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3. Viral Fitness, Population Complexity, Host Interactions, and Resistance to Antiviral Agents

Author

Domingo, Esteban, García-Crespo, Carlos, Soria, María Eugenia, Perales, Celia, Ahmed, Rafi, Series Editor, Akira, Shizuo, Series Editor, Casadevall, Arturo, Series Editor, Galan, Jorge E., Series Editor, Garcia-Sastre, Adolfo, Series Editor, Malissen, Bernard, Series Editor, Rappuoli, Rino, Series Editor, Domingo, Esteban, editor, Schuster, Peter, editor, Elena, Santiago F., editor, and Perales, Celia, editor

Published
2023
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7. Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

Author

Chen, Qian, Perales, Celia, Soria, María Eugenia, García-Cehic, Damir, Gregori, Josep, Rodríguez-Frías, Francisco, Buti, María, Crespo, Javier, Calleja, José Luis, Tabernero, David, Vila, Marta, Lázaro, Fernando, Rando-Segura, Ariadna, Nieto-Aponte, Leonardo, Llorens-Revull, Meritxell, Cortese, Maria Francesca, Fernandez-Alonso, Irati, Castellote, José, Niubó, Jordi, Imaz, Arkaitz, Xiol, Xavier, Castells, Lluís, Riveiro-Barciela, Mar, Llaneras, Jordi, Navarro, Jordi, Vargas-Blasco, Víctor, Augustin, Salvador, Conde, Isabel, Rubín, Ángel, Prieto, Martín, Torras, Xavier, Margall, Nuria, Forns, Xavier, Mariño, Zoe, Lens, Sabela, Bonacci, Martin, Pérez-del-Pulgar, Sofía, Londoño, Maria Carlota, García-Buey, María Luisa, Sanz-Cameno, Paloma, Morillas, Rosa, Martró, Elisa, Saludes, Verónica, Masnou-Ridaura, Helena, Salmerón, Javier, Quíles, Rosa, Carrión, José Antonio, Forné, Montserrat, Rosinach, Mercè, Fernández, Inmaculada, García-Samaniego, Javier, Madejón, Antonio, Castillo-Grau, Pilar, López-Núñez, Carme, Ferri, María José, Durández, Rosa, Sáez-Royuela, Federico, Diago, Moisés, Gimeno, Concepción, Medina, Rafael, Buenestado, Juan, Bernet, Albert, Turnes, Juan, Trigo-Daporta, Matilde, Hernández-Guerra, Manuel, Delgado-Blanco, Manuel, Cañizares, Angelina, Arenas, Juan Ignacio, Gomez-Alonso, Maria Juana, Rodríguez, Manuel, Deig, Elisabet, Olivé, Gemma, Río, Oscar del, Cabezas, Joaquín, Quiñones, Ildefonso, Roget, Mercè, Montoliu, Silvia, García-Costa, Juan, Force, Lluís, Blanch, Silvia, Miralbés, Miguel, López-de-Goicoechea, María José, García-Flores, Angels, Saumoy, María, Casanovas, Teresa, Baliellas, Carme, Gilabert, Pau, Martin-Cardona, Albert, Roca, Rosa, Barenys, Mercè, Villaverde, Joana, Salord, Silvia, Camps, Blau, Silvan di Yacovo, María, Ocaña, Imma, Sauleda, Silvia, Bes, Marta, Carbonell, Judit, Vargas-Accarino, Elena, Ruzo, Sofía P., Guerrero-Murillo, Mercedes, Von Massow, Georg, Costafreda, María Isabel, López, Rosa Maria, González-Moreno, Leticia, Real, Yolanda, Acero-Fernández, Doroteo, Viroles, Silvia, Pamplona, Xavier, Cairó, Mireia, Ocete, María Dolores, Macías-Sánchez, José Francisco, Estébanez, Angel, Quer, Joan Carles, Mena-de-Cea, Álvaro, Otero, Alejandra, Castro-Iglesias, Ángeles, Suárez, Francisco, Vázquez, Ángeles, Vieito, David, López-Calvo, Soledad, Vázquez-Rodríguez, Pilar, Martínez-Cerezo, Francisco José, Rodríguez, Raúl, Macenlle, Ramiro, Cachero, Alba, Mereish, Gasshan, Mora-Moruny, Carme, Fábregas, Silvia, Sacristán, Begoña, Albillos, Agustín, Sánchez-Ruano, Juan José, Baluja-Pino, Raquel, Fernández-Fernández, Javier, González-Portela, Carlos, García-Martin, Carmen, Sánchez-Antolín, Gloria, Andrade, Raúl Jesús, Simón, Miguel Angel, Pascasio, Juan Manuel, Romero-Gómez, Manolo, Antonio del-Campo, José, Domingo, Esteban, Esteban, Rafael, Esteban, Juan Ignacio, and Quer, Josep

Published
2020
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9. Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture

Author

García‐Crespo, Carlos, primary, de Ávila, Ana Isabel, additional, Gallego, Isabel, additional, Soria, María Eugenia, additional, Durán‐Pastor, Antoni, additional, Somovilla, Pilar, additional, Martínez‐González, Brenda, additional, Muñoz‐Flores, Javier, additional, Mínguez, Pablo, additional, Salar‐Vidal, Llanos, additional, Esteban‐Muñoz, Mario, additional, Cañar‐Camacho, Elizabeth, additional, Ferrer‐Orta, Cristina, additional, Zuñiga, Sonia, additional, Sola, Isabel, additional, Enjuanes, Luis, additional, Esteban, Jaime, additional, Fernández‐Roblas, Ricardo, additional, Gadea, Ignacio, additional, Gómez, Jordi, additional, Verdaguer, Nuria, additional, Domingo, Esteban, additional, and Perales, Celia, additional

Published
2024
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10. SARS-CoV-2 mutant spectra as variant of concern nurseries: endless variation?

