An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response.

Influenza A viruses counteract the cellular innate immune response at several steps, including blocking RIG I-dependent activation of interferon (IFN) transcription, interferon (IFN)-dependent upregulation of IFN-stimulated genes (ISGs), and the activity of various ISG products; the multifunctional NS1 protein is responsible for most of these activities. To determine the importance of other viral genes in the interplay between the virus and the host IFN response, we characterized populations and selected mutants of wild-type viruses selected by passage through non-IFN-responsive cells. We reasoned that, by allowing replication to occur in the absence of the selection pressure exerted by IFN, the virus could mutate at positions that would normally be restricted and could thus find new optimal sequence solutions. Deep sequencing of selected virus populations and individual virus mutants indicated that nonsynonymous mutations occurred at many phylogenetically conserved positions in nearly all virus genes. Most individual mutants selected for further characterization induced IFN and ISGs and were unable to counteract the effects of exogenous IFN, yet only one contained a mutation in NS1. The relevance of these mutations for the virus phenotype was verified by reverse genetics. Of note, several virus mutants expressing intact NS1 proteins exhibited alterations in the M1/M2 proteins and accumulated large amounts of deleted genomic RNAs but nonetheless replicated to high titers. This suggests that the overproduction of IFN inducers by these viruses can override NS1-mediated IFN modulation. Altogether, the results suggest that influenza viruses replicating in IFN-competent cells have tuned their complete genomes to evade the cellular innate immune system and that serial replication in non-IFN-responsive cells allows the virus to relax from these constraints and find a new genome consensus within its sequence space. IMPORTANCE In natural virus infections, the production of interferons leads to an antiviral state in cells that effectively limits virus replication. The interferon response places considerable selection pressure on viruses, and they have evolved a variety of ways to evade it. Although the influenza virus NS1 protein is a powerful interferon antagonist, the contributions of other viral genes to interferon evasion have not been well characterized. Here, we examined the effects of alleviating the selection pressure exerted by interferon by serially passaging influenza viruses in cells unable to respond to interferon. Viruses that grew to high titers had mutations at many normally conserved positions in nearly all genes and were not restricted to the NS1 gene. Our results demonstrate that influenza viruses have fine-tuned their entire genomes to evade the interferon response, and by removing interferon-mediated constraints, viruses can mutate at genome positions normally restricted by the interferon response

Lead optimisation of dehydroemetine for repositioned use in malaria

Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine (IC50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action. [Abstract copyright: Copyright © 2020 Panwar et al.

Descubrimiento automático de mappings en un caso de uso real con altas exigencias de certeza

Los sistemas de integración de información resuelven las diferencias entre las fuentes, en la mayoría de los casos, mediante la creación de mappings, puentes semánticos entre los elementos de las fuentes. Hasta ahora se han propuesto comparadores para generar un conjunto de mappings para cada par de elementos de las fuentes a integrar, y se han realizado estudios experimentales con ellos. El valor añadido del presente trabajo frente a los trabajos experimentales anteriores es que se ha llevado a cabo en un caso real embebido en una aplicación real (en el dominio geográfico) con altas exigencias de certeza

OEGMerge: a case-based model for merging ontologies

No long ago ontology merging was a necessary activity, however, the current methods used in ontology merging present neither detailed cases nor an accurate formalization. For validating these methods, it is convenient to have a case list as complete as possible. In this paper we present the OEGMerge model, developed from the OEG (Ontological Engineering Group at UPM) experience, which describes precisely the merging casuistic and the actions to carry out in each case. In this first approach, the model covers only the taxonomy of concepts, attributes and relations

Estudio y formalización del proceso de mezcla de ontologías

Desde hace tiempo la mezcla de ontolog?as es una actividad necesaria, sin embargo, los actuales m?todos de mezcla de ontolog?as no tienen una casu?stica detallada ni una formalizaci?n precisa. Para la validaci?n de estos m?todos, es conveniente disponer de una casu?stica lo m?s completa posible. Por ello, en este art?culo se presenta el modelo OEGMerge, desarrollado a partir de la experiencia del Grupo de Ingenier?a Ontol?gica (OEG) de la UPM, en el que se describe detallada y formalmente la casu?stica de mezcla y las acciones a realizar en cada caso. En esta primera aproximaci?n s?lo se abarca taxonom?a de conceptos, atributos y relaciones

