Prevention and modulation of aminoglycoside ototoxicity (Review)

More than 60 years after their isolation and characterization, aminoglycoside (AG) antibiotics remain powerful agents in the treatment of severe gram-negative, enterococcal or mycobacterial infections. However, the clinical use of AGs is hampered by nephrotoxicity and ototoxicity, which often develop as a consequence of prolonged courses of therapy, or of administration of increased doses of these drugs. The discovery of non-ototoxic antibacterial agents, showing a wider spectrum of activity, has gradually decreased the use of AGs as first line antibiotics for many systemic infections. However, AGs are now undergoing an unexpected revival, being increasingly indicated for the treatment of severe emerging infections caused by organisms showing resistance to most first-line agents (e.g., multidrug-resistant tuberculosis, complicated nosocomially-acquired acute urinary tract infections). Increasing adoption of aminoglycosides poses again to scientists and physicians the problem of toxicity directed to the kidneys and to the inner ear. In particular, aminoglycoside-induced deafness can be profound and irreversible, especially in genetically predisposed patients. For this reason, an impressive amount of molecular strategies have been developed in the last decade to counteract the ototoxic effect of aminoglycosides. The present article overviews: i) the molecular mechanisms by which aminoglycosides exert their bactericidal activity, ii) the mechanisms whereby AGs exert their ototoxic activity in genetically-predisposed patients, iii) the drugs and compounds that have so far proven to prevent or modulate AG ototoxicity at the preclinical and/or clinical level, and iv) the dosage regimens that have so far been suggested to decrease the incidence of episodes of AG-induced ototoxicity

Cloning and characterization of mouse UBPy, a deubiquitinating enzyme that interacts with the Ras guanine nucleotide exchange factor CDC25(Mm)/Ras-GRF1

We used yeast "two-hybrid" screening to isolate cDNA-encoding proteins interacting with the N-terminal domain of the Ras nucleotide exchange factor CDC25(Mm). Three independent overlapping clones were isolated from a mouse embryo cDNA library. The full-length cDNA was cloned by RACE-polymerase chain reaction. It encodes a large protein (1080 amino acids) highly homologous to the human deubiquitinating enzyme hUBPy and contains a well conserved domain typical of ubiquitin isopeptidases. Therefore we called this new protein mouse UBPy (mUBPy). Northern blot analysis revealed a 4-kilobase mRNA present in several mouse tissues and highly expressed in testis; a good level of expression was also found in brain, where CDC25(Mm) is exclusively expressed. Using a glutathione S-transferase fusion protein, we demonstrated an "in vitro" interaction between mUBPy and the N-terminal half (amino acids 1-625) of CDC25(Mm). In addition "in vivo" interaction was demonstrated after cotransfection in mammalian cells. We also showed that CDC25Mm, expressed in HEK293 cells, is ubiquitinated and that the coexpression of mUBPy decreases its ubiquitination. In addition the half-life of CDC25Mm protein was considerably increased in the presence of mUBPy. The specific function of the human homolog hUBPy is not defined, although its expression was correlated with cell proliferation. Our results suggest that mUBPy may play a role in controlling degradation of CDC25(Mm), thus regulating the level of this Ras-guanine nucleotide exchange factor

<i>orsai</i>, the Drosophila homolog of human ETFRF1, links lipid catabolism to growth control

BACKGROUND: Lipid homeostasis is an evolutionarily conserved process that is crucial for energy production, storage and consumption. Drosophila larvae feed continuously to achieve the roughly 200-fold increase in size and accumulate sufficient reserves to provide all energy and nutrients necessary for the development of the adult fly. The mechanisms controlling this metabolic program are poorly understood. RESULTS: Herein we identified a highly conserved gene, orsai (osi), as a key player in lipid metabolism in Drosophila. Lack of osi function in the larval fat body, the regulatory hub of lipid homeostasis, reduces lipid reserves and energy output, evidenced by decreased ATP production and increased ROS levels. Metabolic defects due to reduced Orsai (Osi) in time trigger defective food-seeking behavior and lethality. Further, we demonstrate that downregulation of Lipase 3, a fat body-specific lipase involved in lipid catabolism in response to starvation, rescues the reduced lipid droplet size associated with defective orsai. Finally, we show that osi-related phenotypes are rescued through the expression of its human ortholog ETFRF1/LYRm5, known to modulate the entry of β-oxidation products into the electron transport chain; moreover, knocking down electron transport flavoproteins EtfQ0 and walrus/ETFA rescues osi-related phenotypes, further supporting this mode of action. CONCLUSIONS: These findings suggest that Osi may act in concert with the ETF complex to coordinate lipid homeostasis in the fat body in response to stage-specific demands, supporting cellular functions that in turn result in an adaptive behavioral response. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-022-01417-w

The RIBES strategy for ex situ conservation: conventional and modern techniques for seed conservation