Author

Martínez-González, Brenda, primary, Soria, María Eugenia, additional, Mínguez, Pablo, additional, Lorenzo-Redondo, Ramón, additional, Salar-Vidal, Llanos, additional, López-García, Alberto, additional, Esteban-Muñoz, Mario, additional, Durán-Pastor, Antoni, additional, Somovilla, Pilar, additional, García-Crespo, Carlos, additional, de Ávila, Ana Isabel, additional, Gómez, Jordi, additional, Esteban, Jaime, additional, Fernández-Roblas, Ricardo, additional, Gadea, Ignacio, additional, Domingo, Esteban, additional, and Perales, Celia, additional

Published
2024
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11. Incipient functional SARS-CoV-2 diversification identified through neural network haplotype maps

Author

Delgado, Soledad, primary, Somovilla, Pilar, additional, Ferrer-Orta, Cristina, additional, Martínez-González, Brenda, additional, Vázquez-Monteagudo, Sergi, additional, Muñoz-Flores, Javier, additional, Soria, María Eugenia, additional, García-Crespo, Carlos, additional, de Ávila, Ana Isabel, additional, Durán-Pastor, Antoni, additional, Gadea, Ignacio, additional, López-Galíndez, Cecilio, additional, Moran, Federico, additional, Lorenzo-Redondo, Ramon, additional, Verdaguer, Nuria, additional, Perales, Celia, additional, and Domingo, Esteban, additional

Published
2024
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12. Fluoride anodic films on stainless-steel fomites to reduce transmission infections

Author

Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), European Commission, Instituto de Salud Carlos III, Comunidad de Madrid, Conde del Campo, Ana, Voces, D., Medel-Plaza, Marina, Perales, Celia, Avila, Ana Isabel de, Aguilera-Correa, Jhon, Damborenea, Juan de, Esteban, Jaime, Domingo, E., Arenas, M. A., Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), European Commission, Instituto de Salud Carlos III, Comunidad de Madrid, Conde del Campo, Ana, Voces, D., Medel-Plaza, Marina, Perales, Celia, Avila, Ana Isabel de, Aguilera-Correa, Jhon, Damborenea, Juan de, Esteban, Jaime, Domingo, E., and Arenas, M. A.

Abstract

The growing concern arising from viruses with pandemic potential and multi-resistant bacteria responsible for hospital-acquired infections and outbreaks of food poisoning has led to an increased awareness of indirect contact transmission. This has resulted in a renewed interest to confer antimicrobial properties to commonly used metallic materials. The present work provides a full characterization of optimized fluoride anodic films grown in stainless steel 304L as well as their antimicrobial properties. Antibacterial tests show that the anodic film, composed mainly of chromium and iron fluorides, reduces the count and the percentage of the area covered by 50% and 87.7% for Pseudomonas aeruginosa and Stenotrophomonas maltophilia, respectively. Virologic tests show that the same treatment reduces the infectivity of the coronavirus HCoV-229E-GFP, in comparison with the non-anodized stainless steel 304L. IMPORTANCE The importance of environmental surfaces as a source of infection is a topic of particular interest today, as many microorganisms can survive on these surfaces and infect humans through direct contact. Modification of these surfaces by anodizing has been shown to be useful for some alloys of medical interest. This work evaluates the effect of anodizing on stainless steel, a metal widely used in a variety of applications. According to the study, the fluoride anodic layers reduce the colonization of the surfaces by both bacteria and viruses, thus reducing the risk of acquiring infections from these sources.

Published
2024

13. Incipient functional SARS-CoV-2 diversification identified through neural network haplotype maps

Author

Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Comunidad de Madrid, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Fundació La Marató de TV3, Banco Santander, Fundación Ramón Areces, CSIC-UAM - Centro de Biología Molecular Severo Ochoa (CBM), Ministerio de Economía y Competitividad (España), Ferrer-Orta, Cristina [0000-0002-1072-8463], Verdaguer, Núria [0000-0001-8826-7129], Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72], Delgado, Soledad, Somovilla, Pilar, Ferrer-Orta, Cristina, Martínez-González, Brenda, Vázquez-Monteagudo, Sergi, Muñoz-Flores, Javier, Soria, María Eugenia, García-Crespo, Carlos, de Ávila, Ana Isabel, Durán-Pastor, Antoni, Gadea, Ignacio, López-Galíndez, Cecilio, Moran, Federico, Lorenzo-Redondo, Ramon, Verdaguer, Núria, Perales, Celia, Domingo, Esteban, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Comunidad de Madrid, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Fundació La Marató de TV3, Banco Santander, Fundación Ramón Areces, CSIC-UAM - Centro de Biología Molecular Severo Ochoa (CBM), Ministerio de Economía y Competitividad (España), Ferrer-Orta, Cristina [0000-0002-1072-8463], Verdaguer, Núria [0000-0001-8826-7129], Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72], Delgado, Soledad, Somovilla, Pilar, Ferrer-Orta, Cristina, Martínez-González, Brenda, Vázquez-Monteagudo, Sergi, Muñoz-Flores, Javier, Soria, María Eugenia, García-Crespo, Carlos, de Ávila, Ana Isabel, Durán-Pastor, Antoni, Gadea, Ignacio, López-Galíndez, Cecilio, Moran, Federico, Lorenzo-Redondo, Ramon, Verdaguer, Núria, Perales, Celia, and Domingo, Esteban

Abstract

Since its introduction in the human population, SARS-CoV-2 has evolved into multiple clades, but the events in its intrahost diversification are not well understood. Here, we compare three-dimensional (3D) self-organized neural haplotype maps (SOMs) of SARS-CoV-2 from thirty individual nasopharyngeal diagnostic samples obtained within a 19-day interval in Madrid (Spain), at the time of transition between clades 19 and 20. SOMs have been trained with the haplotype repertoire present in the mutant spectra of the nsp12- and spike (S)-coding regions. Each SOM consisted of a dominant neuron (displaying the maximum frequency), surrounded by a low-frequency neuron cloud. The sequence of the master (dominant) neuron was either identical to that of the reference Wuhan-Hu-1 genome or differed from it at one nucleotide position. Six different deviant haplotype sequences were identified among the master neurons. Some of the substitutions in the neural clouds affected critical sites of the nsp12-nsp8-nsp7 polymerase complex and resulted in altered kinetics of RNA synthesis in an in vitro primer extension assay. Thus, the analysis has identified mutations that are relevant to modification of viral RNA synthesis, present in the mutant clouds of SARS-CoV-2 quasispecies. These mutations most likely occurred during intrahost diversification in several COVID-19 patients, during an initial stage of the pandemic, and within a brief time period.