Algoritmo de agregación de mappings basado en reglas de selección

Los sistemas de integración de información resuelven las diferencias entre las fuentes, en la mayoría de los casos, mediante la creación de mappings, puentes semánticos entre los elementos de las fuentes. Hasta ahora se han propuesto técnicas para generar un conjunto de mappings para cada par de elementos de las fuentes a integrar, sin embargo, hasta la publicación del presente trabajo, no se disponía de un algoritmo de agregación público y general para distintos tipos de fuentes que permitiera sintetizar este conjunto de mappings en uno solo. El enfoque aquí presentado está basado en reglas y ha sido aplicado en la integración de catálogos de mobiliario y en la integración de recursos en el dominio geoespacia

The Unusual Spectral Energy Distribution of a Galaxy Previously Reported to be at Redshift 6.68

Observations of distant galaxies are important both for understanding how galaxies form and for probing the physical conditions of the universe at the earliest epochs. It is, however, extremely difficult to identify galaxies at redshift z>5, because these galaxies are faint and exhibit few spectral features. In a previous work, we presented observations that supported the identification of a galaxy at redshift z = 6.68 in a deep STIS field. Here we present new ground-based photometry of the galaxy. We find that the galaxy exhibits moderate detections of flux in the optical B and V images that are inconsistent with the expected absence of flux at wavelength shortward of the redshifted Lyman-alpha emission line of a galaxy at redshift z>5. In addition, the new broad-band imaging data not only show flux measurements of this galaxy that are incompatible with the previous STIS measurement, but also suggest a peculiar spectral energy distribution that cannot be fit with any galaxy spectral template at any redshift. We therefore conclude that the redshift identification of this galaxy remains undetermined.Comment: 9 pages, 2 figures; To appear in Nature (30 November 2000

A parabolic approach to the control of opinion spreading

We analyze the problem of controlling to consensus a nonlinear system modeling opinion spreading. We derive explicit exponential estimates on the cost of approximately controlling these systems to consensus, as a function of the number of agents N and the control time-horizon T. Our strategy makes use of known results on the controllability of spatially discretized semilinear parabolic equations. Both systems can be linked through time-rescalin

Ontologías y Web Semántica 2005. Resumen del taller

En este artículo se resumen los resultados obtenidos en el taller “Ontologías y Web Semántica 2005”, que fue celebrado el día 14 de noviembre de 2005 en Santiago de Compostela, en el contexto de la Conferencia de la Asociación Española para la Inteligencia Artificial (CAEPIA2005)

Nephroprotective Effect of the Virgin Olive Oil Polyphenol Hydroxytyrosol in Type 1-like Experimental Diabetes Mellitus: Relationships with Its Antioxidant Effect

The aim of this study was to determine whether hydroxytyrosol administration prevented kidney damage in an experimental model of type 1 diabetes mellitus in rats. Hydroxytyrosol was administered to streptozotocin-diabetic rats: 1 and 5 mg/kg/day p.o. for two months. After hydroxytyrosol administration, proteinuria was significantly reduced (67–73%), calculated creatinine clearance was significantly increased (26–38%), and the glomerular volume and glomerulosclerosis index were decreased (20–30%). Hydroxytyrosol reduced oxidative and nitrosative stress variables and thromboxane metabolite production. Statistical correlations were found between biochemical and kidney function variables. Oral administration of 1 and 5 mg/kg/day of hydroxytyrosol produced an antioxidant and nephroprotective effect in an experimental model of type 1-like diabetes mellitus. The nephroprotective effect was significantly associated with the systemic and renal antioxidant action of hydroxytyrosol, which also influenced eicosanoid production