1,720,957 research outputs found
AN APPROACH AGAINST CANCER: TRANSLATIONAL READTHROUGH INDUCING DRUGS (TRIDs) FOR RESTORING P53 EXPRESSION IN STOP MUTATED CELLS
Full text linkStop mutations are gene mutations characterized by the substitution of a single nucleotide in the coding sequence of a gene, which causes the onset of a premature stop codon (PTC) within the reading frame of the mRNA, resulting in the formation of a truncated and non-functional protein. This type of mutation accounts for approximately 11% of genetic diseases, including conditions such as Cystic Fibrosis, Duchenne Muscular Dystrophy, Choroideremia, Schwachman-Diamond syndrome, and certain types of hereditary cancers involving mutations in the TP53 gene. About 10% of TP53 mutations are stop mutations [1, 2]. TP53 encodes a protein made up of 393 amino acid residues called p53, which acts mainly as a transcription factor, regulating numerous pathways such as the cell cycle arrest, DNA damage repair, apoptosis, autophagy, and metabolism when cells are under certain stress conditions. TP53 mutations create a favorable environment for tumor formation, and mutant p53 may exhibit loss of function, dominant-negative repression, or gain of oncogenic function, contributing to tumor stability and progression [2]. Today there is no therapy for the pathologies caused by this type of mutation, but an approach that has proven to be particularly effective is represented by molecules with readthrough activity (TRIDs; Translational Readthrough Inducing Drugs) which intervene on the ribosome allowing the overcoming of the PTC and the restoration of the synthesis and subsequent functionality of the protein [3]. In this work, we investigate the effects of TRID molecules with readthrough activity on the TP53 gene in tumor cells, which harbors the PTC R213X, the most common TP53 stop mutation, that generates a truncated and non-functional p53. We analyzed the restoration of p53 protein expression before and after induction of DNA damage by Western blot, its nuclear localization with fluorescence microscopy, the mRNA expression of p53, and its targets p21 and GADD45 to evaluate the functionality of the protein by Real-Time RT PCR. After 24 hours of treatment with TRIDs, we observed a partial nuclear localization of p53, an increase in mRNA expression of its targets and a restoration of protein expression after the induction of DNA damage. These results represent a promising path for developing targeted cancer therapies against stop mutations, a new approach to impede tumor proliferation, and a solid foundation for the formulation of novel personalized therapy modalities not only against cancer
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
Design of small molecules and identification of putative anticancer therapeutic targets via in silico tools
No full textComputational approaches are a key component in drug design and discovery workflows. Several computational tools have been implemented in the last years to help researchers save time and reduce costs. They can be used to identify a therapeutic target, understand ligand-protein and protein-protein interactions, and identify putative binding sites, even though their principal use remains the identification of hit compounds through ligand-based and structure-based virtual screening and optimizing lead compounds [1]. Here, in the context of the PNRR project "HEAL ITALIA", we present the computational workflows to identify new potential anticancer compounds. Ligand-based approaches will be discussed guiding our research for new active compounds together with advanced docking approaches, biased and unbiased molecular dynamics simulations. In vitro test confirmed the results of the computational approaches and paved the way for the hits optimizatio
Rescuing nonsense in cancer: recovering p53 tumor suppressor gene expression by translational readthrough inducing drugs (TRIDs)
Full text linkMutation-based treatments represent a burgeoning frontier in genetic medicine, wherein therapeutic
interventions are tailored according to the specific mutation profile of a patient. Recently, considerable
attention has been directed towards addressing diseases stemming from premature termination codons
(PTCs). A novel class of drugs, known as Translational readthrough-inducing drugs (TRIDs), has emerged with
the capacity to facilitate the readthrough of PTCs, thereby reinstating the synthesis of full-length functional
proteins. This study focuses on the potential of three newly synthesized TRIDs: NV848, NV914, and NV930,
in promoting the production of functional p53 protein from a cDNA sequence carrying a PTC. The
investigation involved the treatment of a human cancer cell line (H1299-p53R213X) engineered to harbor a
PTC, where significant levels of readthrough were achieved upon treatment with the aforementioned TRIDs.
After 24 hours of treatment with TRID molecules, we analyzed the expression of the p53 mRNA by real-time
RT-PCR, observing that the treatment induces the stabilization of mutant p53 mRNA, resulting in augmented
protein expression that appears functional. The observed upregulation of p53-target genes, after DNA
damage induction by Doxorubicin, further corroborated these findings.
These results herald a promising avenue for the development of targeted cancer therapies tailored to address
nonsense mutations within tumor suppressor genes. They underscore the feasibility of employing molecules
designed to induce stop-codon readthrough as a way to impede tumor proliferation. Moreover, they furnish
a rational groundwork for the formulation of novel personalized treatment modalities, thereby enriching the
existing repertoire of cancer therapeutics
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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