Published
2024

14. Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture

Author

Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Fundació La Marató de TV3, García-Crespo, Carlos, de Ávila, Ana Isabel, Gallego, Isabel, Soria, María Eugenia, Durán-Pastor, Antoni, Somovilla, Pilar, Martínez-González, Brenda, Muñoz-Flores, Javier, Mínguez, Pablo, Salar-Vidal, Llanos, Esteban-Muñoz, Mario, Cañar-Camacho, Elizabeth, Ferrer-Orta, Cristina, Zuñiga, Sonia, Solá Gurpegui, Isabel, Enjuanes, Luis, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Gómez, Jordi, Verdaguer, Núria, Domingo, Esteban, Perales, Celia, Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Fundació La Marató de TV3, García-Crespo, Carlos, de Ávila, Ana Isabel, Gallego, Isabel, Soria, María Eugenia, Durán-Pastor, Antoni, Somovilla, Pilar, Martínez-González, Brenda, Muñoz-Flores, Javier, Mínguez, Pablo, Salar-Vidal, Llanos, Esteban-Muñoz, Mario, Cañar-Camacho, Elizabeth, Ferrer-Orta, Cristina, Zuñiga, Sonia, Solá Gurpegui, Isabel, Enjuanes, Luis, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Gómez, Jordi, Verdaguer, Núria, Domingo, Esteban, and Perales, Celia

Abstract

There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis.

Published
2024

15. SARS-CoV-2 mutant spectra as variant of concern nurseries: endless variation?

Author

Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundació La Marató de TV3, Comunidad de Madrid, #NODATA#, Martínez-González, Brenda, Soria, María Eugenia, Mínguez, Pablo, Lorenzo-Redondo, Ramón, Salar-Vidal, Llanos, López-García, Alberto, Esteban-Muñoz, Mario, Durán-Pastor, Antoni, Somovilla, Pilar, García-Crespo, Carlos, de Ávila, Ana Isabel, Gómez, Jordi, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Domingo, Esteban, Perales, Celia, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundació La Marató de TV3, Comunidad de Madrid, #NODATA#, Martínez-González, Brenda, Soria, María Eugenia, Mínguez, Pablo, Lorenzo-Redondo, Ramón, Salar-Vidal, Llanos, López-García, Alberto, Esteban-Muñoz, Mario, Durán-Pastor, Antoni, Somovilla, Pilar, García-Crespo, Carlos, de Ávila, Ana Isabel, Gómez, Jordi, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Domingo, Esteban, and Perales, Celia

Abstract

SARS-CoV-2 isolates of a given clade may contain low frequency genomes that encode amino acids or deletions which are typical of a different clade.

Published
2024

16. Reply to Qu et al., “Quasispecies are constantly selected through virus-encoded intracellular reproductive population bottlenecking”

Author

Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Fundació La Marató de TV3, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Domingo, Esteban, Martínez-González, Brenda, García-Crespo, Carlos, Somovilla, Pilar, Ávila, Ana Isabel de, Soria, María Eugenia, Durán-Pastor, Antoni, Perales, Celia, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Fundació La Marató de TV3, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Domingo, Esteban, Martínez-González, Brenda, García-Crespo, Carlos, Somovilla, Pilar, Ávila, Ana Isabel de, Soria, María Eugenia, Durán-Pastor, Antoni, and Perales, Celia

Abstract

We appreciate the careful reading by F. Qu, K. Khemsom, C. Perdoncini Carvalho, and J. Han of our minireview on SARS-CoV-2 quasispecies recently published in the Journal of Virology (1). Qu and colleagues disagree with one of our assertions about viral quasispecies in general, namely that the mutant genome copies generated during viral RNA replication can collectively engage in evolution. Their main argument is that when a viral population enters a cell, it becomes strongly bottlenecked, and only one or a few of the viruses have a chance to replicate. The remaining copies are degraded, although they may contribute to the cellular modifications required for the formation of replication organelles. An advantage of such bottlenecking for virus survival is that genomes that, during prior replication, mutated to encode a different phenotype find an unchallenged cellular environment to feely multiply and express the deviant phenotype. This model is termed “Bottleneck, Isolate, Amplify, Select” (BIAS), and it is presented as contrary to the premise of quasispecies theory because “the BIAS model is unapologetically deterministic and predicts natural selection as the primary driver of virus evolution.”

Published
2024

17. Fluoride anodic films on stainless-steel fomites to reduce transmission infections

Author

Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, 0000-0001-7889-8664, #NODATA#, 0000-0002-8971-3167, 0000-0002-0573-1676, Conde, Ana, Voces, Daniel, Medel-Plaza, Marina, Perales, Celia, de Ávila, Ana Isabel, Aguilera-Correa, John Jairo, de Damborenea, Juan Jose, Esteban, Jaime, Domingo, Esteban, Arenas, Maria Angeles, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, 0000-0001-7889-8664, #NODATA#, 0000-0002-8971-3167, 0000-0002-0573-1676, Conde, Ana, Voces, Daniel, Medel-Plaza, Marina, Perales, Celia, de Ávila, Ana Isabel, Aguilera-Correa, John Jairo, de Damborenea, Juan Jose, Esteban, Jaime, Domingo, Esteban, and Arenas, Maria Angeles

Abstract

The growing concern arising from viruses with pandemic potential and multi-resistant bacteria responsible for hospital-acquired infections and outbreaks of food poisoning has led to an increased awareness of indirect contact transmission. This has resulted in a renewed interest to confer antimicrobial properties to commonly used metallic materials. The present work provides a full characterization of optimized fluoride anodic films grown in stainless steel 304L as well as their antimicrobial properties. Antibacterial tests show that the anodic film, composed mainly of chromium and iron fluorides, reduces the count and the percentage of the area covered by 50% and 87.7% for Pseudomonas aeruginosa and Stenotrophomonas maltophilia, respectively. Virologic tests show that the same treatment reduces the infectivity of the coronavirus HCoV-229E-GFP, in comparison with the non-anodized stainless steel 304L.IMPORTANCEThe importance of environmental surfaces as a source of infection is a topic of particular interest today, as many microorganisms can survive on these surfaces and infect humans through direct contact. Modification of these surfaces by anodizing has been shown to be useful for some alloys of medical interest. This work evaluates the effect of anodizing on stainless steel, a metal widely used in a variety of applications. According to the study, the fluoride anodic layers reduce the colonization of the surfaces by both bacteria and viruses, thus reducing the risk of acquiring infections from these sources.