The Italian seed bank network (RIBES) aims to improve the quality and safety of the germplasm reserves of native plant species in Italy to ensure the long-term conservation of endangered and/or endemic flora. The strategy includes traditional methods to secure seed conservation. A comprehensive priority list for seed collection is being defined, it was prepared by crossing data of various checklists (red lists, endemics) and will soon be cross-referenced with an updated list of accessions of the whole network. A safety-backup program of duplicates will quickly be implemented to secure the conservation of the most threatened species in at least two seed banks of the network. On the other hand, the RIBES strategy also includes research by applying modern techniques. In collaboration with the Millennium Seed Bank, research on the storage behaviour of seeds and spores through thermal analysis is ongoing to inform conservation. Using the Differential Scanning Calorimetry (DSC), we could evaluate seed lipid properties such as glass transition temperature, melting, crystallization, oxidation behaviour, and thermal stability. Finally, RIBES participates as a co-funder in the LIFE Nature project SEEDFORCE, coordinating 11 seed banks of the network for collecting seeds/spores of 29 threatened species of EU interest

The RIBES strategy for ex situ conservation: conventional and modern techniques for seed conservation

The Italian seed bank network (RIBES) aims to improve the quality and safety of the germplasm reserves of native plant species in Italy to ensure the long-term conservation of endangered and/or endemic flora. The strategy includes traditional methods to secure seed conservation. A comprehensive priority list for seed collection is being defined, it was prepared by crossing data of various checklists (red lists, endemics) and will soon be cross-referenced with an updated list of accessions of the whole network. A safety-backup program of duplicates will quickly be implemented to secure the conservation of the most threatened species in at least two seed banks of the network. On the other hand, the RIBES strategy also includes research by applying modern techniques. In collaboration with the Millennium Seed Bank, research on the storage behaviour of seeds and spores through thermal analysis is ongoing to inform conservation. Using the Differential Scanning Calorimetry (DSC), we could evaluate seed lipid properties such as glass transition temperature, melting, crystallization, oxidation behaviour, and thermal stability. Finally, RIBES participates as a co-funder in the LIFE Nature project SEEDFORCE, coordinating 11 seed banks of the network for collecting seeds/spores of 29 threatened species of EU interest

Tourismes 3 - La révolution durable

Tourismes 3 poursuit la réflexion entreprise depuis 2002 dans Tourismes 1, lieux communs et Tourismes 2, moments de lieux. Cet ouvrage aborde les temps longs du tourisme en montrant et en expliquant les logiques qui ont contribué à assurer sa durabilité. Inventé il y a plus de deux siècles et réservé alors à une élite, le tourisme est devenu progressivement planétaire, « milliardaire » en personnes concernées et en recettes engrangées, exponentiel dans les tendances à l\u27oeuvre. Face à la révolution industrielle, les territoires et les sociétés touchés précocement ou plus tardivement par le tourisme le restent, voire continuent de se développer. Il y aurait donc une formidable pérennité des pratiques touristiques et une remarquable adaptabilité des lieux touristiques face à l\u27évolution du monde en général et de l\u27univers touristique en particulier. Le tourisme apparaît alors comme cette autre révolution, la révolution silencieuse, la révolution ignorée, mais aussi la révolution durable, au sens où elle n\u27a pas fini de produire des effets sur la Terre et sur le Monde. La trilogie s\u27achève, mais la réflexion se poursuit via la conclusion qui propose deux projets scientifiques d\u27importance : la construction d\u27une théorie générale du tourisme et la mise à l\u27épreuve des sciences sociales par le tourisme

Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; ArgentinaFil: Garavaglia, Matías Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Goya, María Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Tourismes 2 - Moments de lieux

Tourismes 2 prolonge la réflexion entreprise dans Tourismes 1 en proposant une lecture originale des lieux qui ont fait le tourisme tel qu\u27il fonctionne aujourd\u27hui de Bath à Marrakech en passant par Saint-Tropez Benidorm Yellowstone Venise Waikiki ou la Floride Ce livre est un voyage à travers une collection de lieux touristiques qui ont été choisis parce que chacun d\u27eux exprime un moment fort dans l\u27histoire du tourisme en relation avec l\u27évolution du Monde Pourquoi à un moment donné s\u27est-on mis à fréquenter des lieux qui auparavant étaient ignorés ou fuis? Où et comment est-on passé du bain thérapeutique au bain plaisir du bain dans les mers froides au bain dans les mers chaudes? Si les hautes vallées ont d\u27abord été fréquentées en été par les touristes où et comment est née la saison d\u27hiver en montagne ? Sans vouloir constituer une histoire du tourisme cet ouvrage est une invitation à lire autrement le fil du temps le fil des événements à l\u27aide du concept de « moment de lieu » son ambition est de saisir les processus qui ont conduit à l\u27émergence sur quelques décennies tout au plus et dans des lieux identifiés de nouveaux systèmes d\u27acteurs et de nouvelles pratiques qui pour la plupart fonctionnent toujours aujourd\u27hui et ont été reproduits par millier

Characterization of a Gelatin/Chitosan/Hyaluronan scaffold-polymer

Gelatin, chitosan and hyaluronic acid are natural components used to prepare polymeric scaffold in tissue engineering. The physical properties of these materials confer an appropriate microenvironment for cells, which can be used as a regeneration system for skin and cartilage. In this work, we prepared and characterized a Gelatin/Chitosan/Hyaluronan lyophilized-polymer. Physical properties of lyophilized-polymer changed slightly with moisture, but when polymer was totally hydrated the elasticity changed significantly. Thermophysical characterisation indicated that temperatures higher than 30ºC could modify irreversibly the polymeric matrix probably due to protein denaturation. Besides, we used the polymer as scaffold to prepare a biosynthetic-skin, reporting biological behaviour and its mechanical properties