1,721,068 research outputs found
Recent development in fluorinated antibiotics
No full textThis chapter presents the most recent results in the development of fluorinated antibioticsby taking into consideration modern challenges of multidrug-resistant pathogens. After a brief introduction on the direct and indirect effects of fluorine and fluorinated moieties in regulating biological activity, the chapter is developed in three main subsections discussing the two major classes of fluorinated antibiotics, fluoroquinolones and oxazolidinones, plus an overview of recent research on the antibiotic activity of fluorinated analogs of tetracyclines, peptidomimetics, triazoles, and nucleosides. Discussed aspects include: (1) Synthesis and challenges posed by the introduction of fluorinated moieties in specific positions of the main scaffold; (2) mechanism of action and structure–activity relationships in which the introduction or modification of fluorinated substituent is crucial to control efficacy; and (3) resistance mechanisms and solutions to treat resistant pathogens
New Insight on Archaeological Metal Finds, Nails and Lead Sheathings of the Punic Ship from Battle of the Egadi Islands
Full text linkThe wreck of the Punic ship exhibited at the Archaeological Park of Lilybaeum (Marsala, Italy) is a unique example in the world. In this paper, the investigation of some metal finds (30 nails and 3 fragments of sheathings) belonging to the wreck of the Punic ship is reported. Portable X-ray fluorescence and Raman spectroscopy allowed us to identify the elements and compounds constituting them and make some deductions about their composition. X-ray diffractometry, polarised optical microscopy and scanning electron microscopy of the collected micro-samples allowed us to explain the degradation that occurred in the underwater environment
Photochemically Produced Singlet Oxygen: Applications and Perspectives
No full textThis Review aims to provide early stage researchers with an updated guide to applications of photochemically produced singlet oxygen and, at the same time, widen the experienced researcher's perspectives in a holistic approach to singlet oxygen chemistry. Without being exhaustive, literature between 2010 and early 2018 has been surveyed by focusing on a critical evaluation of new knowledge and applications. After an introductory section concerning singlet oxygen production, detection, and interactions with biological systems, subsequent sections describe current applications of singlet-oxygen-enabled technology. Besides strictly chemical synthesis applications, attention has been given to the usage of singlet oxygen in photochemically assisted therapies as well as in environmental remediation. Additionally, the potential of expanding singlet oxygen chemistry to unexplored fields has been discussed
Caffeine boosts Ataluren's readthrough activity
Full text linkThe readthrough of nonsense mutations by small molecules like Ataluren is considered a novel therapeutic approach to overcome the gene defect in several genetic diseases as cystic fibrosis (CF). This pharmacological approach suppresses translation termination at premature termination codons (PTCs readthrough) thus restoring the expression of a functional protein. However, readthrough might be limited by the nonsense-mediated mRNA decay (NMD), a cell process that reduces the amount/level of PTCs containing mRNAs. Here we investigate the combined action of Ataluren and caffeine to enhance the readthrough of PTCs. IB3.1 CF cells with a nonsense mutation were treated with caffeine to attenuate the Nonsense-Mediated mRNA Decay (NMD) activity and thus enhance the stability of the nonsense (ns)-CFTR-mRNA to be targeted by Ataluren. Our results show that NMD attenuation by caffeine enhances mRNA stability and more importantly when combined with Ataluren increase the recovery of the full-length CFTR protein
Deciphering the Nonsense Readthrough Mechanism of Action of Ataluren: An in Silico Compared Study
Full text linkAtaluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's MOA by complementary computational approaches such as induced fit docking (IFD), quantum polarized ligand docking (QPLD), MM-GBSA free-energy calculations, and computational mutagenesis. In addition to CFTR-mRNA, this study considered other model targets implicated in the translation process, such as eukaryotic rRNA 18S, prokaryotic rRNA 16S, and eukaryotic Release Factor 1 (eRF1), and we performed a comparison with a new promising Ataluren analogue (NV2445) and with a series of aminoglycosides, known to suppress the normal proofreading function of the ribosome. Results confirmed mRNA as the most likely candidate target for Ataluren and its analogue, and binding energies calculated after computational mutagenesis highlighted how Ataluren's interaction with the premature stop codon could be affected by ancillary nucleotides in the genetic context
Nonsense Mutations in Rare and Ultra-Rare Human Disorders: An Overview
No full textOver 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associated with human inherited diseases. Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss-of-function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single-nucleotide changes, frameshifts, and splicing mutations. The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough—a process in which the ribosome bypasses the PTC and reaches the natural stop codon—may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense-related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and certain hereditary neuropathies and cancers
Advancing Therapeutic Strategies for Nonsense-Related Diseases: From Small Molecules to Nucleic Acid-Based Innovations
No full textNonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman–Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care
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
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