Published
2024

19. Puzzles, challenges, and information reservoir of SARS-CoV-2 quasispecies

Author

Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Instituto de Salud Carlos III, Fundació La Marató de TV3, Comunidad de Madrid, Fundación Ramón Areces, Fundación Banco Santander, Domingo, Esteban [0000-0002-0573-1676], Perales, Celia [0000-0003-1618-1937], Domingo, Esteban, Martínez-González, Brenda, García-Crespo, Carlos, Somovilla, Pilar, Ávila, Ana Isabel de, Soria, María Eugenia, Durán-Pastor, Antoni, Perales, Celia, Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Instituto de Salud Carlos III, Fundació La Marató de TV3, Comunidad de Madrid, Fundación Ramón Areces, Fundación Banco Santander, Domingo, Esteban [0000-0002-0573-1676], Perales, Celia [0000-0003-1618-1937], Domingo, Esteban, Martínez-González, Brenda, García-Crespo, Carlos, Somovilla, Pilar, Ávila, Ana Isabel de, Soria, María Eugenia, Durán-Pastor, Antoni, and Perales, Celia

Abstract

Upon the emergence of SARS-CoV-2 in the human population, it was conjectured that for this coronavirus the dynamic intra-host heterogeneity typical of RNA viruses would be toned down. Nothing of this sort is observed. Here we review the main observations on the complexity and diverse composition of SARS-CoV-2 mutant spectra sampled from infected patients, within the framework of quasispecies dynamics. The analyses suggest that the information provided by myriads of genomic sequences within infected individuals may have a predictive value of the genomic sequences that acquire epidemiological relevance. Possibilities to reconcile the presence of broad mutant spectra in the large RNA coronavirus genome with its encoding a 3' to 5' exonuclease proofreading-repair activity are considered. Indeterminations in the behavior of individual viral genomes provide a benefit for the survival of the ensemble. We propose that this concept falls in the domain of "stochastic thinking," a notion that applies also to cellular processes, as a means for biological systems to face unexpected needs.

Published
2023

21. Point mutations at specific sites of the nsp12-nsp8 interface dramatically affect the RNA polymerization activity of SARS-CoV-2.

Author

Ferrer-Orta, Cristina, Vázquez-Monteagudo, Sergi, Ferrero, Diego S., Martínez-González, Brenda, Perales, Celia, Domingo, Esteban, and Verdaguer, Nuria

Subjects
SARS-CoV-2, RNA replicase, RNA synthesis, COVID-19 pandemic, RNA regulation
Abstract

In a recent characterization of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variability present in 30 diagnostic samples from patients of the first COVID-19 pandemic wave, 41 amino acid substitutions were documented in the RNA-dependent RNA polymerase (RdRp) nsp12. Eight substitutions were selected in this work to determine whether they had an impact on the RdRp activity of the SARS-CoV-2 nsp12-nsp8-nsp7 replication complex. Three of these substitutions were found around the polymerase central cavity, in the template entry channel (D499G and M668V), and within the motif B (V560A), and they showed polymerization rates similar to the wild type RdRp. The remaining five mutations (P323L, L372F, L372P, V373A, and L527H) were placed near the nsp12-nsp8F contact surface; residues L372, V373, and L527 participated in a large hydrophobic cluster involving contacts between two helices in the nsp12 fingers and the long a-helix of nsp8F. The presence of any of these five amino acid substitutions resulted in important alterations in the RNA polymerization activity. Comparative primer elongation assays showed different behavior depending on the hydrophobicity of their side chains. The substitution of L by the bulkier F side chain at position 372 slightly promoted RdRp activity. However, this activity was dramatically reduced with the L372P, and L527H mutations, and to a lesser extent with V373A, all of which weaken the hydrophobic interactions within the cluster. Additional mutations, specifically designed to disrupt the nsp12-nsp8F interactions (nsp12-V330S, nsp12-V341S, and nsp8-R111A/D112A), also resulted in an impaired RdRp activity, further illustrating the importance of this contact interface in the regulation of RNA synthesis. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Natural languages and RNA virus evolution.

Author

Ariza‐Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino, Francisco, Domingo, Esteban, and Gómez, Jordi

Subjects
NATURAL languages, RNA viruses, HERMENEUTICS, DETECTORS, ARCHAEOLOGY
Abstract

Information concepts from physics, mathematics and computer science support many areas of research in biology. Their focus is on objective information, which provides correlations and patterns related to objects, processes, marks and signals. In these approaches only the quantitative aspects of the meaning of the information is relevant. In other areas of biology, 'meaningful information', which is subjective in nature, relies on the physiology of the organism's sensory organs and on the interpretation of the perceived signals, which is then translated into action, even if this is only mental (in brained animals). Information is involved, in terms of both amount and quality. Here we contextualize and review the main theories that deal with 'meaningful‐information' at a molecular level from different areas of natural language research, namely biosemiotics, code‐biology, biocommunication and biohermeneutics. As this information mediates between the organism and its environment, we emphasize how such theories compare with the neo‐Darwinian treatment of genetic information, and how they project onto the rapid evolution of RNA viruses. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Archaeological approaches to RNA virus evolution.

Author

Ariza‐Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino, Francisco, Domingo, Esteban, and Gómez, Jordi

Subjects
CATALYTIC RNA, PROTEINS, PHYLOGENY, VIROLOGY, LANGUAGE & languages
Abstract

Studies with RNA enzymes (ribozymes) and protein enzymes have identified certain structural elements that are present in some cellular mRNAs and viral RNAs. These elements do not share a primary structure and, thus, are not phylogenetically related. However, they have common (secondary/tertiary) structural folds that, according to some lines of evidence, may have an ancient and common origin. The term 'mRNA archaeology' has been coined to refer to the search for such structural/functional relics that may be informative of early evolutionary developments in the cellular and viral worlds and have lasted to the present day. Such identified RNA elements may have developed as biological signals with structural and functional relevance (as if they were buried objects with archaeological value), and coexist with the standard linear information of nucleic acid molecules that is translated into proteins. However, there is a key difference between the methods that extract information from either the primary structure of mRNA or the signals provided by secondary and tertiary structures. The former (sequence comparison and phylogenetic analysis) requires strict continuity of the material vehicle of information during evolution, whereas the archaeological method does not require such continuity. The tools of RNA archaeology (including the use of ribozymes and enzymes to investigate the reactivity of the RNA elements) establish links between the concepts of communication and language theories that have not been incorporated into knowledge of virology, as well as experimental studies on the search for functionally relevant RNA structures. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Vaccine breakthrough infections with SARS-CoV-2 Alpha mirror mutations in Delta Plus, Iota, and Omicron

