Possible Therapeutic Targets in Cancer Therapy
No full textUbiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification ultimately regulates the stability or degradation of the targeted proteins. Ubiquitination is mediated by three different classes of enzymes: the E1 ubiquitin-activating enzymes, the E2 ubiquitin-conjugating enzymes and, most importantly, the E3 ubiquitin ligases. E3 ligases are responsible for the final step of the ubiquitin cascade, interacting directly with the target proteins. E3 ligases can also be involved in DNA repair, cell cycle regulation and response to stress; alteration in their levels can be involved in oncogenic transformation and cancer progression. Of all the six hundred E3 ligases of the human genome, only three of them are specific to the mitochondrion: MARCH5, RNF185 and MUL1. Their alterations (that reflect on the alteration of the mitochondria functions) can be related to cancer progression, as underlined by the increasing research performed in recent years on these three mitochondrial enzymes. This review will focus on the function and mechanisms of the mitochondrial E3 ubiquitin ligases, as well as their important targets, in cancer development and progression, also highlighting their potential use for cancer therapy
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
An internal ribosome entry site (IRES), present within the third cytoplasmic loop, drives the expression of the Carboxyl-terminal domain of the human muscarinic M2 receptor
No full textAn internal ribosome entry site (IRES) is a nucleotide sequence
that allows cap independent translation initiation by recruiting
the ribosome in proximity of an internal initiation codon. Here,
we describe an IRES driven mechanism of translation initiation
for the human muscarinic M2 receptor. The insertion of a stop
codon in the N-terminal of the third cytoplasmic loop of the M2
receptor, resulted in a mutant receptor (M2-stop) that was still able
to bind muscarinic ligands and to function. The insertion of the
stop codon resulted in the expression of a N-terminal receptor
fragment, constituted by the transmembrane regions I-V, and a
C-terminal receptor fragment, constituted by the transmembrane
regions V and VI. The two fragments could bind to each other
and reconstitute the functional muscarinic receptor. Translation of
the C-terminal fragment was not due to leaky scanning and reinitiation
of translation, as the insertion of a stable hairpin loop did
not prevent its translation. Mutagenesis of the three methionines
in frame after the stop codon, revealed that translation initiation
starts at the third methionine (codon 368). Western blot analysis
showed that the C-terminal fragment of the M2-stop receptor has
an apparent molecular mass of ~15.000 Dalton. Remarkably, a
fragment of the same molecular weight was found also in the
cells transfected with the wild type M2 receptor, suggesting that
the IRES driven mechanism of translation initiation is physiologically
functioning
Mitochondrial and metabolic alterations in cancer cells
Full text linkMetabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of “metabolic reprogramming”, which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a “metabolic phenotype” useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study
Mechanisms of initiation and progression of intestinal fibrosis in IBD
No full textIntestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in
>30% of patients with Crohn’s disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local
chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by
activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance
between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic
interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active
inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the
current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control
of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal
fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved
understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the
mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new
therapeutic approaches in IBD
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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