Author

Martinez-Gonzalez, Brenda, Vazquez-Sirvent, Lucia, Soria, Maria E., Minguez, Pablo, Salar-Vidal, Llanos, Garcia-Crespo, Carlos, Gallego, Isabel, de Avila, Ana I., Llorens, Carlos, Soriano, Beatriz, Ramos-Ruiz, Ricardo, Esteban, Jaime, Fernandez- Roblas, Ricardo, Gadea, Ignacio, Ayuso, Carmen, Ruiz-Hornillos, Javier, Perez-Jorge, Concepcion, Domingo, Esteban, and Perales, Celia

Subjects
Gene mutations -- Research, Immunological research, Health care industry
Abstract

Replication of SARS-CoV-2 in the human population is defined by distributions of mutants that are present at different frequencies within the infected host and can be detected by ultra-deep sequencing techniques. In this study, we examined the SARS-CoV-2 mutant spectra of amplicons from the spike-coding (S-coding) region of 5 nasopharyngeal isolates derived from patients with vaccine breakthrough. Interestingly, all patients became infected with the Alpha variant, but amino acid substitutions that correspond to the Delta Plus, Iota, and Omicron variants were present in the mutant spectra of the resident virus. Deep sequencing analysis of SARS-CoV-2 from patients with vaccine breakthrough revealed a rich reservoir of mutant types and may also identify tolerated substitutions that can be represented in epidemiologically dominant variants., Introduction SARS-CoV-2 continues its diversification worldwide, and a new variant termed Omicron (B.l.1.529), carrying a large number of mutations, was recently described in South Africa and classified as a potential [...]

Published
2022
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28. Quasispecies and Drug Resistance

Author

Perales, Celia, Ortega-Prieto, Ana M., Beach, Nathan M., Sheldon, Julie, Menéndez-Arias, Luis, Domingo, Esteban, Berghuis, Albert, editor, Matlashewski, Greg, editor, Wainberg, Mark A., editor, Sheppard, Donald, editor, and Gotte, Matthias, Editor-in-chief

Published
2017
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34. Antiviral Strategies Based on Lethal Mutagenesis and Error Threshold

Author

Perales, Celia, Domingo, Esteban, Compans, Richard W, Series editor, Cooper, Max D., Series editor, Honjo, Tasuku, Series editor, Oldstone, Michael B. A., Series editor, Vogt, Peter K., Series editor, Malissen, Bernard, Series editor, Aktories, Klaus, Series editor, Kawaoka, Yoshihiro, Series editor, Rappuoli, Rino, Series editor, Galan, Jorge E., Series editor, Ahmed, Rafi, Series editor, Domingo, Esteban, editor, and Schuster, Peter, editor

Published
2016
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36. Comparison of Extracellular Vesicle Isolation Methods for miRNA Sequencing

Author

Llorens-Revull, Meritxell, primary, Martínez-González, Brenda, additional, Quer, Josep, additional, Esteban, Juan Ignacio, additional, Núñez-Moreno, Gonzalo, additional, Mínguez, Pablo, additional, Burgui, Idoia, additional, Ramos-Ruíz, Ricardo, additional, Soria, María Eugenia, additional, Rico, Angie, additional, Riveiro-Barciela, Mar, additional, Sauleda, Silvia, additional, Piron, María, additional, Corrales, Irene, additional, Borràs, Francesc E., additional, Rodríguez-Frías, Francisco, additional, Rando, Ariadna, additional, Ramírez-Serra, Clara, additional, Camós, Silvia, additional, Domingo, Esteban, additional, Bes, Marta, additional, Perales, Celia, additional, and Costafreda, Maria Isabel, additional

Published
2023
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37. Fitness-Dependent, Mild Mutagenic Activity of Sofosbuvir for Hepatitis C Virus

Author

Martínez-González, Brenda, primary, Gallego, Isabel, additional, Gregori, Josep, additional, Soria, María Eugenia, additional, Somovilla, Pilar, additional, de Ávila, Ana Isabel, additional, García-Crespo, Carlos, additional, Durán-Pastor, Antoni, additional, Briones, Carlos, additional, Gómez, Jordi, additional, Quer, Josep, additional, Domingo, Esteban, additional, and Perales, Celia, additional

Published
2023
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39. SARS-CoV-2 Point Mutation and Deletion Spectra and Their Association with Different Disease Outcomes

Author

Ramos-Ruiz, Ricardo [0000-0002-6331-9786], Enjuanes Sánchez, Luis [0000-0002-0854-0226], Esteban, Jaime [0000-0002-8971-3167], Verdaguer, Núria [0000-0001-8826-7129], Domingo, Esteban [0000-0002-0573-1676], Perales, Celia [0000-0003-1618-1937], Martínez-González, Brenda, Soria, María Eugenia, Vázquez-Sirvent, Lucía, Ferrer-Orta, Cristina, Lobo-Vega, Rebeca, Mínguez, Pablo, Fuente, Lorena de la, Llorens, Carlos, Soriano, Beatriz, Ramos-Ruiz, Ricardo, Cortón, Marta, López-Rodríguez, Rosario, García-Crespo, Carlos, Gallego, Isabel, Ávila, Ana Isabel de, Gómez-Castilla, Jordi, Enjuanes Sánchez, Luis, Salar-Vidal, Llanos, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Ayuso, Carmen, Ruíz-Hornillos, Javier, Verdaguer, Núria, Domingo, Esteban, Perales, Celia, Ramos-Ruiz, Ricardo [0000-0002-6331-9786], Enjuanes Sánchez, Luis [0000-0002-0854-0226], Esteban, Jaime [0000-0002-8971-3167], Verdaguer, Núria [0000-0001-8826-7129], Domingo, Esteban [0000-0002-0573-1676], Perales, Celia [0000-0003-1618-1937], Martínez-González, Brenda, Soria, María Eugenia, Vázquez-Sirvent, Lucía, Ferrer-Orta, Cristina, Lobo-Vega, Rebeca, Mínguez, Pablo, Fuente, Lorena de la, Llorens, Carlos, Soriano, Beatriz, Ramos-Ruiz, Ricardo, Cortón, Marta, López-Rodríguez, Rosario, García-Crespo, Carlos, Gallego, Isabel, Ávila, Ana Isabel de, Gómez-Castilla, Jordi, Enjuanes Sánchez, Luis, Salar-Vidal, Llanos, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Ayuso, Carmen, Ruíz-Hornillos, Javier, Verdaguer, Núria, Domingo, Esteban, and Perales, Celia

Abstract

Mutant spectra of RNA viruses are important to understand viral pathogenesis and response to selective pressures. There is a need to characterize the complexity of mutant spectra in coronaviruses sampled from infected patients. In particular, the possible relationship between SARS-CoV-2 mutant spectrum complexity and disease associations has not been established. In the present study, we report an ultradeep sequencing (UDS) analysis of the mutant spectrum of amplicons from the nsp12 (polymerase)- and spike (S)-coding regions of 30 nasopharyngeal isolates (diagnostic samples) of SARS-CoV-2 of the first COVID-19 pandemic wave (Madrid, Spain, April 2020) classified according to the severity of ensuing COVID-19. Low-frequency mutations and deletions, counted relative to the consensus sequence of the corresponding isolate, were overwhelmingly abundant. We show that the average number of different point mutations, mutations per haplotype, and several diversity indices was significantly higher in SARS-CoV-2 isolated from patients who developed mild disease than in those associated with moderate or severe disease (exitus). No such bias was observed with RNA deletions. Location of amino acid substitutions in the three-dimensional structures of nsp12 (polymerase) and S suggest significant structural or functional effects. Thus, patients who develop mild symptoms may be a richer source of genetic variants of SARS-CoV-2 than patients with moderate or severe COVID-19.

Published
2022

40. SARS-CoV-2 Point Mutation and Deletion Spectra, and Their Association with Different Disease Outcome

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Fundació La Marató de TV3, Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Ramón Areces, Banco Santander, Ministerio de Sanidad y Consumo (España), Ministerio de Economía y Competitividad (España), Ramos-Ruiz, Ricardo [0000-0002-6331-9786], Enjuanes Sánchez, Luis [0000-0002-0854-0226], Esteban, Jaime [0000-0002-8971-3167], Verdaguer, Núria [0000-0001-8826-7129], Domingo, Esteban [0000-0002-0573-1676], Perales, Celia [0000-0003-1618-1937], Martínez-González, Brenda, Soria, María Eugenia, Vázquez-Sirvent, Lucía, Ferrer-Orta, Cristina, Lobo-Vega, Rebeca, Mínguez, Pablo, Fuente, Lorena de la, Llorens, Carlos, Soriano, Beatriz, Ramos-Ruiz, Ricardo, Cortón, Marta, López-Rodríguez, Rosario, García-Crespo, Carlos, Gallego, Isabel, Ávila, Ana Isabel de, Gómez-Castilla, Jordi, Enjuanes Sánchez, Luis, Salar-Vidal, Llanos, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Ayuso, Carmen, Ruíz-Hornillos, Javier, Verdaguer, Núria, Domingo, Esteban, Perales, Celia, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Fundació La Marató de TV3, Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Ramón Areces, Banco Santander, Ministerio de Sanidad y Consumo (España), Ministerio de Economía y Competitividad (España), Ramos-Ruiz, Ricardo [0000-0002-6331-9786], Enjuanes Sánchez, Luis [0000-0002-0854-0226], Esteban, Jaime [0000-0002-8971-3167], Verdaguer, Núria [0000-0001-8826-7129], Domingo, Esteban [0000-0002-0573-1676], Perales, Celia [0000-0003-1618-1937], Martínez-González, Brenda, Soria, María Eugenia, Vázquez-Sirvent, Lucía, Ferrer-Orta, Cristina, Lobo-Vega, Rebeca, Mínguez, Pablo, Fuente, Lorena de la, Llorens, Carlos, Soriano, Beatriz, Ramos-Ruiz, Ricardo, Cortón, Marta, López-Rodríguez, Rosario, García-Crespo, Carlos, Gallego, Isabel, Ávila, Ana Isabel de, Gómez-Castilla, Jordi, Enjuanes Sánchez, Luis, Salar-Vidal, Llanos, Esteban, Jaime, Fernández-Roblas, Ricardo, Gadea, Ignacio, Ayuso, Carmen, Ruíz-Hornillos, Javier, Verdaguer, Núria, Domingo, Esteban, and Perales, Celia

Abstract

Mutant spectra of RNA viruses are important to understand viral pathogenesis, and response to selective pressures. There is a need to characterize the complexity of mutant spectra in coronaviruses sampled from infected patients. In particular, the possible relationship between SARS-CoV-2 mutant spectrum complexity and disease associations has not been established. In the present study, we report an ultra-deep sequencing (UDS) analysis of the mutant spectrum of amplicons from the nsp12 (polymerase)- and spike (S)-coding regions of thirty nasopharyngeal isolates (diagnostic samples) of SARS-CoV-2 of the first COVID-19 pandemic wave (Madrid, Spain, April 2020) classified according to the severity of ensuing COVID-19. Low frequency mutations and deletions, counted relative to the consensus sequence of the corresponding isolate, were overwhelmingly abundant. We show that the average number of different point mutations, mutations per haplotype and several diversity indices was significantly higher in SARS-CoV-2 isolated from patients who developed mild disease than in those associated with moderate or severe disease (exitus). No such bias was observed with RNA deletions. Location of amino acid substitutions in the three dimensional structures of nsp12 (polymerase) and S suggest significant structural or functional effects. Thus, patients who develop mild symptoms may be a richer source of genetic variants of SARS-CoV-2 than patients with moderate or severe COVID-19.

Published
2022

42. Comparison of Extracellular Vesicle Isolation Methods for miRNA Sequencing

Author

Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Empresa (España), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundació La Marató de TV3, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Fundación Ramón Areces, Banco Santander, Llorens-Revull, Meritxell, Martínez-González, Brenda, Quer, Josep, Esteban, Juan Ignacio, Núñez-Moreno, Gonzalo, Mínguez, Pablo, Burgui, Idoia, Ramos-Ruiz, Ricardo, Soria, María Eugenia, Rico, Angie, Riveiro-Barciela, Mar, Sauleda, Silvia, Piron, María, Corrales, Irene, Borràs, Francesc E., Rodríguez-Frías, Francisco, Rando, Ariadna, Ramírez-Serra, Clara, Camós, Silvia, Domingo, Esteban, Bes, Marta, Perales, Celia, Costafreda, María Isabel, Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Empresa (España), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundació La Marató de TV3, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Fundación Ramón Areces, Banco Santander, Llorens-Revull, Meritxell, Martínez-González, Brenda, Quer, Josep, Esteban, Juan Ignacio, Núñez-Moreno, Gonzalo, Mínguez, Pablo, Burgui, Idoia, Ramos-Ruiz, Ricardo, Soria, María Eugenia, Rico, Angie, Riveiro-Barciela, Mar, Sauleda, Silvia, Piron, María, Corrales, Irene, Borràs, Francesc E., Rodríguez-Frías, Francisco, Rando, Ariadna, Ramírez-Serra, Clara, Camós, Silvia, Domingo, Esteban, Bes, Marta, Perales, Celia, and Costafreda, María Isabel

Abstract

MicroRNAs (miRNAs) encapsulated in extracellular vesicles (EVs) are potential diagnostic and prognostic biomarkers. However, discrepancies in miRNA patterns and their validation are still frequent due to differences in sample origin, EV isolation, and miRNA sequencing methods. The aim of the present study is to find a reliable EV isolation method for miRNA sequencing, adequate for clinical application. To this aim, two comparative studies were performed in parallel with the same human plasma sample: (i) isolation and characterization of EVs obtained using three procedures: size exclusion chromatography (SEC), iodixanol gradient (GRAD), and its combination (SEC+GRAD) and (ii) evaluation of the yield of miRNA sequences obtained using NextSeq 500 (Illumina) and three miRNA library preparation protocols: NEBNext, NEXTFlex, and SMARTer smRNA-seq. The conclusion of comparison (i) is that recovery of the largest amount of EVs and reproducibility were attained with SEC, but GRAD and SEC+GRAD yielded purer EV preparations. The conclusion of (ii) is that the NEBNext library showed the highest reproducibility in the number of miRNAs recovered and the highest diversity of miRNAs. These results render the combination of GRAD EV isolation and NEBNext library preparation for miRNA retrieval as adequate for clinical applications using plasma samples.

Published
2023

43. Viral Fitness and Evolution

Author

Domingo, Esteban, Schuster, Peter, Elena, Santiago F., Perales, Celia, Domingo, Esteban, Schuster, Peter, Elena, Santiago F., and Perales, Celia

Abstract

This book unifies general concepts of plant and animal virus evolution and covers a broad range of topics related to theoretical and experimental aspects of virus population dynamics and viral fitness. Timely topics such as viral mechanisms to cope with antiviral agents, the adaptability of the virus to new hosts, emergence of new viral phenotypes, and the connections between short- and long-term virus evolution are included. By comparing plant and animal viruses, universal mechanisms responsible for fitness variations, viral emergence and disease mechanisms are explored. Although emphasis is put on specific plant and human viral pathogens, relevant similarities and differences to other viruses are highlighted. Additionally, readers will learn more about the adaptability of coronaviruses, including the recently emerged SARS-CoV-2, the causative agent of the COVID-19 pandemic. The book is aimed at students and scientists interested in basic and applied aspectsof plant and animal virus population dynamics and evolution.

Published
2023

44. Fitness-Dependent, Mild Mutagenic Activity of Sofosbuvir for Hepatitis C Virus

Author

Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundació La Marató de TV3, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Instituto de Salud Carlos III, European Commission, Fundación Ramón Areces, Banco Santander, Global Virus Network, Martínez-González, Brenda, Gallego, Isabel, Gregori, Josep, Soria, María Eugenia, Somovilla, Pilar, de Ávila, Ana Isabel, García-Crespo, Carlos, Durán-Pastor, Antoni, Briones, Carlos, Gómez, Jordi, Quer, Josep, Domingo, Esteban, Perales, Celia, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundació La Marató de TV3, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Instituto de Salud Carlos III, European Commission, Fundación Ramón Areces, Banco Santander, Global Virus Network, Martínez-González, Brenda, Gallego, Isabel, Gregori, Josep, Soria, María Eugenia, Somovilla, Pilar, de Ávila, Ana Isabel, García-Crespo, Carlos, Durán-Pastor, Antoni, Briones, Carlos, Gómez, Jordi, Quer, Josep, Domingo, Esteban, and Perales, Celia

Abstract

The concept of a mild mutagen was coined to describe a minor mutagenic activity exhibited by some nucleoside analogues that potentiated their efficacy as antiretroviral agents. In the present study, we report the mild mutagen activity of sofosbuvir (SOF) for hepatitis C virus (HCV). Serial passages of HCV in human hepatoma cells, in the presence of SOF at a concentration well below its cytotoxic concentration 50 (CC) led to pre-extinction populations whose mutant spectra exhibited a significant increase of C!U transitions, relative to populations passaged in the absence of SOF. This was reflected in an increase in several diversity indices that were used to characterize viral quasispecies. The mild mutagenic activity of SOF was largely absent when it was tested with isogenic HCV populations that displayed high replicative fitness. Thus, SOF can act as a mild mutagen for HCV, depending on HCV fitness. Possible mechanisms by which the SOF mutagenic activity may contribute to its antiviral efficacy are discussed.

Published
2023

45. Atypical Mutational Spectrum of SARS-CoV-2 Replicating in the Presence of Ribavirin

Author

Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), European Commission, Fundació La Marató de TV3, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Fundación Ramón Areces, Banco Santander, Somovilla, Pilar, García-Crespo, Carlos, Martínez-González, Brenda, Soria, María Eugenia, Ávila, Ana Isabel de, Gallego, Isabel, Mínguez, Pablo, Durán-Pastor, Antoni, Ferrer-Orta, Cristina, Salar-Vidal, Llanos, Esteban-Muñoz, Mario, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Enjuanes Sánchez, Luis, Esteban, Jaime, Fernandez-Roblas, Ricardo, Gadea, Ignacio, Gómez-Castilla, Jordi, Verdaguer, Núria, Domingo, Esteban, Perales, Celia, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), European Commission, Fundació La Marató de TV3, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Fundación Ramón Areces, Banco Santander, Somovilla, Pilar, García-Crespo, Carlos, Martínez-González, Brenda, Soria, María Eugenia, Ávila, Ana Isabel de, Gallego, Isabel, Mínguez, Pablo, Durán-Pastor, Antoni, Ferrer-Orta, Cristina, Salar-Vidal, Llanos, Esteban-Muñoz, Mario, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Enjuanes Sánchez, Luis, Esteban, Jaime, Fernandez-Roblas, Ricardo, Gadea, Ignacio, Gómez-Castilla, Jordi, Verdaguer, Núria, Domingo, Esteban, and Perales, Celia

Abstract

We report that ribavirin exerts an inhibitory and mutagenic activity on SARS-CoV-2-infecting Vero cells, with a therapeutic index higher than 10. Deep sequencing analysis of the mutant spectrum of SARS-CoV-2 replicating in the absence or presence of ribavirin indicated an increase in the number of mutations, but not in deletions, and modification of diversity indices, expected from a mutagenic activity. Notably, the major mutation types enhanced by replication in the presence of ribavirin were A→G and U→C transitions, a pattern which is opposite to the dominance of G→A and C→U transitions previously described for most RNA viruses. Implications of the inhibitory activity of ribavirin, and the atypical mutational bias produced on SARS-CoV-2, for the search for synergistic anti-COVID-19 lethal mutagen combinations are discussed.

Published
2023

46. Archaeological approaches to RNA virus evolution

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino Castelló, Francisco, Domingo, Esteban, Gómez-Castilla, Jordi, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino Castelló, Francisco, Domingo, Esteban, and Gómez-Castilla, Jordi

Abstract

Studies with RNA enzymes (ribozymes) and protein enzymes have identified certain structural elements that are present in some cellular mRNAs and viral RNAs. These elements do not share a primary structure and, thus, are not phylogenetically related. However, they have common (secondary/tertiary) structural folds that, according to some lines of evidence, may have an ancient and common origin. The term ‘mRNA archaeology’ has been coined to refer to the search for such structural/functional relics that may be informative of early evolutionary developments in the cellular and viral worlds and have lasted to the present day. Such identified RNA elements may have developed as biological signals with structural and functional relevance (as if they were buried objects with archaeological value), and coexist with the standard linear information of nucleic acid molecules that is translated into proteins. However, there is a key difference between the methods that extract information from either the primary structure of mRNA or the signals provided by secondary and tertiary structures. The former (sequence comparison and phylogenetic analysis) requires strict continuity of the material vehicle of information during evolution, whereas the archaeological method does not require such continuity. The tools of RNA archaeology (including the use of ribozymes and enzymes to investigate the reactivity of the RNA elements) establish links between the concepts of communication and language theories that have not been incorporated into knowledge of virology, as well as experimental studies on the search for functionally relevant RNA structures.

Published
2023

47. Natural languages and RNA virus evolution

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino Castelló, Francisco, Gómez-Castilla, Jordi, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino Castelló, Francisco, and Gómez-Castilla, Jordi

Abstract

Information concepts from physics, mathematics and computer science support many areas of research in biology. Their focus is on objective information, which provides correlations and patterns related to objects, processes, marks and signals. In these approaches only the quantitative aspects of the meaning of the information is relevant. In other areas of biology, ‘meaningful information’, which is subjective in nature, relies on the physiology of the organism's sensory organs and on the interpretation of the perceived signals, which is then translated into action, even if this is only mental (in brained animals). Information is involved, in terms of both amount and quality. Here we contextualize and review the main theories that deal with ‘meaningful-information’ at a molecular level from different areas of natural language research, namely biosemiotics, code-biology, biocommunication and biohermeneutics. As this information mediates between the organism and its environment, we emphasize how such theories compare with the neo-Darwinian treatment of genetic information, and how they project onto the rapid evolution of RNA viruses.

Published
2023

48. Viruses as archaeological tools for uncovering ancient molecular relationships

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Bayo-Jiménez, María Teresa, Domingo, Esteban, Gómez-Castilla, Jordi, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Bayo-Jiménez, María Teresa, Domingo, Esteban, and Gómez-Castilla, Jordi

Abstract

The entry of a virus into the host cell always implies the alteration of certain intracellular molecular relationships, some of which may involve the recovery of ancient cellular activities. In this sense, viruses are archaeological tools for identifying unexpressed activities in noninfected cells. Among these, activities that hinder virus propagation may represent cellular defense mechanisms, for example, activities that mutagenize the viral genome such as ADAR-1 or APOBEC activities. Instead, those that facilitate virus propagation can be interpreted as the result of viral adaptation to—or mimicking—cellular structures, enabling the virus to perform anthropomorphic activities, including hijacking, manipulating, and reorganizing cellular factors for their own benefit. The alternative we consider here is that some of these second set of cellular activities were already in the uninfected cell but silenced, under the negative control of the cell or lineage, and that they represent a necessary precondition for viral infection. For example, specifically loading an amino acid at the 3'-end of the mRNA of some plant viruses by aminoacyl-tRNA synthetases has proved essential for virus infection despite this reaction not occurring with cellular mRNAs. Other activities of this type are discussed here, together with the biological context in which they acquire a coherent meaning, that is, genetic latency and molecular conflict.

Published
2023

49. Viral Fitness, Population Complexity, Host Interactions, and Resistance to Antiviral Agents

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), European Commission, Comunidad de Madrid, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundació La Marató de TV3, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Global Virus Network, Banco Santander, Domingo, Esteban, García-Crespo, Carlos, Soria, María Eugenia, Perales, Celia, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), European Commission, Comunidad de Madrid, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundació La Marató de TV3, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Global Virus Network, Banco Santander, Domingo, Esteban, García-Crespo, Carlos, Soria, María Eugenia, and Perales, Celia

Abstract

Fitness of viruses has become a standard parameter to quantify their adaptation to a biological environment. Fitness determinations for RNA viruses (and some highly variable DNA viruses) meet with several uncertainties. Of particular interest are those that arise from mutant spectrum complexity, absence of population equilibrium, and internal interactions among components of a mutant spectrum. Here, concepts, fitness measurements, limitations, and current views on experimental viral fitness landscapes are discussed. The effect of viral fitness on resistance to antiviral agents is covered in some detail since it constitutes a widespread problem in antiviral pharmacology, and a challenge for the design of effective antiviral treatments. Recent evidence with hepatitis C virus suggests the operation of mechanisms of antiviral resistance additional to the standard selection of drug-escape mutants. The possibility that high replicative fitness may be the driver of such alternative mechanisms is considered. New broad-spectrum antiviral designs that target viral fitness may curtail the impact of drug-escape mutants in treatment failures. We consider to what extent fitness-related concepts apply to coronaviruses and how they may affect strategies for COVID-19 prevention and treatment.

Published
2023

50. Archaeological approaches to mRNA construction

Author

Gómez, Jordi, Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino Castelló, Francisco, Domingo, Esteban, Gómez, Jordi, Ariza-Mateos, Ascensión, Briones, Carlos, Perales, Celia, Sobrino Castelló, Francisco, and Domingo, Esteban

Published
2023

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